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    and the World Health Organization

    World Health Orgnization
    Geneva, 1985

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    1.1. Summary
         1.1.1. Identity and analytical methods
         1.1.2. Production, uses, and sources of exposure
         1.1.3. Kinetics, biotransformation, and biological 
         1.1.4. Effects on experimental animals
         1.1.5. Effects on human beings
         1.1.6. Effects on aquatic and terrestrial organisms in the 
    1.2. Conclusions and recommendations
         1.2.1. Conclusions
         1.2.2. Recommendations


    2.1. Identity
    2.2. Physical and chemical properties
    2.3. Organoleptic properties
    2.4. Conversion factors
    2.5. Analytical methods
         2.5.1. Sampling procedures
                2.5.l.2  Water
        Soils and sediments
         2.5.2. Biological monitoring of toluene exposure
        Blood, expired air, body fluids, and 
        Human breast milk
         2.5.3. Food and food containers
         2.5.4. Detection of marketed toluene purity


    3.1. Natural occurrence
    3.2. Man-made sources
         3.2.1. Production levels, processes, and uses
        World production figures
        Manufacturing processes
         3.2.2. Uses


    4.1. Transport and distribution between media
         4.1.1. Air
         4.1.2. Water
         4.1.3. Soil
         4.1.4. Entry into the food chain

    4.2. Biotransformation
         4.2.1. Biodegradation
         4.2.2. Bioaccumulation


    5.1. Environmental levels
         5.1.1. Air
         5.1.2. Water
    5.2. General population exposure
    5.3. Occupational exposure during manufacture, formulation, or 


    6.1. Microorganisms
    6.2. Aquatic organisms
    6.3. Terrestrial organisms
    6.4. Population and ecosystem effects
    6.5. Effects on the abiotic environment


    7.1. Absorption
         7.1.1. Inhalation
        Human volunteers
         7.1.2. Dermal
        Human volunteers
         7.1.3. Oral
    7.2. Distribution
         7.2.1. Inhalation
        Human volunteers
         7.2.2. Oral
         7.2.3. Intraperitoneal
    7.3. Metabolic transformation
         7.3.1. Oral
         7.3.2. Inhalation
        Human beings
         7.3.3.  In vitro studies
    7.4. Elimination and excretion in expired air, faeces, and 
         7.4.1. Toluene
        Laboratory animals
        Human beings
         7.4.2. Excretion of metabolites
        Human beings


    8.1. Single exposures
         8.1.1. Inhalation
         8.1.2. Oral
         8.1.3. Intraperitoneal and intravenous injection
         8.1.4. Subcutaneous injection
    8.2. Short-term exposures
         8.2.1. Inhalation
         8.2.2. Other animal species and routes
         8.2.3. Oral
    8.3. Skin and eye irritation; sensitization
         8.3.1. Skin
         8.3.2. Eye
    8.4. Long-term exposures
         8.4.1. Inhalation
    8.5. Reproduction, embryotoxicity, and teratogenicity
         8.5.1. Reproduction
         8.5.2. Embryotoxicity and teratogenicity
    8.6. Mutagenicity and related end-points
         8.6.1. DNA damage
         8.6.2. Mutation
         8.6.3. Chromosomal effects
    8.7. Carcinogenicity
         8.7.1. Inhalation
         8.7.2. Oral
         8.7.3. Dermal
    8.8. Special studies
         8.8.1. Central nervous system (CNS)
         8.8.2. Effects on electrical activity in the brain
         8.8.3. Effects on neurotransmitters
         8.8.4. Behaviour
         8.8.5. Liver
    8.9. Factors modifying toxicity; toxicity of metabolites
         8.9.1. Effects of combined exposure to toluene and other 
        Benzene and toluene
        Xylene and toluene
         n-Hexane and toluene
        Toluene and other chemicals


    9.1. Acute toxicity

    9.2. Effect of short- and long-term exposure including 
         controlled human studies
         9.2.1. Controlled human studies
         9.2.2. Short- and long-term abuse in the general 
         9.2.3. Epidemiological studies
    9.3. Occupational exposure
         9.3.1. Skin and mucous membranes
         9.3.2. Central nervous system
         9.3.3. Peripheral nervous system
         9.3.4. Blood and haematopoietic system
         9.3.5. Liver and kidney
         9.3.6. Menstruation
         9.3.7. Chromosome damage


    10.1. Evaluation of human health risks
    10.2. Acute and short-term effects on man
    10.3. Evaluation of environmental hazards of toluene





Dr K.S. Channer, Department of Medicine, Bristol Royal Infirmary, 
   Bristol and Weston Health Authority, Bristol, United Kingdom 

Mr M. Greenberg, Office of Research and Development, Environmental 
   Criteria Assistance Office, US Environmental Protection Agency, 
   Research Triangle Park, North Carolina, USA

Dr I. Gut, Institute of Hygiene and Epidemiology, Prague, 
   Czechoslovakia  (Chairman)

Dr J. Mki-Paakkanen, Institute of Occupational Health, Department 
   of Industrial Hygiene and Toxicology, Helsinki, Finland

Dr C. Maltonia, Institute of Oncology and Centre for Tumours, 
   Bologna, Italy

Dr B.O. Osuntokun, Department of Medicine, University of Ibadan, 
   Ibadan, Nigeria

Dr S.S. Pawar, Department of Chemistry, Marathwada University,
   Aurangabad, Maharashtra, India  (Vice-Chairman)

Dr Y. Takeuchi, Department of Hygiene, Nagoya University School of 
   Medicine, Showa-Ku, Nagoya, Japan

Dr GY. Ungvary, Toxicology Section, National Institute of 
   Occupational Health, Budapest, Hungary

Dr G.D. Veith, Environmental Research Laboratory, US Environmental 
   Protection Agency, Duluth, Minnesota, USA

 Representatives from Other Organizations

Dr J. Wilbourn, International Agency for Research on Cancer, Lyons, 


Dr H.W. de Koning, Environmental Hazards and Food Protection, World 
   Health Organization, Geneva, Switzerland

Dr M. Mercier, International Programme on Chemical Safety, World 
   Health Organization, Geneva, Switzerland

Dr L.A. Moustafa, International Programme on Chemical Safety,
   Interregional Research Unit, Research Triangle Park, North
   Carolina, USA  (Secretary)

Ms F. Ouane, International Register of Potentially Toxic Chemicals, 
   Geneva, Switzerland

a  Invited, but unable to attend.

 Secretariat (contd.)                                              

Dr C. Xintaras, Office of Occupational Health, World Health
   Organization, Geneva, Switzerland


Dr A. Berlin, Commission of the European Communities, Luxembourg, 

Dr M.-A. Boillat, Department de l'Intrieur et de la Sant 
   publique, Institut Universitaire de Medecine du Travail et 
   d'Hygine industrielle, Lausanne, Switzerland


    Every effort has been made to present information in the 
criteria documents as accurately as possible without unduly 
delaying their publication.  In the interest of all users of the 
environmental health criteria documents, readers are kindly 
requested to communicate any errors that may have occurred to the 
Manager of the International Programme on Chemical Safety, World 
Health Organization, Geneva, Switzerland, in order that they may be 
included in corrigenda, which will appear in subsequent volumes. 

                      *    *    *

    A detailed data profile and a legal file can be obtained from 
the International Register of Potentially Toxic Chemicals, Palais 
des Nations, 1211 Geneva 10, Switzerland (Telephone no. 988400 - 


    The WHO Task Group on the Environmental Health Criteria for 
Toluene met in Geneva from 3 to 7 September 1984.  Dr M. Mercier, 
Manager, IPCS, opened the meeting and welcomed the participants on 
behalf of the heads of the three IPCS co-sponsoring organizations 
(UNEP/ILO/WHO).  The Group reviewed and revised the draft criteria 
document for toluene and made an evaluation of the risks for human 
health and the environment from exposure to toluene. 

was responsible for the preparation of the first draft, and 
DR G.J. VAN ESCH, of Bilthoven, The Netherlands, was responsible 
for the final technical editing. 

    The efforts of all who helped in the preparation and 
finalization of the document are gratefully acknowledged. 

                               * * *

    Partial financial support for the publication of this criteria 
document was kindly provided by the United States Department of 
Health and Human Services, through a contract from the National 
Institute of Environmental Health Sciences, Research Triangle Park, 
North Carolina, USA - a WHO Collaborating Centre for Environmental 
Health Effects.  The United Kingdom Department of Health and Social 
Security generously supported the costs of printing. 


1.1.  Summary

1.1.1.  Identity and analytical methods

    Toluene is the common name for methylbenzene.  It is a clear, 
colourless liquid that is volatile (vapour pressure of 3.82 kPa), 
flammable, and explosive in air.  The technical product may contain 
small amounts of benzene.  Toluene will not react with dilute acids 
or bases and is not corrosive.  In the atmosphere, it reacts 
rapidly with hydroxyl radicals to form a variety of oxidation 

    Adequate analytical methods have been developed to measure 
toluene in air, water, biological tissues and fluids, and food 
products, using gas chromatography with conventional flame 
ionization detectors.  The detection limit for toluene depends on 
sampling procedures and matrices, but is of the order of 1 g/m3 or 
1 g/kg or even lower. 

1.1.2.  Production, uses, and sources of exposure

    Toluene is a commercially-important intermediate chemical 
produced throughout the world in enormous quantities (0.5 -1 x 107 
tonnes).  It is produced both in the isolated form and as a 
component of mixtures.  Toluene produced in the form of a mixture 
is used to back-blend gasoline.  Isolated toluene, on the other 
hand, is used in:  (a) the production of other chemicals; (b) as a 
solvent carrier in paints, thinners, adhesives, inks, and 
pharmaceutical products; and (c) as an additive in cosmetic 
products.  Purified toluene usually contains less than 0.01% 
benzene, but the industrial grade may contain up to 25% benzene. 

    The primary man-made sources of toluene released into the 
environment are: 

    (a) inadvertent sources (65%), i.e., emission from motor
        vehicles and aircraft exhaust, and losses during
        gasoline marketing activities, spills, and cigarette

    (b) processes in which toluene is used (33%); and

    (c) toluene production (2%).

    The significance of each of these sources is expected to vary 
widely from country to country.  On the basis of available data and 
estimates, 86% of the toluene produced is eventually released into 
the biosphere (predominantly the troposphere).  The life-time of 
toluene ranges from several days to several months. 

    In urban areas, a toluene level in ambient air of 0.0001 - 
0.204 mg/m3 has been detected.  Background levels monitored at 
sites throughout the world indicate that the general population is 

exposed to trace levels (0.00075 mg toluene/m3).  Toluene has been 
detected in drinking-water (0 - 0.027 mg/litre), well water (0.005 
- 0.1 mg/litre), and in raw water (0.001 - 0.015 mg/litre). 

    The general population is exposed to toluene mainly through 
inhalation of vapour in ambient air, cigarette smoking, and, to a 
minor extent, by ingestion of food or water contaminated with 

    Certain groups of individuals are exposed to high levels of 
toluene occupationally.  Permissible levels of occupational 
exposure established in various countries range from 200 to 
750 mg/m3 as a time-weighted average (TWA) for an 8-h day and a 
40-h week.  A maximum allowable concentration (MAC) of 50 - 100 
mg/m3 has been adopted by other countries. 

    A special group exposed to toluene includes individuals who 
intentionally abuse solvent mixtures containing toluene (e.g., 
"glue-sniffers") and those who are exposed to toluene accidentally.  
Solvent abuse is a world-wide problem, and long-term abusers are 
routinely exposed to concentrations exceeding 3750 mg/m3.

1.1.3.  Kinetics, biotransformation, and biological monitoring

    Studies on laboratory animals and human beings have shown that 
toluene is readily absorbed from the respiratory tract with an 
uptake of 40 - 60% in human beings.  Liquid toluene is also rapidly 
absorbed through the skin (14 - 23 mg/cm2 per h), but absorption 
from the gastrointestinal tract appears to be slower. 

