EPA-540/1-86-033
Environmental Protection
Agency
of Emergency and
Remedial Response
Washington DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
Superfund
vvEPA
HEALTH EFFECTS ASSESSMENT
FOR TOLUENE
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EPA/540/1-86-033
September 1984
HEALTH EFFECTS ASSESSMENT
FOR TOLUENE
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
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DISCLAIMER
This report has been funded wholly or 1n part by the United States
Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse
Research Corporation. It has been subject to the Agency's peer and adminis-
trative review, and 1t has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with toluene.
All estimates of acceptable Intakes and carcinogenic potency presented In
this document should be considered as preliminary and reflect limited re-
sources allocated to this project. Pertinent toxlcologlc and environmental
data were located through on-line literature searches of the Chemical
Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The
basic literature searched supporting this document 1s current up to
September, 1984. Secondary sources of Information have also been relied
upon 1n the preparation of this report and represent large-scale health
assessment efforts that entail extensive peer and Agency review. The
following Office of Health and Environmental Assessment (OHEA) sources have
been extensively utilized:
U.S. EPA. 1982a. Health and Environmental Effects Profile for
Toluene. Prepared by the Environmental Criteria and Assessment
Office, Cincinnati, OH, OHEA for the Office of Solid Waste and
Emergency Response, Washington, DC.
U.S. EPA. 1982b. Health Effects Assessment Document for Toluene.
Environmental Criteria and Assessment Office, Cincinnati, OH.
Internal draft.
U.S. EPA. 1983b. Reportable Quantity for Toluene. Prepared by
the Environmental Criteria and Assessment Office, Cincinnati, OH,
OHEA for the Office of Solid Waste and Emergency Response, Wash-
ington, DC.
U.S. EPA. 1984. Drinking Water Criteria Document for Toluene.
Prepared by the Environmental Criteria and Assessment Office,
Cincinnati, OH, OHEA for the Office of Drinking Water, Washington,
DC. External Review Draft.
U.S. EPA. 1985. Drinking Water Criteria Document for Toluene.
Prepared by the Environmental Criteria and Assessment Office,
Cincinnati, OH, OHEA for the Office of Drinking Water, Washington,
DC. Final Draft.
The Intent in these assessments is to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope tending to generate conservative (I.e., protective) estimates. Never-
theless, the interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemlcal(s) addressed.
111
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Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer is not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronlc, Is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval (I.e., for an Interval that
does not constitute a significant portion of the Hfespan). This type of
exposure estimate has not been extensively used or rigorously defined, as
previous risk assessment efforts have been primarily directed towards
exposures from toxicants 1n ambient air or water where lifetime exposure 1s
assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronlc human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
The AIC, acceptable intake chronic, 1s similar in concept to the ADI
(acceptable daily intake). It is an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the lifespan [see U.S. EPA (1980) for a discussion of
this concept]. The AIC Is route specific and estimates acceptable exposure
for a given route with the Implicit assumption that exposure by other routes
is insignificant.
Composite scores (CSs) for noncarcinogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development is explained 1n U.S. EPA (1983a).
For compounds for which there 1s sufficient evidence of carcinogenicity,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q-|*s have been computed based on oral
and inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate Inter-
pretation and use of the quantitative estimates presented.
Considerable data are available concerning the Inhalation exposure
effects of toluene. U.S. EPA (1985) has explored a number of risk assess-
ment strategies and has chosen to use the CUT (1980) rat Inhalation study
as a basis for their drinking water AADI since H provides the most protec-
tive estimate. The Inhalation AIS and AIC, both 104.9 mg/day, are based on
the same rat Inhalation study (CUT, 1980). It 1s reasonable that the AIS
and AIC should be closely aligned since, as U.S. EPA (1985) points out,
cumulative effects following low level exposures to toluene are not antici-
pated. A CS of 7 based on CNS dysfunction 1n humans occupatlonally exposed
to 300 ppm has been calculated.
Data concerning the toxlcologlcal consequences of oral toluene exposure
are extremely limited. One study was located In which rats were adminis-
tered 118, 354 or 590 mg/kg toluene by gavage, 5 days/week for 27-28 weeks
(Wolf et al., 1956). All of these doses were reported to be NOELs. NOELs
are generally not used for risk assessment purposes 1n the absence of a
LOEL; however, 1n this Instance the estimate agrees with estimates developed
for Inhalation exposure where data are more complete. Therefore, an oral
AIS of 30 mg/day (590 mg/kg x 5/7 x 70 kg * an uncertainty factor of 100)
1s suggested as an Interim estimate. The U.S. EPA (1985) derived an oral
AADI of 20.3 mg/day from the rat Inhalation study by CUT (1980). For the
purposes of this document, the ADI of 20.3 mg/day 1s proposed for the oral
AIC until more appropriate data are available. This estimate should be
reviewed when more complete data are available.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball wasithe Project
Officer. The final documents 1n this series were prepared for the Office of
Emergency and Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by:
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . . ,
2.1.
2.2.
ORAL
INHALATION ,
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS ,
3.1.
3.2.
3.3.
3.4.
SUBCHRONIC
3.1.1. Oral ,
3.1.2. Inhalation ,
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral
3.3.2. Inhalation
TOXICANT INTERACTIONS
CARCINOGENICITY
4.1.
4.2.
4.3.
4.4.
HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
OTHER RELEVANT DATA
WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
Page
1
3
. . . 3
3
4
, , , 4
. . . 4
4
4
, . . 4
4
. . . 9
. . . 9
10
11
, . . 13
13
. . . 13
. . . 13
13
. . . 13
13
. . . 13
. . . 14
. . . 15
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TABLE OF CONTENTS (cont.)
Page
6. RISK ASSESSMENT 16
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 16
6.1.1. Oral 16
6.1.2. Inhalation 16
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 17
6.2.1. Oral 17
6.2.2. Inhalation 18
6.3. CARCINOGENIC POTENCY (q^J 19
7. REFERENCES 20
APPENDIX: Summary Table for Toluene 33
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LIST OF TABLES
No. Title Page
3-1 Subchronlc Toxldty of Toluene. 5
3-2 Effects of Intermittent Subchron1c/Chron1c Vapor Exposures
to Toluene on Humans 7
3-3 Interaction of Toluene With Other Chemicals During
Simultaneous Exposure 12
1x
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LIST OF ABBREVIATIONS
AADI Adjusted acceptable dally Intake
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
BCF Bloconcentratlon factor
CNS Central nervous system
CS Composite score
DNA Deoxyr1bonucle1c add
EEG Electroencephalogram
PEL Frank-effect level
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
ppm Parts per million
RQ Reportable quantity
RVj Dose-rating value
RVe Effect-rating value
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The relevant physical and chemical properties and environmental fate of
toluene (CAS No. 108-88-3) are given below.