    Following absorption, toluene is rapidly distributed, with 
highest levels observed in adipose tissue followed by bone marrow, 
adrenals, kidneys, liver, brain, and blood.  A calculated 
brain/blood ratio of 1.56 was reported in rats exposed via 
inhalation for 3 h.  Controlled studies on volunteers revealed that 
the higher the relative uptake of toluene the lower the alveolar 
concentration of the solvent.  The relationship between arterial 
blood and alveolar air concentration was linear and closely 
correlated.  After exposure at rest for 30 min to 300 mg 
toluene/m3, the relative uptake averaged 52%, the alveolar 
concentration was 28% of the inspired air concentration, and the 
arterial concentration mounted to 0.7 mg/litre of blood.  Thus, by 
measuring the toluene concentration in alveolar air during 
exposure, it is possible to estimate the arterial blood 

    Some 60 - 75% of absorbed toluene is metabolized to benzoic 
acid by the microsomal mixed-function oxidase system, with 
subsequent conjugation with glycine to form hippuric acid.  It is 
eliminated in this form through the kidneys.  About 10 - 20% of the 
absorbed toluene is excreted as benzoyl glucuronide.  Small amounts 
of toluene undergo ring hydroxylation to form  o-,  m-, and  p-cresol, 
which are excreted in the urine as sulfate or glucuronide 
conjugates.  A proportion of the absorbed toluene (20 - 40%) is 
eliminated unchanged in expired air.  After a single exposure, the 

elimination of toluene and its metabolites is almost complete in 
24 h.  The half-life of toluene in subcutaneous adipose tissue has 
been estimated to be between 0.5 and 2.7 days. 

    Analysis of expired air and/or blood during exposure reflects 
current intake.  The determination of the average hippuric acid 
concentration in urine collected at the end of the workshift 
appears to be the most practical method of evaluating the overall 
occupational exposure of workers to toluene levels of more than 
375 mg/m3 (100 ppm).  An average level of hippuric acid of less 
than 2 g/litre (specific gravity = 1016) or per g creatinine 
suggests that the atmosphere was probably contaminated by less than 
375 mg/m3.  The  o-cresol assay in urine should be further
investigated for determining exposures to low levels of toluene. 

1.1.4.  Effects on experimental animals

    Acute inhalation data indicate that the species sensitivity 
decreases as follows:  rabbit, guinea-pig, mouse, and rat.  
Inhalation LC50 values have been reported in the range of 
approximately 20 0000 - 26 000 mg/m3 for mice and approximately 
45 000 mg/m3 for rats.  The oral LD50 in the rat is between 2.6 and 
7.5 g/kg body weight, depending on the strain, age, and differences 
in sex.  Toluene is a slight dermal and a moderate eye irritant in 
animals and man.  Acute dermal toxicity appears to be quite low 
(rabbit:  LD50 14.1 ml/kg body weight). 

    In short- and long-term inhalation studies on experimental 
animals, no effect was seen with exposure to 375 mg toluene/m3 for 
24 months.  In oral studies, administration of 590 mg toluene/kg 
body weight, per day, for 6 months did not produce any effects.  At 
low dose levels, in rats, the target organs seem to be the kidneys 
and testes, while at high dose levels, liver changes and effects on 
the central nervous system are predominantly seen.  Reversible 
functional and/or morphological changes are dose-related. 

    Numerous studies using pure toluene have failed to demonstrate 
haematopoietic effects.  Toluene does not cause permanent 
pathological effects on the heart, but high doses (> 4000 mg/m3) 
may induce cardiac arrhythmia. 

    Contradictory results are reported in the existing literature 
regarding the pathological effects of toluene on the respiratory 
and urinary tracts of dogs, guinea-pigs, and rats. 

    Toluene primarily affects the central nervous system (CNS).  A 
biphasic response to toluene exposure, which is typical of a 
narcotic drug, has been found with initial excitability followed by 
a depression in response.  In most studies, behavioural effects 
have been observed with exposures in excess of 1875 mg/m3.  
Progressive narcosis and seizures have been seen at high exposure 
levels (15 000 mg/m3, 4 h/day).  Initial depression of cortical 
activity resulting in coma was induced in cats at 26 250 mg/m3, 10 
min/day, for 40 days.  Exposure at 7500 mg/m3, for 24 weeks, caused 
interruption of the sleep cycle in the rat.  Toluene has not been 
shown to cause peripheral neuropathy. 

    Skin-painting studies on mice, where toluene was used as a 
vehicle control, and one inhalation study on rats exposed to pure 
toluene (112.5 - 1125 mg/m3, 6 h/day, 5 days/week, for 24 months) 
did not reveal any carcinogenic effects. 

    The results of studies on the mutagenic effects of toluene in 
microbial, mammalian-cell, or whole-organism test systems have, in 
most cases, been negative.  Positive findings were reported in 5 
studies using  in vivo mammalian assays.  In these studies, 
however, the purity of the toluene used was not always stated. 

    Toluene does not appear to be teratogenic in mice, rats, or 
rabbits, but embryotoxic/fetotoxic effects were seen in rats at a 
dose that was non-toxic for the dams exposed to toluene 
concentrations of 1000 mg/m3 air, and spontaneous abortion occurred 
in rabbits exposed to 1000 mg/m3 during the entire period of 
organogenesis.  However, orally administered toluene was reported 
to be teratogenic in CD-1 mice.  Exposure to 870 mg/kg body weight 
on days 6 - 15 significantly increased the incidence of cleft 
palate.  A level of 430 mg/kg body weight was without effect. 

    The ability of toluene to interfere with biotransformation and 
alter the toxic effects of several solvents has been documented by 
several investigators.  For example, toluene decreased  n-hexane 
metabolism and neurotoxicity, and also benzene metabolism and 
effects on the haematopoietic system.  However, it increased the 
hepatotoxicity of carbon tetrachloride. 

1.1.5.  Effects on human beings

    Toxicity studies on human beings have primarily involved 
individuals exposed to toluene via inhalation either in 
experimental or occupational settings or during episodes of 
intentional abuse of solvent mixtures containing toluene. 

    The primary effect of toluene is on the central nervous system 
(CNS).  The effect may be depressant or excitatory, with euphoria 
in the induction phase followed by disorientation, tremulousness, 
mood lability, tinnitus, diplopia, hallucinations, dysarthria, 
ataxia, convulsions, and coma. 

    Acute controlled and occupational exposures to toluene in the 
range of 750 - 5625 mg/m3 (200 - 1500 ppm) caused dose-related CNS 
effects.  Acute exposure to high levels of toluene (e.g., 37 500 
mg/m3 or higher for a few min) during industrial accidents was 
characterized by initial CNS excitative effects (e.g., 
exhilaration, euphoria, hallucinations) followed by progressive 
impairment of consciousness, eventually resulting in seizures and 

    Single, short-term exposures to toluene (750 mg/m3 for 8 h) 
have reportedly caused transient eye and respiratory tract 
irritation with lachrymation at 1500 mg/m3. 

    Repeated occupational exposures to toluene over a period of 
years at levels of 750 - 1500 mg/m3 (200 - 400 ppm) have resulted 
in some evidence of neurological effects. 

    Toluene-containing mixtures have been implicated in the 
causation of peripheral neuropathy but, in most cases, known 
neurotoxins such as  n-hexane or methylethylketone have been 
present, and the role of toluene is not clear. 

    Irreversible neurological sequelae, such as encephalopathy, 
optic atrophy, and equilibrium disorders have been described in 
adult chronic toluene abusers.  Toluene inhalation was reported to 
be an important cause of encephalopathy in children (aged 8 - 14 
years) and may lead to permanent neurological damage. 

    Transient abnormalities of hepatic enzyme activities have been 
found in abusers of toluene mixtures, but significant permanent 
hepatic damage does not occur.  Occasional reports of renal damage 
in glue-sniffers have appeared, characterized by a form of distal 
tubular acidosis.  There is no evidence that toluene damages the 
haematopoietic tissues or the heart. 

    No adequate epidemiological studies on human beings exist. 

    The results of 3 studies indicated an increased frequency of 
chromosome damage in the cultured blood lymphocytes of rotogravure 
workers occupationally exposed to toluene, but, in 3 other similar 
studies, no effects were found.  However, in most cases, the number 
of subjects studied was small.  Moreover, the extent of exposure 
differed among the 6 studies and exposure to other, possibly 
mutagenic agents, such as benzene and tobacco smoke, had usually 
not been adequately considered. 

    Data on human beings are not adequate for the evaluation of the 
teratogenicity of toluene.  Subjective complaints of dysmenorrhoea 
and disturbances in menstruation have been reported in female 
workers exposed concurrently to toluene, benzene, xylene, and other 
unspecified solvents.  The limited data available do not, however, 
specifically associate occupational exposure to toluene with 
reproductive effects in female and male workers. 

1.1.6.  Effects on aquatic and terrestrial organisms in the

    Available data indicate that the production and use of toluene 
do not adversely affect aquatic and terrestrial ecosystems.  The 
acute toxicity levels for fish and aquatic invertebrates (LC50) 
range from 3.7 to 1180 mg/litre, but most organisms show an LC50 in 
the order of 15 - 30 mg/litre.  Photosynthesis and respiration by 
marine phyto-plankton communities are inhibited by toluene at 
34 mg/litre.  No adverse effects were seen in long-term studies on 
3 species of freshwater and marine fish at concentrations ranging 
from approximately 1.4 to 7.7 mg/litre.  Spawning fish may detect 
and avoid waters containing toluene at 2 mg/litre.  The effects of 
sublethal exposure to toluene are reversible, and toluene residues 
do not accumulate in fish or aquatic food-chains. 

    Toluene concentrations in industrial waste waters were reported 
to range from 0.010 to 20 mg/litre.  The biodegradability of 
toluene by microorganisms ranged from 63 to 86% after up to 20 

    The adverse impact of toluene spills will be limited to the 
immediate spill area, because of its fast degradation under aerobic 

    The volatility and biodegradability of toluene suggest that it 
would have a short half-life on soil surfaces. 

    Photolysis of toluene in the air, which also contains other 
pollutants such as nitrous oxides and ozone, may contribute to smog 

1.2.  Conclusions and Recommendations

1.2.1.  Conclusions

    The available data indicate that exposure of the general 
population and environment to toluene does not present any health 
and/or environmental hazards, at present.  However, long-term 
occupational exposure and solvent abuse may be associated with 
permanent pathological changes and further investigations are 

1.2.2.  Recommendations

    (a)  Environmental monitoring data

    Data are needed on the magnitude, frequency, duration, and 
extent of exposure(s) to toluene in the general population. 

    (b)  Biological monitoring data

        (i)  Further investigations are required on the possibility 
             of using determinations of toluene concentrations in
             exhaled air and blood in the evaluation of the 
             integrated exposure during the previous 24 h; and

       (ii)  There is a need for a comparative study of the 
             validity of hippuric acid and cresol determinations in

    (c)  Human reproductive effects

    Information on the possible reproductive effects of toluene in 
males and females is not adequate.  Research in this field is 
therefore recommended.  The similarity of the effects reported on 
human fetal growth and those observed in animals draws attention to 
the need for further studies on women exposed to toluene.  Both 
experimental animal and human case studies give information on the 
supposed role of toluene in causing teratogenic effects through 
toxicokinetic or toxicodynamic interaction.  These reports should 
stimulate further research on laboratory animals. 

    (d)  Respiratory defence mechanisms

    There is a need for further evaluation of the potential effects 
of volatile organic substances such as toluene on respiratory 
defence mechanisms. 

    (e)  Neurobehavioural toxicity

        (i)  There is a paucity of data regarding the behavioural 
             and neurological effects of pure toluene at low levels 
             (i.e., below 375 - 750 mg/m3).  In particular, the 
             extent and nature (including permanance) of neuro- 
             behavioural effects and the threshold of exposure to
             toluene, below which there are no-observed-adverse
             effects, need to be determined to properly evaluate 
             the potential risks.

       (ii)  There is a need for further research to define and
             refine the tests that are most relevant for neuro-
             psychological investigations.

       (iii) Toluene inhalation is a cause of encephalopathy in 
             children and may lead to permanent neurological 
             damage.  Diagnosis is most important if further damage 
             due to continued abuse is to be prevented, and 
             sensitive assays should be further investigated (e.g., 
             toluene levels in expired air and in blood).

    (f) Human studies on the significance of the reported
hepatomegaly and induction and inhibition of microsomal enzyme 
systems for the detoxification or metabolic activation of other 
chemicals are indicated. 


2.1.  Identity

    Toluene is a common name for the chemical formed when one 
hydrogen atom of the benzene molecule is replaced with a methyl 

Chemical Structure

Chemical formula:             C7H8

Relative molecular mass:      92.13

CAS chemical name:            phenylmethane

CAS registry number:          108-88-3

RTECS registry number:        XS 5250000 (Tatken & Lewis, 1983)

Common synonyms:              methylbenzene

Common trade names:           Methacide, Methylbenzol, Toluol

    Technical products in which toluene is the principal ingredient 
are commonly formed from petroleum in which petroleum fractions 
containing methylcyclohexane are catalytically dehydrogenated.  The 
purification of toluene products may include azeotropic 
distillation with paraffinic hydrocarbons, naphthenic hydrocarbons, 
or alcohols.  Because of the variety of methods used to produce 
toluene, the range of impurities varies widely.  Benzene is an 
important common impurity in technical grades of toluene.  Highly-
purified toluene (reagent grade and nitration grade) contains less 
than 0.01% benzene, while industrial grade and 90/120 grade toluene 
contain a significant quantity of benzene.  The 90/120 grade 
contains as much as 25% (US NIOSH, 1973). 

2.2.  Physical and Chemical Properties 

    Toluene is a volatile liquid that is flammable and explosive.  
Some physical and chemical properties of toluene under standard 
conditions are presented in Table 1. 

Table 1.  Physical and chemical properties of toluene
Melting point                     -95 C          Weast (1977)

Boiling point (760 mm Hg)         110.6 C        Weast (1977)

Density (g/ml, 20 C)             0.8669          Weast (1977)

Specific gravity (20 C)          0.8623          Weast (1977)

Vapour pressure (25 C)           28.7 mm Hg      Weast (1977)

Vapour density (air = 1)          3.20            Weast (1977)

Log partition coefficient         2.69            Tute (1971)

Surface tension (20 C)           28.53 dynes/cm  Walker (1976)

Liquid viscosity (20 C)          0.6 cp          Walker (1976)

Refractive index (20 C)          1.4969          Cier (1969)

Percent in saturated air          3.94            Walker (1976)
(760 mm, 26 C)

Density of saturated air-vapour   1.09            Walker (1976)
mixture (760 mm; air = 1, 26 C)

Flammable limits (percent         1.17 - 7.10     Walker (1976)
by volume in air)

Flash point (closed cup)          4.4 C          Walker (1976)

Autoignition temperature          552 C          Walker (1976)

Solubility in:

 Fresh water (25 C)              535 mg/litre    Sutton & Calder
 Sea water (25 C)                380 mg/litre    (1975)

Saturation in:

 Air (25 C)                      112 g/m3        Sutton & Calder

2.3.  Organoleptic Properties

    Toluene is a clear, colourless liquid at ambient temperature 
and has a benzene-like odour.  The odour threshold for toluene in 
air has been determined to be 9.4 mg/m3.  The sensory threshold 
(the concentration at which volunteers, when exposed for 15-min 
inhalation periods, had olfactory fatigue, mild eye irritation, 

"tasting something", "light-headed", and headache, but, neverthe-
less, were willing to work for 8 h) was 700 mg/m3 (section 9.1.2.) 
(Carpenter et al., 1976a,b). 

2.4.  Conversion Factors

    In air (1 atm), at 25 C:  1 ppm (V/V) = 3.75 mg/m3 = 0.0407 

                               1 mg/m3 = 0.266 ppm (Katz, 1969)

2.5.  Analytical Methods

    Many methods have been used to determine the concentration of 
toluene in air, water, and soil. 

    Toluene exhibits characteristic UV, IR, NMR, and mass spectra, 
which are useful in many specific control and analytical problems.  
Analytical methods have included colorimetry, involving nitration 
followed by reaction with various ketones, spectrophotometry, 
direct estimation by means of colorimetric indicator tubes, and gas 
chromatography (Maffett et al., 1956; Dambrauskas & Cook, 1963; 
Whitman & Johnston, 1964; Williams, 1965; Kolekovsky, 1967; Reid, 
1968).  Gas chromatography (GC) offers the greatest specificity and 
sensitivity of the numerous methods of analysis.  Both packed 
columns using silica gel and capillary columns have been used to 
separate toluene from interfering substances (Fett et al., 1968).  
Photoionization detectors provide better selectivity and 
sensitivity for toluene measurements than flame ionization 
detectors (Federal Register, 1979).  Nevertheless, the flame 
ionization detector is the most common detector used in volatile 
hydrocarbon analyses; the use of gas chromatography interfaced with 
computerized mass spectrometry has been developed for samples 
containing toluene (Jermini et al., 1976; Lingg et al., 1977; Dowty 
et al., 1979; Rasmussen & Khalil, 1983).  The detection limit for 
toluene in the environment depends on sampling procedures and 
preparations, but is low, of the order of 1 g/m3 or 1 g/litre or 
even less. 

2.5.1.  Sampling procedures  Air

    When concentrations of toluene are large enough, air samples 
can be collected as grab samples using aluminized plastic bags, 
Tedler bags, or glass containers (Neligan et al., 1965; Lonneman et 
al., 1968; Altshuller et al., 1971; Pilar & Graydon, 1973; 
Schneider et al., 1978).  When smaller concentrations of toluene 
are to be measured, it is quantitatively adsorbed on various large 
surface area materials, such as charcoal, through which the air is 
passed (Reid & Haplin, 1968; White et al., 1970).  Tenax GC(R), 
Porapak Q(R), and a variety of molecular sieves have been used as 
sorbents for toluene.  The sorbent is heated and the enriched 
toluene sample is flushed with an inert gas directly into a high-
resolution glass or fused capillary tube for characterization and 

measurement by gas chromatography/mass spectrometry/computer 
techniques (Krost et al., 1982).  Passive air sampling using 
charcoal as a sorbent has been designed specifically for the long-
term sampling of indoor and ambient air (Seifert & Abraham, 1982, 
1983).  If equipment for the thermal desorption of toluene from 
sorbents is not available, toluene can be extracted from the 
sorbent using carbon disulfide (Reid & Halpin, 1968; Fraser & 
Rappaport, 1976; Esposito & Jacobb, 1977; Fracchia et al., 1977). 

    The detection limit for toluene in air depends on the volume of 
air passed through the sorbent, but is approximately 0.1 g/m3 
(Holzer et al., l977).  For the passive collection methods, 
detection limits of approximately 1 g/m3 are obtained for ambient 
air monitoring (Hester & Meyer, 1979). 

    Cigarette smoke, a source of toluene for human beings, requires 
a special sampling method (Dalhamn et al., 1968b).  Water

    Other methods, apart from direct aqueous injection and 
dichloromethane extraction, have been used to determine toluene in 
industrial waste waters (Jungclaus et al., 1976, 1978).  The three 
most commonly used methods for the determination of toluene in 
aqueous media are the purge and trap, headspace, and sorption on 
solid sorbents (including different variations of these methods, 
concerning the temperature of the purging system, the stripping 
rate, the duration of stripping, etc). 

    Purge and trap

    The most widely used method for the determination of toluene in 
drinking-water, waste water, and rain-water is the purge and trap 
method (Bertsch et al., 1975; Grob & Zurcher, 1976; Lingg et al., 
1977; Bellar & Lichtenberg, 1979; Dowty et al., 1979).  The 
detection limit is generally 1 g/litre. 

    Headspace analysis

    This method has not been applied frequently for the analysis of 
environmental samples; however, the method was standardized with 
water samples spiked with model compounds.  Toluene concentrations 
of the order of 0.1 - 1.0 g/litre can be determined by this method 
(Vitenberg et al., 1977; Drozd et al., 1978). 

    Sorption on solid sorbents

    This method, which is rarely used, is used for monitoring 
toluene in drinking-water (Ryan & Fritz, 1978).  Soils and sediments

    The purge and trap method has been modified for the 
determination of volatile organic compounds in soil and sediment 
samples.  In general, the recovery of toluene from these samples is 
low.  A detection limit of approximately 0.2 g/kg can be attained. 

2.5.2.  Biological monitoring of toluene exposure

    A number of biological tests have been investigated for 
evaluating human exposure to toluene:  toluene in expired air 
and/or in blood and human breast milk; hippuric acid in urine 
and/or blood; and benzoic acid, and  o-cresol in urine (section 
7.4).  The time of sampling of biological material is very critical 
in all cases, because of the rapid metabolism of toluene.  In 
addition, the possibility that toluene metabolism might be modified 
by the presence of other chemicals must be considered (Waldron et 
al., 1983).  Blood, expired air, body fluids, and tissues

    Toluene in blood has been determined by the GC analysis of 
headspace samples (detection limit:  10 g/litre) (Premel-Cabic et 
al., 1974; Anthony et al., 1978; Radzikowska-Kintzi & Jakubowski, 
1981; Oliver, 1982).  A direct injection method applicable to GC in 
the determination of toluene in whole blood has been reported by 
Aikawa et al. (1982). 

    Cocheo et al. (1982) have developed a purge and trap method for 
the detection of toluene in blood in which the detection limit is 
estimated to be less than 7.5 g/litre.  Bellanca et al. (1982) 
described a similar method using GC-FID for detecting toluene and 
other organic compounds in tissues and body fluids. 

    The concentration of toluene in alveolar air samples, collected 
during exposure, is related to the intensity of the exposure 
(Astrand et al., 1972; Brugnone et al., 1976, 1980; Carlsson, 
1982,a,b; Astrand, 1983). 

    Under steady-state conditions, a constant relationship between 
the uptake rate of toluene and toluene concentrations in venous 
blood has been observed.  Under non-steady-state conditions, 
however, no simple relation exists between uptake and the venous 
blood concentration of toluene. 

    Direct measurements confirmed a previous hypothesis that the 
concentration of toluene in arterial blood during and after 
exposure could be estimated from concentrations in alveolar air. 

    While there is no unanimity, it can be concluded that analysis 
of expired air and/or blood reflects actual intake and may be a 
useful indicator of exposure to toluene (King et al., 1981).  Urine


    Trace amounts of absorbed toluene, excreted in the urine, can 
be analysed by one of the methods outlined in section 

    Metabolites of toluene

    The major metabolite, hippuric acid, is eliminated in the 
urine.  It can be determined by a number of methods including 
colorimetry, UV spectrometry, and thin-layer chromatography (TLC) 
(Umberger & Fiorese, 1963; Pagnotto & Lieberman, 1967; Bieniek & 
Wilczok, 1981; Bieniek et al., 1982).  The sensitivity of the TLC 
method is 6 mg hippuric acid/litre urine.  Another sensitive method 
for estimating hippuric acid in urine was developed by Caperos & 
Fernandez (1977).  In this method, the hippuric acid in urine is 
extracted, methylated, and quantified by GC-FID.  The sensitivity 
of the method was determined to be 5 mg/litre urine. 

    Bergert et al. (1982), Hansen & Dossing (1982), and Poggi et 
al. (1982) determined the levels of urinary-hippuric acid and other 
metabolites of toluene by a high-performance liquid chromatographic 
(HPLC) method. 

    Hippuric acid is a normal constituent of urine, originating 
mainly from food containing benzoic acid or benzoates.  For the 
occurrence of hippuric acid in the urine of unexposed compared with 
that in toluene-exposed persons, see Table 6.  The mean urinary-
hippuric acid excretion is higher in females than in males. 

    Unexposed persons excreted a mean concentration of < 1.0 g 
hippuric acid/litre, while workers exposed to toluene excreted 
hippuric acid concentrations that were at least 2 - 6 times higher, 
depending on exposure levels. 

    Taking into account the levels of hippuric acid in urine 
observed for unexposed persons and the individual variation in 
these levels, separation between exposed and unexposed workers 
cannot be done on an individual basis.  On a group basis, however, 
the methods are sufficiently sensitive. 

    At present, the determination of the average hippuric acid 
concentration in urine collected at the end of workshift appears 
to be the most practical method for evaluating overall occupational 
exposure to toluene levels exceeding 375 mg/m3 air.  A group 
average of less than 2 g/litre (specific gravity = 1.016) or 
g creatinine suggests that the atmosphere was probably contaminated 
by less than 375 mg/m3 (100 ppm) toluene.  The possibility of using 
the determination of toluene in expired air and/or blood and 
 o-cresol in urine, particularly for exposure to low levels of 
toluene, should be further investigated. 

    Sufficient data are not available to give an opinion about the 
measurement of other metabolites such as benzoic acid or  o-cresol
in urine to estimate exposure to toluene in the air.  Human breast milk

    Toluene in human breast milk can be determined by the purge and 
trap method, followed by thermal desorption and capillary GC-MS 
analysis (Pellizzari et al., 1982). 

2.5.3.  Foods and food containers

    A headspace GC technique for quantification, and a GC-MS 
technique for confirmation, were used to determine trace amounts of 
toluene in plastic containers.  Toluene present in the g/kg range 
can be determined by this method (Hollifield et al., 1980). 

2.5.4.  Detection of marketed toluene purity

    Toluene is marketed in different purity grades.  The purity as 
well as the number, concentrations, and identity of other 
components can be determined by HPLC, GC, and GC-FID methods (Fett 
et al., 1968; Grizzle & Thomson, 1982).  The toluene content of 
high purity samples can be accurately measured by determining the 
freezing point (Hoff, 1983). 


3.1.  Natural Occurrence

    Some types of vegetation are natural sources of toluene in the 
environment (US NRC, 1980). 