Chemical class:
Molecular weight:
Vapor pressure:
Water solubility:
Octanol/water partition
coefficient:
Soil mobility:
(predicted as retardation
factor for soil depth of
140 cm and organic carbon
content of 0.087%)
BCF:
Half-life 1n air:
Half-life 1n water:
monocycllc aromatic hydrocarbon
(purgeable aromatic)
92.1
28.1 mm Hg at 25°C
(Mackay et al., 1982)
534.8 mg/8. at 25°C (U.S. EPA, 1982b)
537 (Hansch and Leo, 1981)
1.8 (WHson et al., 1981)
13.2 (1n eel, Angullla japonlca)
(Ogata and Mlyake, 1978)
20 (1n blueglll, Lepomls macrochlrus)
(Berry, 1980)
24.5 (1n crayfish, Orconectes rustlcus)
(Berry, 1980)
1.3 days (Singh et al., 1981)
4.1 hours (Mackay and Yeun, 1983)
The half-life of toluene (1.3 days) 1n air 1s based on Us reaction with
OH» radicals. In the presence of smog, however, the half-life of toluene
may be shorter because of Its reaction with NO (Van Aalst et al., 1980).
-1-
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The values for the half-life of toluene 1n soil could not be located In
the available literature. However, evaporation Is expected to be the
predominant loss mechanism from the soil surface. The half-life for soil
evaporation 1s expected to be longer than Its evaporation half-life from
water. In subsurface soil, toluene may undergo variable degrees of bio-
degradation depending on the nature of the soil (Wilson et al., 1981, 1983;
McNabb et al., 1981), but a certain portion of the undegraded toluene may
percolate through soil Into groundwater (Wilson et al., 1981).
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL MAMMALS
2.1. ORAL
Urinary excretion accounted for 74-80% and pulmonary exhalation account-
ed for an additional 18-19% of the toluene administered orally to rabbits
(El Masry et al., 1956; Smith et al., 1954), Indicating that toluene 1s
almost completely absorbed from the gastrointestinal tract In rabbits.
Maximum absorption of toluene from the gastrointestinal tract of rats occurs
within 2 hours of Intubation, as evidenced by blood-toluene levels (Pyykko
et al., 1977).
2.2. INHALATION
Dogs absorbed 85-94% of the toluene that entered their lungs (Egle and
Gochberg, 1976). Mice retained -60% of the Inspired toluene after a
I0-m1nute exposure (Bergman, 1979).
In humans, the arterial concentration of toluene was Increased quickly
as compared with both the concentration of toluene 1n the alveolar air and
Us concentration 1n the Inspired air (Astrand et al., 1972; Astrand, 1975).
Although the human absorption rate during the first hour of toluene Inhala-
tion was 57%, Us absorption rate leveled off at 37% of the Inspired dose
2-4 hours after the start of exposure (Nomlyama and Nomlyama, 1974).
Exercise affects the absorption rate of toluene 1n humans (Astrand et al.,
1972; Carlsson, 1982).
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. In the only animal study on subchronlc oral exposure to
toluene, 30 female Wlstar rats received 118, 354 or 590 mg/kg/day of toluene
1n olive oil, 5 days/week for 27-28 weeks (Wolf et a!., 1956). There were
20 control rats. After clinical and gross Inspection as well as hlstologl-
cal evaluation of the kidneys and liver, no effects were reported for any
dose level (Table 3-1}.
3.1.2. Inhalation. Subchronlc Inhalation studies 1n animals Indicate
that female rats are more sensitive to toluene than male rats (Ungvary et
a!., 1980) and that changes In the liver, blood and body weight are the
first effects seen after subchronlc Inhalation of toluene (see Table 3-1)
(Ungvary et al., 1980; American Petroleum Institute, 1980; Pryor et al.,
1983a,b). Male and female CFY rats were exposed to 1000 mg/m3 (265 ppm)
toluene for 6 hours/day, 5 days/week for 6 months. (Ungvary et al., 1980).
No effect was seen 1n the males. However, the females had an Increased
level of cytochrome P-450, decreased body weight and an Increased ratio of
liver weight to total body weight. At the next exposure level, 3500 mg/m3
(928 ppm), male rats were exposed for 8 hours/day, 5 days/week for 6 months.
Effects were similar to those seen 1n the females at the lower dose. No
females were tested at the higher dose level.
3.2. CHRONIC
3.2.1. Oral. Pertinent data regarding chronic oral exposure to toluene
could not be located 1n the available literature.
3.2.2. Inhalation. Male and female Fischer rats were exposed to 30, 100
and 300 ppm of toluene for 6 hours/day, 5 days/week for 24 months (CUT,
1980). At a dose of 30 ppm, there was no difference 1n hematology,
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TABLE 3-1
Subchronlc Toxlclty of Toluene
Route
Oral*
Inhalation
Dose/Exposure
controls
118 mg/kg/day
354 mg/kg/day
590 mg/kg/day
265 ppm
Duration of Exposure
5 days/week for 27.6
weeks (138 doses)
6 hours/day. 5 days/
week, 3 months
Species/Sex
Ulstar rats/F
CFt rats/M&F
Number
20
10
10
10
NR
Effect
No effect after gross and clinical
Inspection and htstologlcal evalua-
tion of kidneys and liver at any
dose level tested.
Cytochrome P-450 Increased; de-
creased body weight and Increased
Reference
Wolf et al..
1956
Ungvary
et al.. 1980
Inhalation 928 ppm
in
i
Inhalation
Inhalation
0 ppm
100 ppm
1500 ppm
controls
900 ppm
1400 ppm
Inhalation
107 ppm
6 hours/day. 5 days/
week, 6 months
8 hours/day. 5 days/ CFY rats/N
week. 6 months
liver weight In females.
Cytochrome P-4SO Increased; In-
creased liver to body weight ratio;
decreased body weight In females.
NR Increased cytochrome P-450; In-
creased dilation of rough endo-
plasmlc retlculum and autophagous
bodies In hepatocytes; decreased
glycogen and total body weight;
Increased relative liver weight.
6 hours/day. 5 days/
week. 26 weeks
14 hours/day. 7 days/
week, 14 weeks
Sprague-Dawley
rats/H&F
F-344 rats/H
15/sex/
exposure
level
11-12
continuous for
90 days
rats/NR
guinea ptgs/NR
dogs/NR
monkeys/NR
None
900 ppm: Initial decreased body
weight; reduction In motor neuron
activity 2-8 weeks.
1400 ppm: Sustained decreased body
weight; reduction In motor neuron
activity 2-8 weeks; loss of tone-
Intensity discrimination hearing
ability; decreased learning behavior.
NR Two rats died, but other effects not
NR observed. The parameters evaluated
NR were hematology. body weight and
NR histology of lung, liver, kidney,
heart and spleen.
Ungvary
et al., 1980
American
Petroleum
Institute.
1980
Pryor et al.
1983a,b
Jenkins
et al., 1970
'Administered by gavage In olive oil
NR = Not reported
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urlnalysls or clinical chemistry between the treated and control groups. At
the 100 and 300 ppm dose levels, the only reported effect was a decrease In
the hematocrH of female rats.
Because of Us widespread use In the workplace and because of toluene
abuse (glue sniffing), the effects of chronic exposure to toluene have been
studied extensively In humans. Some of the occupational exposure studies
are summarized In Table 3-2. One of the more striking features of the data
on the subchronlc and chronic effects of toluene exposure on humans 1s the
failure of Increased periods of Intermittent exposures to cause clearly
Increasing severe effects. Although the utility of the available studies
for estimating firm dose-response relationships 1s somewhat limited by the
failure to define precise levels and duration of exposure, problems of
sample size, the potential role of other toxic agents 1n eliciting the
reported effects, and some apparent Inconsistencies among the available
studies, the weight of evidence suggests that the types of effects seen and
the levels at which effects are seen are relatively Independent of the dura-
tion of exposure. For mean exposure levels >200 ppm, all of the available
studies except that of Suhr (1975) report some evidence of neurologic
effects (see Table 3-2); Interpretation of the significance of the large
scale, Suhr (1975) study 1s confounded by the factors outlined 1n the
footnote to Table 3-2.
For exposures of >200 ppm, the reports of headache, nausea and concen-
tration-related Impairment of coordination (Wilson, 1943) are consistent
with the relatively well-documented CNS effects of single exposures to
toluene. This 1s not unexpected since blood levels of toluene decline
rapidly following cessation of Inhalation exposure (toluene 1s rapidly
absorbed and eliminated) (SRC, 1981). For single experimental exposures
-6-
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TABLE 3-2
Effects of Intermittent Subchronlc/Chronlc Vapor Exposures to Toluene on Humans
Exposure
Effects
Reference
Dally exposure to commercial toluene
for 1-3 weeks:
500-1500 ppm (-10% of the patients)
200-500 ppm (-30% of the patients)
50-200 ppm (-60% of the patients)
200-800 ppm for "many" years
250 ppm for "diverse" years
125 ppm
200-400 ppm pure toluene (<0.3%)
100 of a total of 1000 workers showed symptoms
severe enough to cause them to present them-
selves for hospital examination
Nausea, headache, dizziness, anorexia, palpita-
tion, extreme weakness; pronounced loss of
coordination and Impaired reaction
Headache, nausea, bad taste In mouth, anorexia,
lassitude, slight Impairment of coordination
and reaction time, transient memory loss
Headache, lassitude and loss of appetite; mild
symptoms that were attributed to psychogenlc
and other factors rather than exposure
Signs of "nervous hyperexcltablllty" In 6/11
paint and pharmaceutical Industry workers
Stupor, nervousness and Insomnia In one V-belt
manufacturing worker
No CNS effects In 17 V-belt manufacturing
workers
No evidence of adverse neurological effects
(subjective complaints Indicative of CNS
depression, abnormal reflex reactions. Impaired
muscular coordination) In 100 rotogravure
workers*; responses compared with an unexpected
control group of equal size.
Wilson, 1943
Wilson, 1943
Wilson. 1943
Wilson. 1943
Parmegglanl and
Sassl, 1954
CapelUnl and
Alesslo, 1971
CapelUnl and
Alesslo, 1971
Suhr, 1975
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TABLE 3-2 (cont.)
Exposure
Effects
Reference
300 ppm for 18 years
430 ppm for 12 years
30 ppm toluene and 2-7 ppm other
organic solvents for 1-40 years
CXI
60-100 ppm toluene with 20-50 ppm
gasoline In a "few" working places
>250 ppm and trlchloroethylene
(concentration not stated)
Subjective memory, thinking and activity dis-
turbances In 21% of the 300 ppm group (printers)
and 40?t of the 430 ppm group (printers' helpers);
110 workers tested (no control subjects);
Rorschach test results consistent with the
findings In 835t of the cases
Impaired behavioral responses In 100 car
painters relative to 101 age-matched nonexposed
controls; a battery of behavioral tests Indi-
cated that Impairments In visual and verbal
Intelligence and In memory as well as a reduc-
tion In emotional reactivity (Rorschach test)
were the predominant effects of exposure
Evidence of peripheral neuropathy (e.g., ab-
normal tendon reflexes and grasping power) In up
to 14/38 female shoemakers; responses compared
with 16 unexposed controls; 19/38 exposed women
(3 of 16 controls) complained of dysmenorrhea
Changes In EEG response to photic stimulation
Hunchlnger,
1963
Hannlnen
et al.. 1976
Matsushita
et al.. 1975
Rouskova, 1975
*Th1s conclusion Is considered equivocal (SRC, 1981) because the control group was undefined, because
blood toluene levels may have significantly declined at the time of reflex reaction and muscular coordina-
tion testing, and because muscular coordination was evaluated with an apparently unvalldated device
(sphallograph).
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that approximated a normal working day (7-8 hours) and Involved a combined
total of five subjects on multiple exposure/recovery schedules, 1t was found
that subjective complaints such as fatigue, muscular weakness, confusion,
Impaired coordination, slight exhilaration, enlarged pupils and accommoda-
tion disturbances were first observed at levels of 200 ppm (von Oettlngen et
al., 1942a,b; Carpenter et al., 1944). These effects Increased 1n severity
with Increases 1n toluene concentrations until at 800 ppm the subjects
experienced changes such as severe fatigue, pronounced nausea, mental con-
fusion, headaches, considerable 1ncoord1nat1on and staggering gait, strongly
Impaired accommodation to light and scotomata (areas of depressed vision).
Carpenter et al. (1944) also reported that toluene causes mild throat and
eye Irritation at 200 ppm and lacrlmatlon at 400 ppm. Short-term experi-
mental exposures to toluene at concentrations >100 ppm have also elicited
Increases 1n reaction time (200 ppm x 3 hours) (Ogata et al., 1979) and
reduction 1n perceptual speed (300 ppm x 20 minutes) (Gamberale and
Hultengren, 1972).
Toluene abuse, 1n several cases for as long as 10-14 years, caused
severe effects Including ataxla, tremors, 1ncoord1nat1on, emotional Insta-
bility, nystagmus, a positive Bablnskl response, psychoses and decreased
cerebellar functioning (Knox and Nelson, 1966; Satran and Oodson, 1963;
Kelly, 1975; Boor and Hurtig, 1977; Welsenberger, 1977; Sasa et al., 1978;
Keane, 1978; Tarsh, 1979; Malm and Lylng-Tunell, 1980).
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. In an abstract, Nawrot and Staples (1979) reported that
there was a significant Increase 1n fetal mortality when pregnant CD-I mice
were treated by gavage with 0.3, 0.5 and 1.0 ma/kg/day (0.26, 0.43 and
0.87 g/kg/day) of toluene 1n cottonseed oil on days 6-15 of gestation.
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Increased (statistically significant) fetal mortality was observed at all
dose levels and fetal weights were decreased when the pregnant mice were
exposed to 0.43 and 0.87 g/kg/day toluene on days 6-15 of gestation. Only
the highest dose level (0.87 g/kg/day) caused an Increased Incidence of
cleft palate In the offspring. Maternal toxldty was not seen under any of
the conditions described above. Because these results appeared only In an
abstract without statistical analysis they must be considered preliminary.
3.3.2. Inhalation. Pregnant ICR mice were exposed to toluene vapor at a
level of 100 ppm (377 mg/m3) and 1000 ppm (3770 mg/m3) for 6 hours/day
on days 1-17 of gestation (Shlgeta et al., 1982). There were 18 mice
exposed to the low dose, 14 mice exposed to the high dose and 15 controls.
Approximately two-thirds of each group of animals were sacrificed on day 18
of gestation. The fetuses were examined for extra ribs, fused ribs, cleft
vertebrae, cleft sternum, cran1osch1s1s and polydactyly, and 1n the absence
of observed effects, the authors concluded that toluene was not fetotoxlc or
teratogenlc. Although there were more resorbed fetuses 1n treated mice, the
Increased resorptlon was neither statistically significant nor dose-related.