3.2.  Man-Made Sources

3.2.1.  Production levels, processes, and uses  Production

    Production of toluene as a by-product of the carbonization of 
coal was the major source of toluene during the latter part of the 
19th century.  Since the second World War, the manufacture of 
toluene from petroleum sources has steadily increased, and that 
from coke and coal-tar products has decreased.  At present, toluene 
is principally produced (87%) by the catalytic reforming of 
refinery streams (Hoff, 1983).  An additional 9% is separated from 
pyrolysis gasoline produced in steam crackers during the 
manufacture of ethylene and propylene.  The other 4% originates as 
a by-product of other processes.  World production figures

    World production figures for toluene are summarized in Table 2, 
according to different geographical areas, for the years 1979 - 81.  
From Table 2, it is clear that, in 1981, the world production of 
toluene was more than 10 000 metric tonnes.  Manufacturing processes

    Loss into the environment during normal production and handling

    The three primary man-made sources of toluene released into the 
environment are: 

    (a) production sources; toluene can be released into the
        environment during its production as process losses,
        fugitive emissions, and storage losses (approximately

    (b) toluene when used as a solvent; toluene is released
        into the ambient air, as a result of evaporation
        (approximately 34%);

    (c) inadvertent sources; the emission of toluene through
        its use in gasoline can occur from three distinct
        sources including:  evaporative losses from automobile 
        service stations; evaporation from marketing
        activities (handling and transfer of bulk
        quantities); and emissions from motor vehicles and
        aircraft (approximately 65%).

Table 2.  World-wide annual toluene production 
in metric tonnes
Geographical area   Total toluene production
                    1979a  1980a   1981b
Africa                             43

Canada              941

Europe (western)    1179   913     1666

Israel                             63
Japan               962            > 2193

Oceania                            46

South America                      382

Thailand            21c            16c

USA                 3273   5104b   6234

USSR                               > 1179d

a From:  Chemical Industry (1980).
b From:  World Petrochemicals (1982) (as cited 
  by Hoff, 1983).
c From IRPTC (1984) (special inquiry).
d Includes capacity data for three USSR toluene 
  plants, which may not have been completed.

    Other inadvertent sources of toluene emissions into the 
environment include other manufacturing processes, by-product 
formation, and cigarette smoke (Anderson et al., 1980).  There is 
substantial contamination of the environment from seepage in the 
oceans, on land, and from the weathering of exposed coal strata. 

3.2.2.  Uses

    Toluene is of great importance as a chemical intermediate and 

    Up to 95% of the annually-produced toluene in the USA is 
blended directly into the gasoline pool as a component to increase 
the pyrolysis of gasoline (to increase the octane number) (Hoff, 

    Isolated toluene is much more important as a solvent than 
either benzene or xylene.  Approximately two-thirds of its use as a 
solvent is in paints, inks, thinners, coatings, adhesives, 
degreasers, and other formulated products requiring a solvent 
carrier (Kumai et al., 1983; Inoue et al., 1983). 

    Furthermore, toluene is used as a raw material in the organic 
synthesis of a large number of chemicals such as toluene 
diisocyanate, benzoic acid, benzaldehyde, xylene, toluene-
sulfonylchloride (the  o-isomer is converted to saccharin), other 
derivatives of toluene used as dye intermediates, resin modifiers, 
germicides, etc.  Lastly, toluene is used as a denaturant in 
specially-denatured alcohol. 


4.1.  Transport and Distribution Between Media

4.1.1.  Air

    Toluene released into the environment mainly enters the 
atmosphere (because of its high vapour pressure) and surface 
waters.  Transport from the water (low solubility) to the 
atmosphere is rapid.  MacKay & Wolkoff (1973) and Mackay & 
Leiononen (1975) reported the calculated evaporation half-life for 
toluene from 1 m deep water to be approximately 5 h; in a state of 
equilibrium, only 26% of toluene would be present in the gaseous 
phase above sea water (US NRC, 1980). 

    Atmospheric oxidation of toluene removes 50% of the compound in 
less than 2 days (half-life was estimated to be 12.8 h).  Because 
of this rapid removal, toluene will most probably not remain in the 
atmosphere long enough to be removed by air to surface transfer 
mechanisms, such as dry deposition or precipitation (US EPA, 1980). 

    Toluene has been detected in rain water at levels of 0.13 - 
0.7 g/litre (Lahmann et al., 1977). 

    Toluene does not absorb radiation at wavelengths longer than 
295 nm.  Although it absorbs insignificant amounts of sunlight in 
the lower atmosphere, a charge-transfer complex between toluene and 
molecular oxygen absorbs radiation of wavelengths up to 350 nm.  
According to Wei & Adelman (1969), it is the photolysis of this 
complex that may be responsible for some of the observed 
photochemical reactions of toluene related to smog production.  
Photolysis of toluene in air that also contains nitrous oxides 
yields ozone, peroxyacetylnitrate, and peroxybenzoylnitrate. 

    Toluene is removed from the atmosphere primarily through free 
radical chain processes, of which reactions with hydroxy radicals 
are the most important processes (Brown et al., 1975; Perry et al., 
1977).  In the atmosphere, there are several free radicals that are 
likely to combine with toluene, including hydroxyl radicals (OH), 
atomic oxygen (O), and peroxy radicals (RO2), where R is an alkyl 
or aryl group, and also ozone (O3).  The tropospheric lifetime of 
toluene at high latitudes during summer has been estimated to be 
about 4 days; in winter, the lifetimes may be of the order of 
months.  At tropical latitudes, the lifetimes are short (days to 
weeks) and do not vary with season.  The average concentrations of 
toluene found in different regions of the world vary between 0 and 
approximately 0.75 g/m3 air (Rasmussen & Khalil, 1983). 

4.1.2.  Water

    Sauer et al. (1978) concluded, from their studies of the 
coastal waters of the Gulf of Mexico, that toluene and other alkyl 
benzenes are present at low levels in the marine environment. 

    The presence of toluene in surface water in the USA has been 
monitored by the US EPA STORET system (US EPA, 1980).  Only 17% of 
all surface waters monitored contained toluene at concentrations 
higher than 10 g/litre.  Factors affecting toluene levels in 
surface water and groundwater include volatilization, solubility, 
and, where groundwater is concerned, degradation and/or adsorption 
of toluene during percolation through soils.  Toluene was detected 
in 85% of the 39 wells tested in 1978.  The toluene concentration 
in these well waters was below 10 g/litre.  Toluene has been 
detected in raw water and in finished water supplies (up to 
19 g/litre) in several communities in the USA (US EPA, 1975a,b, 
1977).  It has been suggested that toluene may be chlorinated 
during the chlorination process of waste water (Carlson et al., 
1975).  However, this could not be confirmed in laboratory 
experiments, and it was concluded that chlorine added to waste 
water would not bind with toluene (US EPA, 1980). 

4.1.3.  Soil

    Toluene probably exists in soils in the adsorbed state.  The 
adsorption of toluene by clay minerals (bentonite and kaolinite) 
was found to follow Freundlich's adsorption isotherm and the 
adsorption capacity increased as the pH value decreased (El-Dib et 
al., 1978).  It can be anticipated, therefore, that a portion of 
toluene in soil will be transferred to air and water.  The part 
that stays in soil may participate in chemical reactions (including 
photochemical reactions) and biological degradation and 

    The results of 2 laboratory experiments (US EPA, 1980; Wilson 
et al., 1981) showed that, about 40 - 80% of toluene applied to the 
surface of sandy soils at 0.9 and 0.2 mg/litre, respectively, 
volatilized into the air (estimated half-life of 4.9 h).  The 
volatilization rate is, for instance, dependent on the nature and 
organic content of the soil, and the laboratory studies showed that 
toluene moved through sandy soils with low organic carbon content.  
The transfer of toluene from soil to groundwaters is of importance 
with regard to the contamination of these sources of drinking-

4.1.4.  Entry into the food chain

    In 59 samples of edible fish (not specified), 95% showed 
toluene concentrations of less than 1 mg/kg (w/w) (US EPA, 1980).  
Toluene was also detected in fish caught from polluted waters in 
the proximity of petroleum and petrochemical plants in Japan (Ogata 
& Miyake, 1973, 1978). 

4.2.  Biotransformation

4.2.1.  Biodegradation

    Toluene is easily degraded by activated sludge in sewage plants 
(Malaney & McKinney, 1966; Matsui et al., 1975) and by bacteria in 
estuarine and marine environments (Walker & Colwell, 1976; Tabak et 

al., 1981).  It is also biodegraded by a variety of soil 
microorganisms using toluene (up to 0.1%) as the sole source of 
carbon (Tausson, 1929; Kaplan & Hartenstein, 1979; Wilson et al., 

    Biodegradation of toluene accounted for 0.31, 4.81, 0.36, 0.09, 
and 18.47% of the total toluene loss in oligotrophic lakes, 
eutrophic lakes, clean rivers, turbid rivers, and ponds, 
respectively.  Using the standard dilution method and a settled 
domestic filtered waste-water effluent as the seed to determine the 
biochemical oxygen demand, the biodegradability of toluene (percent 
bio-oxidized) ranged from 63% to 86% after up to 20 days (Price et 
al., 1974; Bridi et al., 1979; Davis et al., 1981). 

    The degradation of toluene has also been studied in mixed 
cultures of bacteria (predominantly  Pseudomonas).  Chambers et al. 
(1963), using these phenol-adapted bacteria, reported 38% 
degradation of toluene after 180 min.  In another study, Dechev & 
Damyanova (1977) grew sludge cultures using phenol, xylene, or 
toluene as the sole carbon source and found that phenol-adapted 
bacteria proved less able to degrade xylene and toluene, while 
toluene-adapted microorganisms showed greater versatility in their 
ability to oxidize phenol and xylene.  For information on the 
metabolism of toluene by various types of microorganisms, see 
Gibson (1971), Smith & Rosazza (1974), Subramanian et al. (1978), 
and Kaplan & Hartenstein (1979). 

4.2.2.  Bioaccumulation

    The quantities of organic chemicals that accumulate in aquatic 
organisms depends on uptake, excretion, and metabolism (Hansen et 
al., 1978). 

    Bioaccumulation of toluene has not been studied adequately.  
The log octanol/water partition coefficient is 2.69, a value that 
indicates that slight to moderate accumulation takes place. 

    Roubal et al. (1978) did not find any toluene, while higher 
homologues of toluene were present, in the tissues of Coho salmon 
 (Oncorhynchus kisutch).  Berry (1980) detected only small 
quantities of 14C activity in different tissues of bluegills 
 (Lepomis machrochirus).  Mean concentrations of 12.4 mg/kg muscle 
tissue and 1.5 mg/kg liver tissue were found in eels  (Anguilla 
 japonica) kept in sea water containing 16.1 mg toluene/litre 
(Ogata & Miyake, 1978).  They showed that the half-life of toluene 
was 1.4 days.  Berry & Fisher (1979) determined that 14C-toluene in 
4th-instar mosquito larvae was transferred to the bluegill stomach 
and intestine, but that levels of toluene residues in other organs 
and tissues were indistinguishable from those in the controls.  
Consequently, it is unlikely that toluene accumulates in an 
ecosystem food chain. 


5.1.  Environmental Levels

5.1.1.  Air

    The reported concentrations of toluene in air reflect, 
undoubtedly, the regional differences in terms of production, use, 
and emission patterns, the effects of meteorological processes 
affecting transport and fate, sample siting and averaging times, 
and differences in sampling, analysis, and detection.  The toluene 
concentrations in the vicinity of industrial sources of toluene may 
represent a burden for the general population in such areas (Smoyer 
et al., 1971; Mayrsohn, et at., 1976).  Sexton & Westberg (1980) 
carried out an ambient air monitoring programme near an automotive 
painting plant.  Toluene concentrations downwind within 1.6, 6, and 
16.5 km of the plant were 0.600, 0.075, and 0.055 mg/m3, 
respectively.  The background toluene concentration at a distance 
of 1.6 km upwind of the plant was 0.0055 mg/m3. 

    In the period between 1971 and 1980, atmospheric concentrations 
of toluene were estimated in Canada, Europe, and the USA.  The 
average concentrations found varied widely.  In rural areas, the 
levels were low whereas, in cities and airports, very high 
concentrations were found.  The average concentrations ranged from 
0.0005 to 1.31 mg/m3.  The highest level found was 5.5 mg/m3 
(Altshuller et al., 1971; Grob & Grob, 1971; Pilar & Graydon, 1973; 
Leonard et al., 1976; Lahmann et al., 1977; Johansson, 1978; 
Pellizzari, 1979; Arnts & Meeks, 1981; Hsnen et al., 1981; 
Brodzinsky & Singh, 1982; Tsani-Bazaca et al., 1982; Wathne, 1983). 