No abnormalities were detected up to 14 weeks after birth 1n the offspring
of toluene-exposed mothers (Shlgeta et al., 1982). CFLP mice (Hudak and
Ungvary, 1978) were exposed to toluene vapor at a level of 500 and 1500
mg/m3 continuously on days 6-13 of gestation. All of the mice exposed to
1500 mg/m3 died within 24 hours of exposure. Decreased fetal weight,
Indicating fetotoxldty, occurred 1n the offspring of mice treated at
500 mg/m3.
The offspring of Charles River rats exposed to toluene vapor at concen-
trations of 100 and 400 ppm (377 and 1500 mg/m3), respectively, for 6
hours/day on days 6-15 of gestation (Litton Blonetlcs, Inc., 1978a) did not
-10-
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have an Increased Incidence of visceral or skeletal 'abnormalities as. com-
pared with a control group. No maternal or fetal toxldty was reported
(Litton B1onet1cs, Inc., 1978a). A group of 20 CFY pregnant rats were
exposed to toluene vapor at a concentration of 1000 mg/m3 (ppm) for 24
hours/day on days 7-14 of gestation (Tatral et a!., 1980). A group of 22
pregnant CFY rats constituted the control group. Although toluene exposure
at this level did not significantly alter maternal or fetal mortality or
body weights, retarded skeletal growth as judged by Inspection of alizarine
stained fetuses occurred at a statistically significant level 1n the toluene
exposure group. In another experiment, one group of 10 CFY rats was exposed
to toluene vapors at a concentration of 1000 mg/m3 for 8 hours/day on days
1-21 of gestation; another group of 9 rats was exposed to 1500 mg/m3 con-
tinuously on days 1-8 of gestation; and a third group of 26 rats was exposed
to 1500 mg/m3 continuously on days 9-14 of gestation. Although there were
no visceral or external malformations because of toluene exposure at the
levels tested, retarded skeletal development (poorly ossified sternebrae,
split vertebral centra and shortened free ribs) or skeletal anomalies (extra
ribs and fused sternebrae) occurred at all three levels tested (Hudak and
Ungvary, 1978).
3.4. TOXICANT INTERACTIONS
The Interactions of toluene with benzene, xylene, hexane, ethanol,
acetylsallcyHc add, tMchloroethylene and perchloroethylene are summarized
1n Table 3-3.
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1ABLE 3-3
Interaction of Toluene with Other Chemicals During Simultaneous Exposure
i
IS)
Route of
Toluene
Exposure
NR
Inhalation
Inhalation
Inhalation
Inhalation
Intraperl-
toneal
Oral
Intrapert-
toneal
Dose of
Toluene
Exposure
NR
100 ppm.
2 hours
1060 ppm.
6 hours/day,
5 days/week,
4 weeks
80 ppm, 3 hours
1000. 2000 and
3600 mg/m».
continuously on
days 10-13 of
pregnancy
430 mg/kg
NR
0.1 mg/kg
0.2 mg/kg
Other Route of Dose of
Chemical Exposure Other Chemical Species
benzene NR 24.2-97.7 mg/kg rats
390.6 mg/kg
benzene Inhalation 25 ppm, 2 hours humans
ethanol oral NR rats
ethanol oral 1.5 ml/kg humans
acetylsall- oral 250 mg (on CFY rats
cyllc acid day 12)
(aspirin)
trlchloro- Intraperl- 730 mg/kg NR
ethylene toneal
perchloro- oral NR rats
ethylene
m-xylene Intraperl- 0.1 mg/kg male rats
toneal 0.2 mg/kg
Effect
Dose-dependent Inhibition
of benzene metabolism by
toluene at higher dose
levels
No effect on metabolism of
toluene or benzene
Additive effect on myo-
cardlal Increased vascular
resistance
Inhibited toluene metabo-
lism (however, regular
alcohol consumption lowered
blood toluene levels In
workers occupatlonally
exposed to toluene)
Toluene potentiated the
effect of aspirin on
mothers (decreased weight
gain and Increased liver
weight) and on fetuses
(Increased skeletal and
renal anomalies and In-
creased Incidence of club-
foot, cleft palate and
polydactyly).
Competitive Inhibition
Toluene toxlclty poten-
tiated.
No effect on total urinary
excretion, but the rate was
slightly depressed.
Reference
Sato and
Nakajlma, 1979
Sato and
Nakajlma. 1979
Horval and
Ungvary, 1979
Ualdron
et al., 1983
Ungvary
et al., 1983
Ikeda, 1974
Smyth et al.,
1969
Ogata and
Fujll. 1979
NR = Not reported
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4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Pertinent data regarding the human cardnogenldty of
toluene following oral exposure could not be located In the available
literature.
4.1.2. Inhalation. Pertinent data regarding the human cardnogenldty of
toluene following Inhalation exposure could not be located 1n the available
literature.
4.2. BIOASSAYS
4.2.1. Oral. Pertinent data regarding the cardnogenldty of toluene to
experimental animals following oral exposure could not be located 1n the
available literature.
4.2.2. Inhalation. The chronic bloassay (2 years) of toluene In Fischer
344 rats of both sexes showed no carcinogenic effects (CUT, 1980). Approx-
imately 90 rats/sex/dose were exposed to 30, 100 or 350 ppm (113, 377 or
1130 mg/m3, respectively) toluene for 6 hours/day, 5 days/week. Although
females exposed to 100 and 300 ppm (370 or 1130 mg/m3) had significantly
reduced hematocrlt levels, no dose-response effect was present. After
hematologlcal and hlstopathologlcal evaluation, no other difference between
treated and control groups was observed. However, there was a high spon-
taneous Incidence (16%) of mononuclear cell leukemia 1n the control group.
4.3. OTHER RELEVANT DATA
Toluene has been shown not to be mutagenlc 1n the presence or absence of
rat liver homogenate 1n Salmonella typhlmuMum strains TA98, TA100, TA1535,
TA1537 and TA1538 (Litton Blonetlcs, Inc., 1978b; Mortelmans and R1cdo,
1980; Nestmann et al., 1980; Snow et al., 1981; Bos et al., 1981), 1n Esche-
rlchla coll strain WP2 (Mortelmans and R1cdo, 1980) and In Saccharomyces
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cerevlslae strains D4 and D7 (Mortelmans and Rlccio, 1980). Toluene did not
damage DNA 1n DNA repair deficient strains of E_. coll (Pluck et al., 1976)
and S>. typhlmurium (Mortelmans and R1cdo, 1980).
Preliminary data Indicate that toluene may decrease fetal weight gain
and Increase fetal mortality and the Incidence of cleft palate 1n the fetus
when CD-I mice are exposed orally on days 6-15 of gestation at doses of 260,
430 and 870 mg/kg/day (Nawrot and Staples, 1979). Maternal Inhalation of
toluene 1n mice and rats during pregnancy did not cause a statistically
significant effect, although skeletal anomalies and resorptlon were
Increased 1n some experiments (Tatral et al., 1980; Litton Blonetlcs, Inc.,
1978a; Shlgeta et al., 1982).
j
4.4. WEIGHT OF EVIDENCE
The rate and Incidence of tumor formation 1n rats exposed to toluene for
2 years were not significantly different from the rate and Incidence of
tumor formation In control rats (CUT, 1980). Because human exposure to
toluene 1n the workplace occurs often and because toluene 1s an abused
substance, there are many reports of human exposure 1n the literature. None
of the reports associates toluene exposure with Increased rate or Incidence
of cancer. IARC has not evaluated the risk to humans associated with oral
or Inhalation exposure to toluene. Applying the criteria proposed by the
Carcinogen Assessment Group of the U.S. EPA (Federal Register, 1984),
toluene Is most appropriately designated a Group D - Not Classified chemical.
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5. REGULATORY STANDARDS AND CRITERIA
ACGIH (1983) currently recommends a TWA-TLV of 100 ppm and a STEL of 150
ppm. NIOSH (1973) recommends a TWA of 100 ppm, with a celling of 200 ppm.
OSHA currently limits occupational exposure to toluene to a TWA concentra-
tion of 200 ppm, with a celling of 300 ppm (Code of Federal Regulations,
1981).
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1. Oral. In the only study available on oral subchronlc exposure to
toluene (Wolf et al., 1956), all the dose levels Including the highest dose
level of 590 mg/kg/day, 5 days/week for 27.6 weeks were NOELs. In an
abstract, Nawrot and Staples (1979) reported Increased embryo death 1n all
treatment groups when pregnant mice received 260, 430 and 870 mg/kg/day of
toluene by gavage on days 6-15 of gestation. Although the experimental
design and results were sparsely reported In this abstract, the data cannot
be discounted.
An AIS for oral exposure can be calculated using the highest freestand-
ing NOEL (590 mg/kg) from the Wolf et al. (1956) study. Multiplying by 5/7
to estimate continuous exposure, by 70 (the assumed human body weight) and
dividing by an uncertainty factor of 1000 (10 for Interspecles extrapola-
tion, 10 for Intraspecies differences 1n sensitivity and 10 because of
concern for potential fetotoxlc effects) results 1n an estimated AIS of 30
mg/day.
6.1.2. Inhalation. Animal studies Indicate that toluene is fetotoxlc In
mice and rats (Hudak and Ungvary, 1978; Tatral et al., 1980; Litton
Bionetics, Inc., 1978b; Shigeta et al., 1982). However, the NOAEL for feto-
toxlclty in mice Is 833.33 mg/kg/day (Hudak and Ungvary, 1978), obtained by
multiplying the continuous exposure level of 500 mg/m3 by the mouse
inhalation rate of 0.05 mVday and dividing by the estimated body weight
of a mouse (0.03 kg). In rats, the retarded skeletal development was judged
to be a PEL and occurred at a dose of 247.6 mg/kg/day (Hudak and Ungvary,
1978), obtained by multiplying the intermittent exposure level by 1/3 (8
hours/day) and the rat Inhalation rate (0.26 mVday) and dividing by the
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estimated body weight of a rat (0.35 kg). Following the same dose conver-
sion methods, a dose of 278.6 mg/kg/day was reported to be a NOEL 1n the rat
(Litton B1onet1cs, Inc., 1978a).
Other subchronlc Inhalation studies from which a NOAEL or NOEL could be
derived were not located, Ungvary et al. (1980) and American Petroleum
Institute (1980) and Pryor et al. (1983a,b), provide Insufficient Informa-
tion on results and experimental design for adequate evaluation and risk
assessment. However, the chronic Inhalation data from the CUT (1980) study
can be used. The concentration of toluene 1n air, 1130 mg/m3, 1s multi-
plied by 6/24 and 5/7 to correct for an exposure of 6 hours/day, 5 days/
week, and the result 1s multiplied by 0.26 m3/day (an assumed respiratory
volume 1n rats) and divided by 0.35 kg (the assumed body weight of rats). A
dose of 149.90 mg/kg/day 1s calculated. Application of an uncertainty
factor of 100 (10 to afford greater protection for sensitive Individuals and
10 for Interspedes extrapolation) and multiplying by 70 kg, the assumed
average body weight of humans, results 1n an AIS of 104.9 mg/day. This Is
the same value estimated for chronic exposure. Since toluene 1s rapidly
metabolized and cleared, cumulative effects would not be anticipated.
Therefore, 1t 1s not unreasonable to estimate the same value for both AIS
and AIC exposures.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral. It 1s suggested that the U.S. EPA (1985) ADI of 20.3 mg/day
be adopted as an Interim oral AIC. This value 1s based on an Inhalation
NOAEL 1n rats of 1130 mg/m3 (CUT, 1980). Since the U.S. EPA (1985) based
an oral ADI on Inhalation data, a route-to-route extrapolation was required.
-17-
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This was accomplished by expanding the exposure (1130 mg/m3) from 6 hours/
day, 5 days/week to continuous exposure, and multiplying by 20 m3 (an
assumed dally respiratory volume for humans) and by 0.5 to reflect an
assumed 50% absorption factor. Application of an uncertainty factor of 100
(10 to afford greater protection for sensitive individuals and 10 for Inter-
species extrapolation) results 1n an ADI of 20.3 mg/day for oral exposure to
toluene. This value should be reviewed when chronic oral data are avail-
able. For corroborative purposes, U.S. EPA (1985) also projected ADIs based
upon human Inhalation data (Hannlnen et al., 1976; Seppalalnen et al., 1978)
(projected ADI 41 mg/day); as well as the TLV (projected ADI 135 mg/day).
They also cite the subchronic oral NOAEL of 590 mg/kg in the rat (Wolf et
al., 1956) as supporting data.
6.2.2. Inhalation. Considerable Information is available regarding the
CNS effects on humans of chronic inhalation exposure to toluene (see Table
3-1). None of the human studies taken individually are suitable for use in
human risk assessment because they involve a relatively small number of
subjects, Inadequately document exposure levels or durations, or do not
consider the potential role of concomitant exposure to other toxicants.
Collectively, however, the human studies provide a relatively consistent
pattern of dose-response relationships for CNS effects.
An AIC for Inhalation can be calculated from the chronic (106 week) data
1n rats (CUT, 1980). The calculations are based on the rat NOAEL of 1130
mg/m3, and are identical to those in Section 6.1.2. An AIC of 104.9 is
calculated.
An RQ for toluene was derived by U.S. EPA (1983b) based on the accumu-
lated data in humans in the workplace summarized 1n Section 3.2.2. Although
none of these studies is by Itself suitable for derivation of an RQ, collec-
tively, they consitute a considerable body of data on humans and provide a
-18-
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fairly consistent pattern of dose-response relationships. Although the CUT
(1980) chronic Inhalation experiment defined an effect at 300 ppm In rats,
the uncertainty Involved 1n extrapolating from an experimental animal to
humans makes selection of the human data a more prudent choice for calcula-
tion of a CS.
Consideration of the Intermittent subchronlc/chronic Inhalation exposure
data and the supporting acute exposure data leads to the conclusion that
exposure periods of <8 hours to toluene concentrations <100 ppm may result
1n mild subjective symptoms (fatigue of headache), but are not likely to
Induce observable effects. Concentrations >100 ppm may cause Impaired reac-
tion time, and concentrations of >300 ppm would be expected to cause gross
signs of 1ncoord1nat1on. Based on all of the available data, 300 ppm (1130
mg/m3) can be regarded as an unequivocal effect level 1n humans. Since
this effect level 1s applicable to Intermittent occupational exposures that
are assumed to occur 5 days/week, an MED can be calculated by expanding the
exposure from 5 to 7 days/week, and assuming that a human breathes 10 m3
of air/workday with an absorption efficiency of 50% for toluene (SRC, 1981).