    Rainwater from a residential area, an airport, and a busy 
traffic intersection in Berlin (FRG) showed toluene concentrations 
of 0.00013, 0.0007, and 0.00025 mg/m3, respectively (Lahmann et 
al., 1977). 

5.1.2.  Water

    Toluene has been detected in the drinking-water supplies of 
several communities.  The average and maximum concentrations of 
toluene in treated Canadian water were reported to be 0.002 
mg/litre and 0.027 mg/litre, respectively, with a frequency of 20% 
during the months of August and September.  The corresponding 
values for the raw water were < 0.001 mg/litre and 0.015 mg/litre, 
respectively.  The frequency of occurrence and the concentration of 
toluene in water showed seasonal variation, the summer-time values 
being higher than the winter-time values (Otsun et al., 1980). 

    In a nation-wide survey of water supplies from 17 cities in the 
USA, 7 were discovered to be contaminated with toluene (0.0008 up 
to 0.011 mg/litre) (US EPA, 1975a,b).  Saunders and colleagues 
(1975) found that the concentration of the various contaminants 
including toluene in tap water fluctuated from week to week, but 
that the chemical composition remained the same. 

    Toluene was detected in well water at 0.005 - 0.1 mg/litre. 

    The concentration of toluene in a variety of industrial 
wastewaters was reported to be in the range of 0.01 up to 
10 mg/litre (Jungclaus et al., 1976; Yamaoka & Tanimoto, 1977; 
Rawlings & Samfield, 1979; US EPA, 1980). 

5.2.  General Population Exposure

    Human exposure to toluene through the inhalation of urban air 
and oral intake is summarized in Table 3.  The air intake estimate 
is based on a breathing rate of 1.2 m3/h for an adult during waking 
hours and 0.4 m3/h during sleep (8 h/day).  The average drinking-
water intake and fish consumption have also been considered.  It 
should be remembered that Table 3 shows estimates of the toluene 
uptake per week by human beings under certain conditions of 
exposure and not the amount observed.  Only 40 - 60% of inhaled 
toluene is absorbed by human organs.  Also, part of the absorbed 
toluene is rapidly excreted from the body (sections 7.1, 7.4). 

    Rasmussen & Khalil (1983) suggested that 0.75 g/m3 could be 
regarded as an upper background level to which all populations are 
exposed.  Inferences from the total air monitoring data base 
(Brodzinsky & Singh, 1982) suggest that urban residents throughout 
the world are likely to be exposed to considerably higher levels 
(Table 3). 

    The three most likely sources that may lead to dermal exposure 
to toluene in the general population are the use of vehicular 
fuels, toluene-containing solvents, and cosmetic products.  
Although cosmetic products may involve smaller exposures compared 
with the other two sources, the population exposed is large 
(Anderson et al., 1980). 

5.3.  Occupational Exposure During Manufacture, Formulation, or Use

    Available information suggests that particular occupational 
subgroups are likely to be exposed to considerably higher levels 
than the general population.  Such subgroups include, printers, 
shoemakers, and those associated with the production of toluene 
and/or toluene-containing products.  Atmospheric levels such as 
those cited in Table 4 can reflect only the conditions prevailing 
at the time of an investigation.  They do not represent the peak 
exposures to which workers may be subjected during such incidents 
as breakdown or leakage of process equipment, transfer operations, 
etc.  However, the adoption of lower exposure limits in several 
countries is likely to have decreased actual exposure to toluene at 
the work-place. 

Table 3.  Toluene exposure estimates under different conditions of exposure
Exposure conditions        Observed range of   Frequency of       Total volume of     Inhalation or 
                           concentrations      exposure           exposure or amount  ingestion
                                                                  consumed per week   rate (mg/week)
General population


 Urban areas               0.1 - 204 g/m3     168 h/week         156.8 m3            0.02 - 32
 Rural and remote areas    trace to 3.8 mg/m3  168 h/week         156.8 m3            trace to  0.6
 Areas near manufacturing  0.1 - 600 g/m3     168 h/week         156.8 m3            0.02 - 94
  and user sites


 Drinking-water            0 - 19 g/litre     2 litre/day        14 litre            0 - 0.3
 Food (fish only)          0 - 1 mg/kg         6.5 g/day          45.5 g              0 - 0.45

Occupational group

Inhalation                 377 mg/m3a          40 h/week          48 m3               18 100

 Dermal                    0 - 170 g/litreb   0 - 30 min/week    5.9 litre           0 - 1.0

Cigarette smokers

Inhalation                 0.1 mg/cigarettec   20 cigarettes/day  140 cigarettes      14
a This value is similar to permissible standards in various countries and represents the worst-case
  estimate.  In some industries, the exposure level rarely exceeds 37.5 mg/m3.
b This value represents exposure to blood due to dermal contact and represents absorbed levels.
c From:  Dalhamn et al. (1968a); toluene content may be higher depending on tobacco type.
Table 4.  Concentrations of toluene in the air at work-places
Occupation/work-place           Toluene concentration    Reference
                                Range          Average
24 workers in paint and         750 - 3000;              Parmeggiani &  
 pharmaceutical industry        560 - 7100               Sassi (1954)
rotogravure printers and        750 - 1500               Banfer (1961)

11 workshops in 8 factories     15 - 828                 Ikeda & Ohtsuji 
 (rotary processes for                                   (1969)
 rotogravure printers)

39 workers in:                                                      

 rotogravure plant 1954/56      0 - 900                  Forni et al. 
 1957/1965 CTR of room          525 - 896      761       (1971)
  near fold machine             210 - 1039     761
  between  machine              1148 - 3090    1616
 1967 near fold machine                        585
  between  machine                             994

rotogravure printer             68 - 1875                Szadkowski et 
                                                         al. (1976)

rotogravure printer             200 - 300      3000      Szilard et al. 

11 leather-finishing plants
 -rinsh area                   71 - 319       199       Pagnotto &
 -washing & topping operations  109 - 731      420       Lieberman (1967)

rubber coating plants           128 - 450      274
 (< 1% benzene)

19 workers in V belts for
 industrial machine plants
 (1)                            300 - 600      468.8     Capellini &
 (2)                            788 - 1125     937.5     Allessio (1971)

rotogravure printer             60 - 615                 Ovrum et al. 

24 workers in                   81 - 706                 Veulemans et al. 
 rotogravure printer                                     (1979)

32 workers in                   26 - 420                 Mki-Paakkanen 
 rotogravure printer                                     et al. (1980)

Table 4.  (contd.)
Occupation/work-place           Toluene concentration    Reference
                                Range          Average
500 women/leather and rubber                   250       Michon (1965)
 shoe factory

53 women/leather factory                       250       Kowal-Gierczak 

1000 workers/vapour
 commercial toluene
 1 - 3 weeks exposure           188 - 5625               Wilson (1943)
 (1)                            188 - 750
 (2)                            750 - 1875
 (3)                            1875 - 5625

29 workers spraying             approximately
 merchant ship                  37 500 - 112 500         Longley et al. 
 2 h after incident             18 750 - 37 500          (1967)


    The atmosphere is a major reservoir of toluene emissions and 
photochemical reactions are capable of rapidly degrading it.  
Toluene discharged into natural waters and soils is removed by 
volatization and biodegradation.  This section reviews the effects 
of toluene on organisms in the aquatic and terrestrial 

6.1.  Microorganisms

    Microorganisms capable of degrading toluene are widely 
distributed in the environment (Gibson, 1971; Subramanian et al., 
1978; Bridi et al., 1979; Wilson et al., 1981).  Although toluene 
can be toxic for microorganisms, microorganisms are of great 
importance for the degradation of toluene in natural waters and 
soils.  The metabolism of toluene in microorganisms is similar to 
that in mammals, except that ring hydroxylation to cresols is more 
prevalent (Gibson, 1971).  In addition, the metabolic pathway 
involves oxidation of the benzyl carbon to form benzoic acid, which 
is further metabolized as a carbon source. 

    Bridi et al. (1979) showed that toluene has a biological 
oxygen demand (BOD) in conventional waste-water treatment of 69% 
(expressed as a percentage of the theoretical demand-ThoD) in a 
standard 5-day test.  BOD values greater than 50% are indicative of 
a readily-degradable chemical that can be adequately treated by 
municipal and industrial waste-treatment facilities.  Moreover, 
toluene spilled in the environment would be expected to be degraded 
under aerobic conditions. 

6.2.  Aquatic Organisms

    The threshold for the acute effects of toluene in aquatic biota 
is 1 mg/litre.  Aquatic organisms are exposed to toluene via 
respiration, resulting in changes in gill permeability and internal 
carbon dioxide (CO2) poisoning. 

    Data on environmental factors affecting the toxicity of toluene 
are not extensive, but neither temperature nor water hardness have 
been found to have any significant effects (US EPA, 1980). 

    As in mammals, toluene causes adverse effects in aquatic 
organisms through the mechanism of narcosis.  Symptoms in aquatic 
organisms progress from mild stimulation, to lethargy, loss of 
equilibrium accompanied by shallow breathing and slowed heart rate, 
anaesthesia, and death (Bakke & Skjoldal, 1979; Maynard & Weber, 
1981; Veith et al., 1983).  The effects are largely reversible 
except for residual CNS effects as evidenced by alteration of 
schooling behaviour for longer periods after near lethal exposure.  
Narcosis is expected to occur at concentrations of 11 mg/litre in 
fresh water and 8 mg/litre in seawater. 

    A summary of aquatic toxicity data for fish and invertebrates 
from fresh water and marine environments is presented in Table 5.  
Because of the high volatility of toluene, only flow-through tests 
and static tests with measured concentrations are included.  The 
acute LC50 for freshwater organisms varies from 21.5 mg/litre for 
mosquito larvae to 29 and 26 mg/litre for day-old fry and juvenile 
fathead minnows, respectively.  The results of long-term studies 
have shown the no-observed-adverse-effect concentration for the 
early life stage of fathead minnow to be 4 - 6 mg/litre. 

    The acute LC50 for marine organisms varies from 3.7 mg/litre in 
bay shrimp to 28 mg/litre in the Dungeness crab.  However, the 
mosquito fish had an LC50 of 1180 mg/litre.  Newly-hatched fry from 
Coho salmon and pink salmon were slightly less sensitive to toluene 
than the bay shrimp with 96-h LC50 values of 5.5 mg/litre and 
7.0 mg/litre, respectively.  Long-term effects of toluene in marine 
organisms were measured in the sheepshead minnow and Coho salmon.  
The 28-day no-observed-adverse-effect concentration for the minnow 
was between 3.2 and 7.7 mg/litre.  The 40-day no-observed-adverse-
effect concentration for the early life-stage of salmon was between 
1.4 and 2.8 mg/litre. 

    Potera (1975) studied the effects of toluene on marine 
phytoplankton.  Photosynthesis was inhibited at toluene 
concentrations of 34 mg/litre.  The same concentration caused a 62% 
inhibition in respiration. 

    An important long-term effect of chemicals on fish reproduction 
is the avoidance response in spawning areas.  Maynard & Weber 
(1981) found that Coho salmon could avoid water containing toluene 
at concentrations greater than 2 mg/litre. 

6.3.  Terrestrial Organisms

    Data on the toxicity of toluene for terrestrial organisms are 
not available. 

6.4.  Population and Ecosytem Effects

    The Task Group was unaware of studies of effects of toluene on 
ecosystems within natural populations. 

6.5.  Effects on the Abiotic Environment

    The primary effect of toluene on the abiotic environment is in 
contributing to irritating reaction products in the atmosphere.  
However, there are no studies reporting the specific contributions 
of toluene to smog formation. 

Table 5.  Toxicity of toluene for fish and aquatic invertebrates
Species                   Duration  Effect     Concentration   Reference
                          (h)                  (mg/litre)
Mosquito larvae           24        LC50       21.5            Berry & Brammer (1977)
 (Aedes aegypti)

Zebrafish                 48        LC50       25              Sloof (1979)
 (Brachydanio rerio)

Goldfish                  96        LC50       23a; 58b        Brenniman et al. (1976)
 (Carassius auratus)

Fathead minnow            96        LC50       63 (embryos)    Devlin et al. (1982)
 (Pimephales promelas)     96        LC50       29 (1-day fry)
                          96        LC50       26 (juvenile)
                          32 days   no effect  4 - 6

Sheepshead minnow         96        LC50       13 (juvenile)   Ward et al. (1981)
 (Cyprinodon variegatus)   28 days   no effect  3.2 - 7.7       Ward et al. (1981)

Coho salmon               96        LC50       5.5 (fry)       Moles et al. (1981)
 (Oncorhynchus kisutch)    40 days   no effect  1.4 - 2.8
                                    avoidance  2.0             Maynard & Weber (1981)
                                    no effect

Pink salmon               96        LC50       7.0 (fry)       Korn et al. (1979)
 (Oncorhynchus gorbuscha)  24        LC50       5.4             Thomas & Rice (1979)

Guppy                     96        LC50       59.3            US EPA (1980)
 (Poecilia reticulata)

Bluegill                  96        LC50       24              US EPA (1980)
 (Lepomis machrochirus)

Mosquito fish             96        LC50       1180            US EPA (1980)
 (Gambusia affinis)

 Daphnia magna             ?         LC50       313             US EPA (1980)

Striped bass              96        LC50       7.3             Benville & Korn (1977)
 (Morone saxatilis)

Grass shrimp              24        LC50       17.2 (adult)    Potera (1975)
 (Palaemonetes pugio)      24        LC50       25.8 (larvae)

Dungeness crab            96        LC50       28              Caldwell et al. (1976)
 (Cancer magister)         48        LC50       170             US EPA (1980)

Bay shrimp                96        LC50       3.7             Benville & Korn (1977)
 (Crago franciscorum)

Table 5.  (contd.)
Species                   Duration  Effect     Concentration   Reference
                          (h)                  (mg/litre)
Brine shrimp              24        LC50       33              US EPA (1980)
 (Artemia salina)

Copepode                  24        LC50       24.2 - 74.2     US EPA (1980)
 (Nitocra spinipes)

 Marine algaec

 Chlorella vulgaris        24        EC50       245             US EPA (1980)

 Selenastrum capri         96        EC50       > 433           US EPA (1980)
a Flow-through system.
b Static system.
c Besides these 2 algae, at least 5 other marine algae were tested, and all had a low 

7.1.  Absorption

7.1.1.  Inhalation  Rat

    In rats exposed to 2156 mg toluene/m3 for up to 240 min, the 
estimated asymptotic value of toluene for blood was 10.5 mg/litre 
and, for brain, 18 mg/kg tissue.  To reach the 95% level during 
uptake required 53 min for blood and 58 min for brain (Benignus et 
al., 1981).  Dog

    The respiratory retention of inhaled toluene was studied in 
dogs, at concentrations of 400 - 600 mg/m3.  Retention in the total 
respiratory tract was found to be approximately 90% of the inhaled 
toluene.  Varying the ventilation rate, tidal volume, or the 
concentration of toluene up to 825 mg/m3 did not have any effect on 
the respiratory retention (Egle & Gochberg, 1976).  Human volunteers

    In human studies, uptake of toluene has been estimated by 
different authors to be 40 - 60% of the total amount inhaled 
(Nomiyama & Nomiyama, 1974a; Astrand, 1975; Carlsson & Lindqvist, 
1977; WHO, 1981; Carlsson, 1982a). 

    Nomiyama & Nomiyama (1974a) measured pulmonary uptake in 
volunteers exposed to 431 mg toluene/m3 for 4 h.  Uptake at the end 
of 1 h was approximately 52% and decreased to 37% at the end of 
2 h, remaining constant at that level for the remaining 2 h.  This 
was later confirmed by Carlsson (1982a) and Astrand (1983). 

    The asymptote during uptake of toluene was estimated by 
different authors.  Because of the differences in the methods and 
designs used, these data are not comparable, but the values ranged 
from 10 - 80 min (Astrand et al., 1972; Gamberale & Hultengren, 
1972; Veulemans & Masschelein, 1978a). 

    Carlsson (1982a) investigated the effects of physical exercise 
on the rate of toluene uptake.  Twelve male volunteers were exposed 
to 300 mg toluene/m3 during 4 consecutive 30-min workloads at 150 
watts (W), 100 W, 50 W, and at rest.  During the initial 30-min 
period at 150 W, the mean relative uptake declined from about 55% 
initially to 29% at the end of the period.  During continued 
exposure at 100 W, 50 W, and rest for 2 h, the relative uptake 
averaged 32, 36, and 39%, respectively (Carlsson, 1982a).  
Consequently, there was an increase in the relative uptake (from 29 
to 39%) with decreasing workloads during exposure.  These findings 
were confirmed by Astrand (1983).  Astrand also found that doubling 
the concentration of toluene in inspired air gave a 2-fold uptake, 
which is in agreement with the results of Veulemans & Masschelein 

7.1.2.  Dermal  Guinea-pig

    Jakobson et al. (1982) monitored the concentration of toluene 
in the arterial blood of anesthetized guinea-pigs following 
epicutaneous exposure.  In this study, a 3.1 cm2 area of clipped 
back skin was continuously exposed to liquid toluene by means of a 
sealed glass ring.  Toluene in the blood increased rapidly within 
1 h to a concentration of 1.3 mg/litre, and then decreased, in 
spite of continuing exposure, to a plateau concentration of 
0.5 mg/litre after 6 h.  Human volunteers

    In human volunteer studies, Dutkiewicz & Tyras (1968a,b) showed 
that absorption through the skin occurred following exposure to 
liquid toluene (rate of absorption 14 - 23 mg/cm2 per h), and, to a 
much lesser extent, following exposure to saturated aqueous 
solutions (rate of absorption 0.16 - 0.6 mg/cm2 per h). 

    Sato & Nakajima (1978) reported that a maximum toluene 
concentration in the blood of 0.17 mg/litre was found when the skin 
of volunteers was immersed in liquid toluene for 30 min.  In 
studies conducted by Riihimki & Pfffli (1978), volunteers, 
wearing light, loose-fitting clothing and respiratory protection, 
were exposed to 2250 mg toluene/m3 for 3.5 h.  The authors 
estimated, on the basis of toluene measured in expired air, that 
uptake through the skin was approximately 1% of the theoretical 
uptake through the respiratory system.  Similar conclusions were 
reached by Piotrowski (1967). 

7.1.3.  Oral

    Oral absorption appears to occur more slowly than that through 
the respiratory tract.  On the basis of measurements of toluene 
excreted unchanged in the expired air (18%) and levels of hippuric 
acid in the urine of rabbits, toluene appears to be completely 
absorbed from the gastrointestinal tract (Smith et al., 1954; El 
Masry et al., 1956). 

7.2.  Distribution

7.2.1.  Inhalation

    The dynamic distribution in the body of any organic solvent 
vapour, e.g., toluene, is determined by its solubility in the body 
fluids and tissues.  Determination of the solubility of toluene in 
various body fluids, tissues, and tissue components has been 
carried out in mammals.  The solubility was expressed in terms of 
partition coefficients, which numerically equal the Ostwald 
solubility coefficients (Sato et al., 1974a,b; Sherwood, 1976; Sato 
& Nakajima, 1979a).  Mouse

    The concentrations of toluene in the liver, brain, and blood of 
mice exposed to 15 000 mg toluene/m3 for 3 h rose continuously 
throughout the exposure period, to 625 mg/kg in liver, 420 mg/kg in 
brain, and 200 mg/kg in blood, at the end of exposure.  Intermittent 
exposure to about 40 000 mg/m3 in cycles of 5 min on, 10 min off, 
or 10 min on, 20 min off, for a total of 3 h, produced tissue and 
blood levels approximately 3 times higher than those produced by a 
single 10-min exposure and similar to those produced by the 3-h 
exposure (Peterson & Bruckner, 1978; Bruckner & Peterson, 1981a). 

    Whole-body autoradiography techniques were used to study the 
distribution and fate of toluene and its metabolites, and 
covalently bound reactive intermediates in mice exposed to methyl-
14C-toluene by inhalation.  High levels of radioactivity were 
observed in adipose tissue, bone marrow, spinal nerves, spinal 
cord, and the white matter of the brain.  Radioactivity was also 
registered in the blood, liver, and kidneys (particularly in the 
medullary region).  Since the radioactivity in the central nervous 
system (CNS), spinal nerves, and adipose tissues was volatile, it 
was proposed that it was probably toluene itself.  All radio-
activity in the nervous tissues had disappeared by 1 h after 
exposure.  Toluene was still present in body fat 2 h after exposure 
but had been almost cleared from fatty tissues in 4 h.  Four hours 
after inhalation, only traces of non-volatile radioactivity 
remained in the liver; after 24 h, all radioactivity had 
disappeared from the body (Bergman, 1978, 1979, 1983).  Rat

    Benignus et al. (l984a) developed a log-log model relating 
venous-blood and brain levels of toluene to inspired air levels.  
Groups of 15 Long-Evans hooded rats were exposed to 188, 375, 1875, 
or 3750 mg toluene/m3 for 3 h.  The data showed that a 3-h exposure 
was sufficient to produce toluene levels in both blood and brain 
that were close to asymptote.  The calculated brain/blood toluene 
ratio in rats was estimated to be 1.56.  Values reported by, or 
that could be estimated from, others compare well, considering the 
various exposure times:  1.27 in rats (Pyykk et al., 1977); 2.50 
in rats (Pryor et al., 1978); 1.26 in mice (Ogata et al., 1974); 
2.05 mice (Bruckner & Peterson, 1981a).  Benignus et al. (1984b) 
reported that blood-toluene concentrations rose at a rate that was 
independent of dose level (50 - 1000 mg/kg body weight, sc), and 
that blood levels fell at different rates, depending on dose level. 

    After adult male rats were exposed for 1 h through inhalation 
to 14C-labelled toluene (1950 mg/m3), the highest concentrations of 
radioactivity were found in the adipose tissue and were up to 2 
orders of magnitude higher than those found in blood.  The next 
highest concentration of radioactivity occurred in the adrenals and 
kidneys, followed by liver, cerebrum, and cerebellum.  Loss of 
radioactivity from adipose tissue and bone marrow during the 
following 6 h appeared to occur more slowly than the loss from the 
other tissues (Carlsson & Lindqvist, 1977; Pyykk et al., 1977). 

    Pregnant CFY rats were  exposed for 24 h (on days 10 - 13 of 
gestation) to 1375 or 2700 mg toluene/m3 (Ungvry, 1984).  Toluene 
concentrations in maternal blood, 2 h after exposure, were 6.44 and 
13.69 mg/litre, at the lower and higher exposure, respectively.  In 
fetal blood, the concentrations were about 76% of the maternal 
levels, and the concentrations of toluene in amniotic fluid were 
0.24 and 0.96 mg/litre.  Toluene concentrations, 4 and 6 h after 
exposure, were similiar to those measured after 2 h.  Human volunteers

    Male volunteers (19 - 43 years of age) were exposed to a 
toluene concentration of 300 mg/m3 for four 30-min periods at rest 
and/or during stepwise-increased workload (50 W, 100 W, 150 W).  
The relative uptake averaged 52% at rest, and 49%, 40%, and 29% at 
50-, 100-, and 150-W workload, respectively, at the end of 30 min 
of exposure (section 7.1.1).  The corresponding alveolar 
concentrations were 29, 39, 53, and 69% of the inspired 
concentrations.  The arterial concentration amounted to 0.7 
mg/litre blood at rest and 3.3 mg/litre blood at 150-W workload for 
30 min (Carlsson, 1982b).  Consequently, the arterial concentration 
increased, not only when the concentration of the inspired solvent 
increased, but also with increasing workloads, when the 
concentration in the inspired air was constant (Astrand, 1983). 

    The relationship between the relative uptake and the alveolar 
concentration (as a percentage of the concentration in inspired 
air) was linear and in close agreement with the ratio found by 
other investigators (Astrand, 1975).  The higher the relative 
uptake, the lower the alveolar concentration of the solvent.  The 
relationship between arterial-blood and alveolar-air concentrations 
for toluene was linear and thus the arterial-blood concentrations 
were closely correlated with the alveolar-air concentration.  Thus, 
by measuring the concentration of toluene in alveolar air during 
exposure, it is possible to estimate the arterial-blood 
concentration (Piotrowski, 1967; Carlsson & Lindqvist, 1977; Ovrum 
et al., 1978; Carlsson, 1982a,b; Astrand, 1983). 

    In the study carried out with male subjects described above, 
Carlsson and co-workers also estimated the toluene concentrations 
in subcutaneous fat.  At rest, the peak concentration in the fat 
was approximately 2 mg/kg.  After exercise, the toluene 
concentration was 5 - 10 times higher than at rest.  Subjects with 
the least amount of adipose tissue showed the smallest accumulation 
of toluene in body fat and those that were overweight showed a high 

    In a male subject with about 12% body fat, the estimated 
quantity of toluene in this fat amounted to 5% of the total uptake, 
after 2 h exposure at rest.  After 2 h of exposure at 50 W, it 
amounted to 20%.  The elimination half-life for toluene in 
subcutaneous adipose tissue ranged between 0.5 and 2.7 days, and 
increased with increasing amounts of body fat. 