This calculation gives an MED of 57.6 mg/kg/day, or 4036 mg/day for a 70 kg
man. The RV associated with a human MED of 4036 mg/day 1s 1, since log
MED 1s >3. An appropriate RV reflecting the (reversible) CNS dysfunction
1s 7. The CS would therefore be 7, which corresponds to an RQ of 1000.
6.3. CARCINOGENIC POTENCY (q^)
There are no data pertaining to the cardnogenldty of toluene by oral
exposure to either humans or animals. An Inhalation bloassay 1n rats (CUT,
1980) yielded decidedly negative results. Quantitative carcinogenic risk
assessment 1s therefore not appropriate.
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7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1983.
Threshold Limit Values for Chemical Substances and Physical Agents 1n the
Workroom Environment with Intended Changes for 1983-1984. Cincinnati, OH.
p. 33.
American Petroleum Institute. 1980. A 26-Week Inhalation Toxlclty Study of
Toluene 1n the Rat. Project No. 78-7234 conducted by Blodynamlcs, Inc. for
American Petroleum Institute, Washington, DC. (CHed 1n U.S. EPA, 1984}
Astrand, I. 1975. Uptake of solvents 1n the blood and tissues of man. A
review. Scand. J. Work, Environ. Health. 1(4): 199-218. (CHed In U.S.
EPA, 1984)
Astrand, I., H. Ehrner-Samuel, A. Kllbom and P. Ovrum. 1972. Toluene expo-
sure. I. Concentration 1n alveolar air and blood at rest and during
exercise. Work Environ. Health. 72(3): 119-130. (CHed 1n U.S. EPA, 1984)
Bergman, K. 1979. Whole-body autoradlography and allied tracer techniques
1n distribution and elimination studies of some organic solvents. Scand. J.
Work Environ. Health. 5: 263. (CHed 1n U.S. EPA, 1984)
Berry, W.O. 1980. A comparative study of the uptake of toluene by blueglll
sunflsh, Lepomls macrochlrus. and crayfish, Oronectls rustlcus. Environ.
Pollut. Ser. A. 21: 109-119.
-20-
-------
Boor, 3.W. and H.I. Hurtlg. 1977. Persistent cerebellar ataxla after expo-
sure to toluene. Ann. Neurol. 2(5): 440-442. (CHed In U.S. EPA, 1984)
Bos, R.P., R.M.E. Brouns, R. Van Doom, J.L.6. Theuws and P.T. Henderson.
1981. Non-mutagen1c1ty of toluene, o-, m- and o-xylene, o-methylbenzyl
alcohol and o-methylbenzyl sulfate In the Ames assay. Mutat. Res. 88(3):
273-279. (Cited 1n U.S. EPA, 1984)
Carlsson, A. 1982. Exposure to toluene. Uptake, distribution and elimina-
tion 1n man. Scand. J. Work, Environ. Health. 8(1): 43-55. (Cited In U.S.
EPA, 1984)
CapelUnl, A. and Alesslo L. 1971. The urinary excretion of hlppurlc add
In workers exposed to toluene. Med. Lavoro. 62: 196-201. (Ita.) (CHed
1n U.S. EPA, 1983b)
Carpenter, C.P., C.B. Shaffer, C.S. Well and H.F. Smyth, Jr. 1944. Studies
on the Inhalation of 1,3-butad1ene; with a comparison of Us narcotic effect
with benzol, toluol, and styrene, and a note on the elimination of styrene
by the human. J. Ind. Hyg. Toxlcol. 26: 69-78. (CHed In U.S. EPA, 1983b)
CUT (Chemical Industry Institute of Toxicology). 1980. A twenty-four
month Inhalation toxicology study In F1scher-344 rats exposed to atmospheric
toluene. Executive Summary and Data Tables. October 15, 1980. (CHed 1n
U.S. EPA, 1984)
Code of Federal Regulations. 1981. OSHA Safety and Health Standards. (29
CFR 1910.1000)
-21-
-------
Egle, J.L. and 8.J. Gochberg. 1976. Respiratory retention of Inhaled
toluene and benzene In the dog. J. Toxlcol. Environ. Health. 1(3):
531-538. (Cited 1n U.S. EPA, 1984)
El Masry, A.M., J.N. Smith and R.T. Williams. 1956. Studies 1n detoxifica-
tion. The metabolism of alkylbenzenes, n-propylbenzene and n-butylbenzene
with further observations on ethylbenzene. Blochem. J. 64: 50-56. (CHed
1n U.S. EPA, 1984)
Federal Register. 1984. Environmental Protection Agency proposed guide-
lines for carcinogenic risk assessment. 49 FR 46294-46299.
Fluck, E.R., L.A. Polrler and H.W. Reullus. 1976. Evaluation of a DNA
polymerase-defldent mutant of E.. coll for the rapid detection of carcino-
gens. Chem. B1ol. Interact. 15: 219. (CHed 1n U.S. EPA, 1984)
Gamberale, F. and M. Hultengren. 1972. Toluene exposure. II.
Psycho-physiological functions. Work Environ. Health. 9(3): 131-139.
(CHed In U.S. EPA, 1983b)
Greenburg, L., M.R. Mayers, H. Helmann and S. MoskowHz. 1942. The effects
of exposure to toluene In Industry. J. Am. Med. Assoc. 118: 573-578.
(CHed 1n U.S. EPA, 1984)
Hannlnen, H., L. Eskellnen, K. Husman and M. Nurmlnen. 1976. Behavioral
effects of long-term exposure to a mixture of organic solvents. Scand. J.
Work Environ. Health. 2(4): 240-255. (CHed 1n U.S. EPA, 1984)
-22-
-------
Hansch, C. and A.J. Leo. 1981. Medchem. Project Issue No. 19, Pomona
College, Claremont, CA.
Hudak, A. and 6. Ungvary. 1978. Embryotoxlc effects of benzene and Its
methyl derivatives: Toluene and xylene. Toxicology. 11: 55.
Ikeda, M. 1974. Reciprocal metabolic Inhibition of toluene and trlchloro-
ethylene in vivo and jm vitro. Int. Arch. Arbeltsmed. 33(2): 125-130.
(Cited 1n U.S. EPA, 1984)
Jenkins, L.J., Jr., R.A. Jones and J. Siege!. 1970. Long-term Inhalation
screening studies of benzene, toluene, o-xylene and cumene on experimental
animals. Toxlcol. Appl. Pharmacol. 16: 818-823. (Cited 1n U.S. EPA, 1984)
Keane, J.R. 1978. Toluene optic neuropathy. Ann. Neurol. 4(4): 390.
(Cited 1n U.S. EPA, 1984)
Kelly, T.W. 1975. Prolonged cerebellar dysfunction associated with paint
sniffing. Pediatrics. 56: 605-606. (Cited 1n U.S. EPA, 1984)
Knox, J.W. and J.R. Nelson. 1966. Permanent encephalopathy from toluene
Inhalation. N. Engl. J. Med. 275: 1494-1496. (Cited In U.S. EPA, 1984)
Litton B1onet1cs, Inc. 1978a. Teratology Study In Rats. Toluene. Final
Report. Submitted to the American Petroleum Institute, Washington, DC, 1n
January, 1978. LBI Project No. 20698-4. Kensington, MD. 17 p. (Cited In
U.S. EPA, 1984)
-23-
-------
Litton Blonetlcs, Inc. 1978b. MutagenicHy Evaluation of Toluene. Final
Report. Submitted to the American Petroleum Institute, Washington, DC, in
May, 1978. LBI Project No. 20847. Kensington, MD. 150 p. (Cited in U.S.
EPA, 1984)
Mackay, 0. and A.T.K. Yeun. 1983. Mass transfer coefficient correlations
for volatilization of organic solutes from water. Environ. Sci. Technol.
17: 211-217.
Mackay, D., A. Bolera, D.W. Chan and W.Y. Shiu. 1982. Vapor pressure cor-
relations for low-volatility environmental chemicals. Environ. Sci.
Technol. 16: 645-649.
Malm, 6. and U. Lying-Tunell. 1980. Cerebellar dysfunction related to
toluene, sniffing. Acta. Neurol. Scand. 62(3): 188-190. (Cited in U.S.
EPA, 1984)
Matsushita, T., Y. Arimatsu, A. Ueda, K. Sutoh and S. Nomura. 1975. Hema-
tological and neuro-muscular response of workers exposed to low concentra-
tion of toluene vapor. Ind. Health. 13: 115. (Cited in U.S. EPA, 1984)
McNabb, J.F., B.H. Smith and J.T. Wilson. 1981. B1odegradat1on of toluene
and chlorobenzene in soil and groundwater. 81st Annual Meeting of the Am.
Soc. Microbiol., Dallas, TX. March 1-6. p. 213.
-24-
-------
Mortelmans, K.E. and E.S. Rlcclo. 1980. in vitro microbiological genotox-
1c1ty assays of toluene. Prepared by SRI International, Menlo Park, CA,
under Contract No. 68-02-2947. U.S. EPA, Research Triangle Park, NC.
(Cited 1n U.S. EPA, 1984)
Morval, V. and 6. Ungvary. 1979. Effects of simultaneous alcohol and
toluene poisoning on the cardiovascular system of rats. Toxlcol. Appl.
Pharmacol. 50(3): 381-389. (Cited In U.S. EPA, 1984)
Munchlnger, R. 1963. Oer Nachwels central nervoser Storungen be1 Losung-
smlttel exponlerten Arbeltern. Excerpta Medlca Series, Madrid; 16-21.
2(62): 687-689. (Cited 1n U.S. EPA, 1984)
Nawrot, P.S. and R.E. Staples. 1979. Embryo-fetal toxldty and teratogeni-
dty of benzene and toluene In the mouse. Teratology. 19: 41A. (CHed In
U.S. EPA, 1984)
Nestmann, E.R., G.G.-H. Lee, T.I. Matula, 6.R. Douglas and J.C. Mueller.
1980. Mutagen1c1ty of constituents Identified In pulp and paper mill ef-
fluents using the Salmonella/mammal1an-m1crosome assay. Mutat. Res. 79:
203-212. (CHed In U.S. EPA, 1984)
NIOSH (National Institute for Occupational Safety and Health). 1973.
Criteria for a Recommended Standard...Occupational Exposure to Toluene.
Final Report. Contract No. HSM-99-72-118. NTIS PB-222-219/8. (CHed In
U.S. EPA, 1984)
-25-
-------
Nomlyama, K. and H. Nomlyama. 1974. Respiratory retention, uptake and
excretion of organic solvents 1n man. Benzene, toluene, n-hexane,
tMchloroethylene, acetone, ethyl acetate and ethyl alcohol. Int. Arch.
ArbeHsmed. 32(1-2): 75-83. (Cited 1n U.S. EPA, 1984)
Ogata, M. and T. Fuj11. 1979. Urinary excretion of hlppurlc acid and
m-methylh1ppur1c add after administration of toluene and m-xylene mixture
to rats. Int. Arch. Occup. Environ. Health. 43(1): 45-51. (Cited 1n U.S.
EPA, 1984)
Ogata, M. and Y. Mlyake. 1978. Disappearance of aromatic hydrocarbons and
organic sulfur compounds from fish flesh reared in crude oil suspension.
Water Res. 12: 1041-1044.
Ogata, M., K. Tomokunl and Y. Takatsuka. 1979. Urinary excretion of
hlppuric add and m- or p-methylh1ppuric add In the urine of persons
exposed to vapors of toluene and m- or p-xylene as a test of exposure. Br.
J. Ind. Med. 27(1): 43-50. (Cited in U.S. EPA, 1983b)
Parmegglana, L. and C. Sassl. 1954. Occupational risk of toluene: Environ-
mental studies and clinical Investigations of chronic Intoxication. Med.
Lavoro. 45: 475483. (Hal.) (Cited 1n U.S. EPA, 1983b)
Pryor, G.T., J. Dickinson, R.A. Howd and C.S. Rebert. 1983a. Neuro-
behavloral effects of subchronlc exposure of weanling rats to toluene or
hexane. Neurobehav. Toxicol. Teratol. 5(1): 47-52. (Cited in U.S. EPA,
1984)
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-------
Pryor, 6.T., J. Dickinson, R.A. Howd and C.S. Rebert. 1983b. Transient
cognitive deficits and high-frequency hearing loss 1n weanling rats exposed
to toluene. Neurobehav. Toxlcol. Teratol. 5(1): 53-57. (Cited In U.S.
EPA, 1984)
Pyykko, K., H. Tahtl and H. Vapaatalo. 1977. Toluene concentrations 1n
various tissues of rats after Inhalation and oral administration. Arch.
Toxlcol. 38: 169-176. (Cited 1n U.S. EPA, 1984)
Rouskova, V. 1975. Photic stimulation 1n early diagnosis of the effects of
some harmful Industrial substances on the central nervous system. Int.
Arch. Arbeltsmed. 34(4): 283-299. (Cited 1n U.S. EPA, 1983b)
Sasa, M., S. Igarashl, T. M1yazak1, K. Mlyazaki and S. and Nakano. 1978.
Equilibrium disorders with diffuse brain atrophy 1n long-term toluene
sniffing. Arch. Otorhlnolaryngol. 221(3): 163-169. (Cited 1n U.S. EPA,
1984)
Sato, A. and T. Nakajima. 1979. Dose-dependent metabolic Interaction
between benzene and toluene jjn vivo and j_n vitro. Toxlcol. Appl. Pharmacol.
48(2): 249-256. (Cited in U.S. EPA, 1984)
Satran, R. and V. Dodson. 1963. Toluene habitation — Report of a case.
N. Engl. J. Med. 263(13): 219-220. (Cited in U.S. EPA, 1984)
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-------
Seppalalnen, A.M., K. Husman and C. Martenson. 1978. Neurophyslologlcal
effects of long-term exposure to a mixture of organic solvents. Scand. J.
Work Environ. Health. 4(4): 304-314. (Cited In U.S. EPA, 1984)
Shlgeta, S., H. Alkawa and T. Mlsawa. 1982. Effects of maternal exposure
to toluene during pregnancy on mouse embryos and fetuses. Tokai J. Exp.