    The quotients between the concentrations of toluene in 
subcutaneous adipose tissue and arterial blood ranged from 1.2 
after exposure at rest to 4.7 after exposure combined with a 50-W 
work-load.  It took about 2 days of continuous exposure to toluene, 
at rest, for the concentration in the subcutaneous adipose tissue 
to reach 63% of the solvent partial pressure in the arterial blood. 

    During prolonged exposure, persons with a high body fat content 
may be exposed to a more prolonged effect of toluene on the central 
nervous system than thin persons, since toluene disappears more 
slowly from the adipose tissue and blood. 

    By increasing the blood circulation, physical exercise produces 
conditions favouring a high uptake in the skeletal muscles, heart, 
CNS (especially the brain), and adipose tissues.  Consequently, 
there is a decrease in the toluene concentration in the liver, 
kidneys, and gastrointestinal tract (Carlsson & Lindquist, 1977; 
Carlsson, 1982a,b). 

7.2.2.  Oral  Rat

    Oral administration of 4-3H-toluene (100 l toluene in 400 l 
peanut oil by intubation) to adult male rats produced a pattern of 
tissue distribution similar to that produced with inhalation 
exposure.  Distribution appeared to be delayed, because of the time 
needed for absorption from the digestive tract.  Maximum tissue 
concentrations occurred 2 - 3 h after administration for most 
tissues and 5-h after administration for adipose tissue (Pyykk et 
al., 1977). 

7.2.3.  Intraperitoneal  Rat

    Savolainen (l978) observed that after ip injection of rats with 
500 mol methyl-14C-toluene, the concentration of radioactivity in 
the CNS was highest in the cerebrum.  Toluene was rapidly removed 
from the CNS and was almost undetectable after 24 h. 

7.3.  Metabolic Transformation

7.3.1.  Oral

    The initial step in the metabolic transformation of toluene to 
benzoic acid, after oral administration, appears to be 
hydroxylation of toluene to benzyl alcohol (Fig. 1) by the 
microsomal mixed-function oxidase system.  In rats, rabbits, and 
man, approximately 20% of the dose is excreted unchanged via the 
lungs, while approximately 80% is converted to benzoic acid and 
excreted in the urine unchanged or as its glycine conjugate, 
hippuric acid.  Furthermore, it has been found that toluene is 
excreted as benzylmercapturic acid in smaller quantities in rats.  
Small amounts of benzoic acid may be conjugated with glucuronic 

acid and excreted as benzoyl glucuronic acid in the urine.  Minor 
amounts (less than 1%) of toluene undergo ring hydroxylation to 
form  o-,  m, and  p-cresol, which are excreted in the urine as 
sulfate or glucuronide conjugates (Smith et al., 1954; El Masry et 
al., 1956; Daly et al., 1968; Bakke & Scheline, 1970; Angerer, 
1976, 1979; Pfffli et al, 1979; Van Doorn et al., 1980; Woiwode & 
Drysch, 1981). 

    Ikeda & Ohtsuji (1971) demonstrated that the induction of 
hepatic mixed-function oxidases, by pretreatment of adult female 
rats for 4 days with phenobarbital, increased the metabolism of 
toluene when administered ip.  A clear (3-fold) increase in 
hippuric acid levels in urine was already found after 2 h in 
comparison with levels in rats administered only toluene.  High 
levels of benzoic acid were found in the blood compared with none 
in non-induced rats.  Treatment of rats with phenobarbital enhanced 
the  in vivo metabolism of toluene and resulted in increased 
tolerance in the rats to the narcotic action of toluene.  No 
effects of the pretreatment was observed on the rates of oxidation 
of aromatic alcohol to the corresponding acid, phenolic 
sulfatation, or on the glucuronidation or glycine conjugation of 
benzoic acid.  Rapid disappearance of toluene from the blood 
because of enhanced metabolism, together with reduced sensitivity 
of the central nervous system, could explain the shortened sleeping 
time after the ip injection of toluene. 


7.3.2.  Inhalation  Human beings

    Toluene is metabolized in human beings by the pathway outlined 
in Fig. 1.  The excretion of hippuric acid in the urine was 
elevated within 30 min of the initiation of inhalation exposure, 
indicating that the metabolism of toluene is rapid.  The urinary 
hippuric acid levels reached a steady-state level after 4 h of 
continuous exposure (mean toluene concentration in air of 
350 mg/m3) under a moderate energy load (Ogata et al., 1970; 
Nomiyama & Nomiyama, 1978; Veulemans & Masschelein, 1979).  The 
maximum rate of transformation of benzoic acid to hippuric acid 
seemed to be limited by the availability of glycine (Quick, 1931; 
Amsel & Levy, 1969). 

    During the inhalation of toluene, the rate of uptake was 
estimated to equal the full conjugating capacity at toluene 
concentrations of about 2950 mg/m3, at rest, or about 1015 mg/m3 
during moderately-heavy work (Riihimki, 1979). 

     o-Cresol was identified in the urine of workers exposed to 26 - 
420 mg toluene/m3 (Angerer, 1979; Pfffli et al., 1979; Apostoli et 
al., 1982; Hansen & Dossing, 1982; Kawai et al., 1984).   p-Cresol 
may also be a metabolite of toluene as it was present in higher 
concentrations in the urine of workers exposed to toluene than in 
the urine of unexposed workers (Angerer, 1979).  The difference, 
however, was not significant.  Apostoli et al. (1982) and Woiwode 
et al. (1979) reported finding  m-cresol and  p-cresol in addition 
to  o-cresol in the urine of workers exposed to 1050 mg toluene/m3.  
No  m-cresol was detected in the urine of unexposed workers. 

7.3.3.   In vitro studies

    Toluene has been shown to produce a Type I binding spectrum 
with cytochrome P 450 (EC from rats and hamsters (Canady 
et al., 1974; Al-Gailany et al., 1978). 

    Incubation of toluene with rat or rabbit liver microsomes 
resulted in the production of small amounts of  o-cresol and 
 p-cresol.  The migration of deuterium, when toluene was labelled in 
the 4-position, and a comparison of the rearrangement products of 
arene oxides of toluene with the cresols obtained by microsomal 
metabolism of toluene suggest that arene oxides are intermediates 
in the metabolism of toluene to  o- and  p-cresols (Daly et al., 
1968; Kaubisch et al., 1972). 

7.4.  Elimination and Excretion in Expired Air, Faeces, and Urine

7.4.1.  Toluene  Laboratory animals

    Toluene is rapidly exhaled as the unchanged compound 
(approximately 20 - 40% of the absorbed toluene).  Only trace 
amounts of toluene (about 0.06%) are excreted unchanged in urine.  

Whole-body autoradiography of laboratory animals, including mice, 
showed that excretion of toluene metabolites took place mainly via 
the kidneys.  Most of the absorbed toluene was excreted within 12 h 
of the end of exposure (Bergman, 1978, 1979, 1983). 

    Mice exposed to a high initial concentration of methyl-14C-
toluene in a closed chamber for 10 min excreted ~ 10% of the 
absorbed dose as volatile material in the exhaled air and about 68% 
of the radioactivity in the urine within 8 h (Bergman, 1979). 

    Rates of urinary hippuric acid excretion in rabbits exposed to 
toluene vapour at 1313 mg/m3 for 100 min or 16 835 mg/m3 for 10 min 
increased to reach maximum values 1.5 h after exposure (Nomiyama & 
Nomiyama, 1978).  Excretion rates returned to baseline levels, 7 h 
after the initiation of exposure to the lower dose level, and 3 h 
after exposure to the higher dose level. 

    Rats given 50 mg 14C-toluene/kg body weight, ip, excreted less 
than 2% of the administered radioactivity in the bile within 24 h 
(Abou-El-Markarem et al., 1967).  Bergman (1979) showed excretion 
of toluene metabolites (benzoic acid) via bile into the intestinal 
tract in mice after inhalation of toluene. 

    In a study in rats, methyl-14C-toluene was administered, sc, in 
a dose of 184 mg/kg body weight (Gut, 1983).  About 20% of the 
radioactivity had been excreted in the urine after 8 h and 50% 
after 48 h.  Human beings

    Human beings exposed through inhalation to toluene 
(concentrations ranging from 350 to 700 mg/m3) exhaled 5 - 20% of 
the absorbed toluene after exposure was terminated (Srbova & 
Teisinger, 1952, 1953; Nomiyama & Nomiyama, 1974a,b).  Alterations 
in physical activity influenced the elimination rate.  Astrand 
(1983) reported that the elimination rate was doubled under 
conditions of a light workload at 50 W compared with resting 
conditions.  The concentrations of toluene in the alveolar air, and 
arterial and venous blood of human subjects declined rapidly, 
immediately after the end of exposure and then the rate of decline 
gradually decreased (Astrand et al., 1972; Sato et al., 1974b; 
Carlsson & Lindqvist, 1977; Ovrum et al., 1978; Veulemans & 
Masschelein, 1979; Carlsson, 1982a,b). 

    In the desaturation period, male and female volunteers expired 
17.6 and 9.4%, respectively, of the total amount of toluene 
calculated to have been absorbed during exposure (Nomiyama & 
Nomiyama, 1974b).  They reported rate coefficients for the rapid 
phase of 5.10/h (t1/2 = 8.16 min) for men and 3.22/h (t1/2 = 12.9 
min) for women; the rate coefficient for the slow phase was 0.335/h 
(t1/2 = 124 min) for both sexes.  Toluene retained in the body fat 
is eliminated by pulmonary ventilation and by biotransformation.  
The half-time for toluene was 0.5 - 3 days (Carlsson, 1982a, 
Astrand, 1983). There was a correlation between the half-time and 
the individual's content of body fat (section 

    Brugnone et al. (1983) reported the cases of 2 workers who were 
admitted to a hospital because of coma due to an accidental high-
level occupational exposure to a mixture of solvents; the levels of 
toluene were, respectively, 823 - 1122 g/litre in the blood and 52 
- 38 g/litre in the alveolar air, on the second day of admission 
(36 h after the accidental exposure).  At 112 h after exposure, the 
alveolar-toluene concentration was 1 - 3 g/litre.  The blood-
toluene concentrations at 112 h were 45 and 120 g/litre, 
respectively.  The mean decline rate of toluene, expressed as half-
life, was calculated to be between 19 and 21 h both in the alveolar 
air and in the blood.  During the first 2 days, the lung clearance 
of toluene was of the order of 350 ml/min in the first worker and 
270 ml/min in the second worker. 

    Dermal exposure of human subjects to toluene liquid or vapour 
resulted in the appearance of toluene in the expired air.  When 
exposure ceased, a rapid decrease in toluene levels in alveolar air 
was noticed (Guillemin et al., 1974; Riihimki & Pfffli, 1978).  
The excretion of toluene in the expired air appeared to consist of 
at least 2 exponential phases (Riihimki & Pfffli, 1978). 

7.4.2.  Excretion of metabolites  Human beings

    Volunteers inhaling toluene at concentrations of approximately 
200 - 550 mg/m3, for 3 - 4 h, excreted 60 - 70% of the absorbed 
dose as hippuric acid in the urine (Ogata et al., 1970; Veulemans & 
Masschelein, 1979). 

    A relatively wide range of hippuric acid excretion levels has 
been reported for groups of workers exposed to toluene during 
different operations (Table 6).  For example, Pagnotto & Lieberman 
(1967) found a range of 2.75 - 6.80 g/litre urine (mean, 3.66 
g/litre) for spreaders in the rubber-coating industry exposed to 
274 mg toluene/m3.  Ikeda & Ohtsuji (1969) reported a range of 2.28 
- 3.54 g/litre (mean, 2.84 g/litre) for 8 workers exposed to 469 mg 
toluene/m3.  In a control group of 17 unexposed workers, a mean 
level of 0.95 g/litre (range 0.55 - 1.6 g/litre) was recorded by 
Capellini & Alessio (1971). 

    From the studies carried out by Pagnotto & Lieberman (1967), 
Ikeda & Ohtsuji (1969), Ogata et al. (1971), and Apostoli et al. 
(1982), it is concluded that the urinary levels of hippuric acid 
are proportional to the concentrations of toluene in the air, 
though within wide variations. 

    Ogata et al. (1970) carried out a study on human volunteers and 
found that the quantity of hippuric acid excreted was proportional 
to the total exposure (mg/m3 x h).  In descending order of 
precision, the following were also related to exposure:  rate of 
excretion during the exposure period; concentrations of hippuric 
acid in urine corrected to constant urine density; and 
concentrations in urine uncorrected for density.  With the 

exception of the latter, these variables could be used in screening 
tests to show whether workers could have been exposed to 
concentrations greater than the maximum allowable concentration. 