CUn. Med. 7(2): 265-270. (Cited 1n U.S. EPA, 1984)
Singh, H.B., L.3. Salas, A.J. Smith and H. Shlgelshl. 1981. Measurements
of some potentially hazardous organic chemicals In urban environments.
Atmos. Environ. 15: 601-612.
Smith, J.N., R.H. Smithies and R.T. Williams. 1954. Studies 1n detoxlca-
tion, 55. The metabolism of alkylbenzenes, a/Glucuron1c acid excretion fol-
lowing the administration of alkylbenzenes; b/E!1m1nat1on of toluene 1n the
expired air of rabbits. Blochem. J. 56: 317-320. (Cited In U.S. EPA, 1984)
Smyth, H.F., Jr., C.S. Well, J.S. West and C.P. Carpenter. 1969. Explora-
tion of joint toxic action: Twenty-seven Industrial chemicals Intubated 1n
rats In all possible pairs. Toxlcol. Appl. Pharmacol. 14(2): 340-347.
(Cited In U.S. EPA, 1984)
Snow, L., P. MacNalr and B.C. Casto. 1981. Mutagenesls testing of toluene
1n Salmonella strains TA100 and TA98. Prepared for the U.S. EPA by Northrup
Services, Inc., P.O. Box 12313, Research Triangle Park, NC 27709. (Cited
1n U.S. EPA, 1984)
-28-
-------
SRC (Syracuse Research Corporation). 1981. Health Risk Assessment for
Toluene. Draft report prepared under Contract 68-03-377 for U.S. EPA,
Research Triangle Park, NC. (Cited In U.S. EPA, 1983b)
Suhr, E. 1975. Comparative Investigation of the State of Health of Gravure
Printers Exposed to Toluene. Gesellschaft zur Forderung des Tlefdrucks
E.V., Welsbaden, Federal Republic of Germany. 92 p. (Cited 1n U.S. EPA,
<
1983b)
Tarsh, M.J. 1979. Sch1zophren1form psychosis caused by sniffing toluene.
J. Soc. Occup. Med. 29(4): 131-133. (Cited 1n U.S. EPA, 1984)
Tatral, E., K. Rodlcs and G. Ungvary. 1980. Embryotoxlc effects of simul-
taneously applied exposure of benzene and toluene. Folia Morphologlca.
28(3): 286-289. (Cited 1n U.S. EPA, 1984)
Ungvary, G., S. Manyal, E. Tatral, et al. 1980. Effect of toluene Inhala-
tion on the liver of rats — Dependence on sex, dose and exposure time. J.
Hyg. Ep1dem1ol. Nlcroblol. Immunol. 24: 242-252. (Cited 1n U.S. EPA, 1984)
Ungvary, G., E. Tatral, M. LoMncz and G. Barcza. 1983. Combined embryo-
toxic action of toluene, a widely used Industrial chemical and acetyl-
sallcylic add (aspirin). Teratology. 27(2): 261-269. (Cited In U.S. EPA,
1984)
-29-
-------
U.S. EPA. 1980. Guidelines and Methodology Used In the Preparation of
Health Effects Assessment Chapters of the Consent Decree Water Quality
Criteria. Federal Register. 45:79347-79357.
U.S. EPA. 1982a. Health and Environmental Effects Profile for Toluene.
Environmental Criteria and Assessment Office, Cincinnati, OH.
U.S. EPA. 1982b. Health Effects Assessment Document for Toluene. Environ-
mental Criteria and Assessment Office, Cincinnati, OH. Internal draft.
U.S. EPA. 1983a. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxldty Data. Prepared by the Environmental
Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Solid
Waste and Emergency Response, Washington, DC.
U.S. EPA. 1983b. Reportable Quantity for Toluene. Prepared by the
Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA for the
Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1984. Drinking Water Criteria Document for Toluene. Prepared by
the Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA for
the Office of Drinking Water, Washington, DC. External review draft.
U.S. EPA. 1985. Drinking Water Criteria Document for Toluene. Prepared by
the Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA for
the Office of Drinking Water, Washington, DC. Final draft.
-30-
-------
Van Aalst, R.M., A.C. Besemer, T. Lems and H. Nleboer. 1980. Photochemical
conversion of aromatic hydrocarbons under simulated tropospherlc conditions.
Comm. Eur. Communities Eur. 6621, Proc. Eur. Symp. Phys-Chem. Behav. Atmos.
Pollut. 1: 136-149.
von Oettlngen, W.F., P.A. Neal and O.D. Donahue. 1942a. The toxldty and
potential dangers of toluene - Preliminary report. J. Amer. Med. Assoc.
118: 579-584. (Cited In U.S. EPA, 1983b)
von Oettlngen, W.F., P.A. Neal, D.O. Donahue, et al. 1942b. The toxlclty
and potential dangers of toluene, with special reference to Us maximal per-
missible concentration. U.S. Publ. Health Serv. Publ. Health Bull. No.
279. 50 p. (Cited In U.S. EPA, 1983b)
Waldron, H.A., N. Cherry and J.D. Johnston. 1983. The effects of ethanol
on blood toluene concentrations. Int. Arch. Occup. Environ. Health. 51(4):
365-369. (Cited 1n U.S. EPA, 1984)
Welsenberger, B.L. 1977. Toluene habltuatlon. J. Occup. Med. 19(8):
569-570. (Cited In U.S. EPA, 1984)
Wilson, J.T., C.G. Enfleld, W.J. Dunlap, R.L. Cosby, D.A. Foster and L.B.
Baskln. 1981. Transport and fate of selected organic pollutants In a sandy
soil. J. Environ. Qual. 10: 501-506.
-31-
-------
Wilson, 3.T., J.F. McNabb, R.H. Wilson and M.J. Noonan. 1983. Blotrans-
formatlon of selected organic pollutants 1n groundwater. Dev. Ind.
M1crob1ol. 24: 225-233.
Wilson, R.H. 1943. Toluene poisoning. J. Am. Med. Assoc. 12: 1106.
(Cited 1n U.S. EPA, 1983b)
Wolf, M.A., V.K. Rowe, D.D. McColllster, R.L. Holllngsworth and F. Oyen.
1956. Tox1colog1cal studies of certain alkylated benzenes and benzene.
Arch. Ind. Health. 14: 387. (Cited 1n U.S. EPA, 1984)
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APPENDIX
Summary Table for Toluene
Species
Inhalation
AIS rat
AIC rat
Maximum
composite human
, score
CO
CO
1
Oral
AIS rat
AIC rat
Experimental
Dose/Exposure
1130 mg/m3
1130 mg/m3
300 ppm (1130 mg/m3)
occupational (RV(j=1)
590 mg/kg
1130 mg/m3
Effect Acceptable Intake
(AIS or AIC)
NOAEL 104.9 mg/day
NOAEL 104.9 mg/day
CNS dysfunction 7
(RVe=7)
NOEL 30 mg/day
NOAEL 20.3 mg/day*
Reference
CUT, 1980
CUT, 1980
SRC, 1981;
U.S. EPA,
Wolf et al
1956
CUT, 1980
1983b
* »
*Th1s oral AIC Is based on an Inhalation study as proposed by U.S. EPA (1984).
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