    Apostoli et al. (1982) found that, besides a good correlation 
between urinary-hippuric acid levels and air levels of toluene, 
there was also a good correlation between urinary- o-cresol and 
blood-toluene concentrations and toluene concentrations in the air. 

Table 6.  Hippuric acid excretion levels
Number of workers     Toluene concentration  Hippuric acid excretion     Reference
and/or                (mg/m3)                levels (g/litre urine)
operation             ---------------------  --------------------------
                      Mean  Range            Mean           Range
Spreaders             73    34 - 120         3.66           2.75 - 6.80  Pagnotto & Lieberman (1967)
in rubber


 automatic spraying   53    19 - 85          2.38           1.50 - 3.66  Pagnotto & Lieberman (1967)
 washing and tapping  112   29 - 195         4.48           2.15 - 5.85  Pagnotto & Lieberman (1967)
 unexposed workers                           0.8            0.4 - 1.4    Pagnotto & Lieberman (1967)

31 unexposed                                 0.35           0.20 - 0.62  Ikeda & Ohtsuji (1969)

118 exposed workers   356   15 - 900         3.25           0.45 - 6.48  Ikeda & Ohtsuji (1969)

18 exposed workers    469   300 - 600        2.1  0.83                  Capellini & Alessio (1971)

17 unexposed                                 0.95  0.33    0.55 - 1.6   Capellini & Alessio (1971)

23 male volunteers    375                    2.55  0.55                 Ogata et al. (1970)
(3-h exposure)        750                    5.99  1.20                 Ogata et al. (1970)

53 exposed workers    101                    2.04                        Angerer (1976)

30 unexposed                                 0.79                        Angerer (1976)

20 workers in art-          15 - 164         approximately  0.21 - 2.2   Apostoli et al. (1982)
furniture industry                           0.75

8.1.  Single Exposures

    The acute toxicity of toluene by various routes of exposure is 
summarized in Table 7. 

    In all species studied, the symptoms found with increasing dose 
were irritation of the mucous membranes, incoordination, mydriasis, 
narcosis, tremors, prostration, anaesthesia, and death.  From the 
acute toxicity studies, especially the inhalation studies, there is 
some indication that sensitivity differed between the species 
tested.  However, it should be kept in mind that the studies are 
hardly comparable. 

    From the oral and inhalation studies, there is evidence that 
there is a difference in sensitivity between the rat strains used 
and also at different ages. 

8.1.1.  Inhalation

    Bruckner & Peterson (1981a,b) found an age-dependent 
sensitivity in outbred male rats (ARS/Sprague Dawley) and male IRC 
mice.  Animals of 4 weeks of age were found to be more susceptible 
to toluene narcosis, when exposed to toluene vapour at 9750 mg/m3 
for 3 h, than 8- and 12-week-old animals.  In contrast, Cameron et 
al. (1938) stated that very young Wister rats (9-day-old) were less 
sensitive to toluene exposure than adults. 

    von Oettingen et al. (1942b) observed that 6 dogs showed an 
increase in respiratory rate and a decrease in respiratory volume 
after 1 h of exposure to 3188 mg toluene/m3 (containing only 0.01% 

8.1.2.  Oral

    Immature 14-day-old Sprague Dawley rats were more sensitive to 
ingested toluene (analytical grade) than juvenile or adult males 
(Table 7). 

8.1.3.  Intraperitoneal and intravenous injection

    Batchelor (1927) and Cameron et al. (l938) reported the ip 
lethal dose for rats and mice to be approximately 1.7 g/kg body 
weight.  Female mice were less sensitive to toluene than males 
(Ikeda & Ohtsuji, 1971). 

    Keplinger et al. (l959) determined the ip LD50 of toluene in 
rats of both sexes at three different environmental temperatures.  
It was found that the LD50 was 800 mg/kg body weight at 26 C, 
530 mg/kg at 8 C, and 225 mg/kg at 36 C. 

Table 7.  Acute toxicity of toluene
Route/species               Dose                   Duration  Effect          Reference

Rat                         45 750 mg/m3            6.5      LC50            Cameron et al. (1938)

Rat                         15 000 mg/m3            4        16% mortality   Smyth et al.  (1969a)

Mouse                       45 750 mg/m3            6.5      100% mortality  Cameron et al. (1938)

Mouse (Swiss)               19 950 mg/m3            7        LC50            Svirbely et al. (1943)

Mouse                       26 033 mg/m3            6        LC50            Bonnet et al. (1979)

Dog                         3188 mg/m3              1        no mortality    von Oettingen et al. (1942b)


Rat                         7.53 g/kg body weight            LD50            Smyth et al. (1969a)

Rat (CFY males)             5.90 g/kg body weight            LD50            Ungvry et al (1979)

Rat (Sprague Dawley)(male)  5.58 g/kg body weight            LD50            Withey & Hall (1975)
 14-day-old (both sexes)    2.6 g/kg body weight             LD50            Kimura et al. (1971)
 juvenile (male)            5.5 g/kg body weight             LD50
 adults (male)              6.4 g/kg body weight             LD50


Rabbit                      14.1 mg/kg body weight           LD50            Smyth et al. (1969a)


Rat (female)                1.64 g/kg body weight            LD50            Ikeda & Ohtsuji (1971)
    Paksy et al. (1982) demonstrated that ip administration of 553 
or 1843 mg toluene/kg body weight caused muscular weakness and 
equilibrium disturbances in male rats, within 30 min of exposure. 

    Toluene administered iv as a 2 - 5% infusion (2.75 mg/kg body 
weight per min) in Intralapid(R), for 1 h, caused vestibular 
disturbances in female rats (Tham et al., 1982). 

8.1.4.  Subcutaneous injection

    Quantities of 1.1 - 1.25 g/kg body weight and 4.3 - 8.7 g/kg 
have been found to cause death in rats and mice, respectively, when 
injected sc (Batchelor, 1927; Cameron et al., 1938).  Braier (1973) 
reported that all rabbits injected with 3.46 g/kg body weight died 
by the end of the second day. 

8.2.  Short-Term Exposures 

8.2.1.  Inhalation  Mouse

    Mice exposed to 3750 mg/m3 for 20 days did not show 
histological damage to the lungs and kidneys.  However, 
leukocytosis, and decreased thrombocyte count and RBC count were 
seen, particularly at the highest dose level.  There was some 
evidence of hypoplasia in bone marrow (Horiguchi & Inoue, 1977).  
The same was found by Bruckner & Peterson (1981b) in mice exposed 
to 15 000 mg/m3 for 8 weeks. 

    Effects were found in mice with exposure to 45 000 mg toluene 
(99.9% pure)/m3, in cycles of 10 min inhalation exposure with 
20-min recovery periods for 7 cycles/day, 5 days/week, for 8 weeks.  
These included a depression in body weight gain (food intake was 
not measured).  The animals became ataxic with blood-toluene levels 
of between 40 - 70 g/litre, immobile with levels of 75 - 125 
g/litre, drowsy and difficult to arouse with levels of 125 - 150 
g/litre, and unconscious with levels exceeding 150 g/litre.  Blood-
urea nitrogen (BUN) levels were consistently reduced during the 
exposure period.  Recovery occurred 2 weeks after exposure.  No 
detectable histopathological effects were seen in the brain, lungs, 
liver, heart, or kidneys, though decreases in kidney, brain, and 
lung weights were found.  Substantial toluene residues were found 
in the brain, 1 h after exposure (Bruckner & Peterson, 1981a,b).  Rat

    von Oettingen et al. (1942b) reported increasing numbers of 
casts in the collecting tubules of rat kidneys during inhalation of 
99.9% pure toluene at concentrations of 750, 2250, 9375, and 18 750 
mg/m3 for 5 or 15 weeks (7 h/day, 5 days/week).  There was no clear 
influence on the composition of the blood, with the exception of a 
temporary decrease in WBC count at the highest dose level.  A few 
casts in the kidneys were seen after the third week of exposure at 
2250 mg/m3 and earlier at the higher dose levels. 

    Furnas & Hine (1958) reported on the neurotoxicity of toluene 
(pure product) in rats.  An initial exposure to 18 750 mg/m3 proved 
to be ineffective in producing CNS changes.  Exposures were 
increased to 37 500 mg/m3 for 20 min and then to 75 000 mg/m3 for 
1 h.  At the highest level, there was decreased mobility but no 
quivering or twitching and no hyperresponse to auditory stimuli. 

    A significant depression was observed in the relative adrenal 
weight in Donryu strain rats exposed to 99% pure toluene at 750, 
3750, or 7500 mg/m3 during 8-h daily exposures, for 32 weeks 
(Takeuchi, 1969).  No influence on blood composition was found.  
Histologically, the zona glomerulosa of the adrenal cortex of 
toluene-exposed rats was thicker, while the zona fasciculata and 
zona reticularis were reduced.  The author suggested that toluene 
affected the hypothalamo-pituitary-adrenal system.  In another 
study, it was noted that exposure of male Sprague Dawley rats to 
3750 mg toluene/m3, for 8 h daily for 4 weeks, significantly 
increased adrenal weight after 2 weeks and that the weight remained 
higher after 4 weeks.  Eosinophile count increased and, after 4 
weeks, it was significantly greater than in the controls (Takeuchi 
et al., 1972). 

    Matsumoto et al. (1971) found degeneration of germinal cells in 
the testes in 4 out of 12 Donryu male rats exposed by inhalation to 
750 mg toluene/m3, for 8 h/day, 6 days/week, for 1 year.  Absolute 
testicular weight at 1 year was lower in rats exposed to 375 and 
750 mg/m3 in comparison with controls, and there was a trend toward 
a decrease in the relative testes weight. 

    In the studies of Matsumoto et al. (1971), exposure of rats 
through inhalation to toluene concentrations of 375, 750, or 
7500 mg/m3 for 8 h/day, 6 days/week, for 43 weeks, produced hyaline 
droplets in renal tubules.  There was an absolute and relative 
increase in kidney weight.  No change in the morphological blood 
picture was found. 

    Exposure of rats to 4095 mg toluene/m3 for 6 weeks or to 15 000 
mg/m3 for 8 weeks did not induce histological changes in the liver 
or changes in blood composition (Jenkins et al., 1970; Bruckner & 
Peterson, 1981b). 

    Dose-dependant effects were found in rats with high-level 
intermittent exposure to 45 000 mg/m3 (toluene 99.9% pure), in 
cycles of 10 min inhalation exposure with 20-min recovery periods 
for 7 cycles/day, 5 days/week, for 8 weeks (Bruckner & Peterson, 
1981a).  After several cycles of exposure, progressive 
deterioration in performance was noted in rats after each exposure.  
A depression in body weight gain was seen in rats during the 8 
weeks of intermittent toluene exposure.  Food intake was not 
measured.  An increase in aspartate aminotransferase (SGOT) (EC levels was noted in rats.  An increase in lactate 
dehydrogenase (LDH) (EC was also seen.  Recovery occurred 
2 weeks after exposure.  There were no detectable histopathological 
changes in brain, lung, liver, heart, or kidneys, though a decrease 
in organ weights (kidneys, brain, and lung) was noted in treated 

rats (Bruckner & Peterson, 1981b).  Substantial toluene residues 
were found in the brain, 1 h after exposure.  Previous work by 
these authors showed that performance was inversely correlated with 
the toluene concentration in brain tissue. 

    A group of rats was exposed to 4000 mg toluene/m3 through 
inhalation, for 6 h/day, 5 days/week, for 4 weeks.  The toluene 
increased myocardial vascular resistance and reduced cerebral 
nutritive blood flow.  It did not change the ECG, blood pressure, 
cardiac output, distribution of cardiac output to the organs, 
nutritive blood flow, the circulatory resistance of other organs, 
and the histological structure of the heart (Morvai & Ungvry, 

    Pyykk (1983a) reported that inhalation of 7500 mg toluene 
vapour/m3 for 8 h/day for 1 - 16 days, caused insignificant changes 
in rat kidney microsomes.  After discontinuation of exposure, the 
activities of enzymes and the concentration of cytochromes returned 
to the control level in 1 - 4 days.  A decrease in the activities 
of monooxygenases and the concentration of cytochrome P-450 (EC of adult male rat lung microsomes after 6 - 24 h toluene 
exposure was found, but those of cytochrome-b5 (EC and 
NADPH-cytochrome c reductase (EC were not changed (Pyykk, 

    Gut (1983) demonstrated a post-inhalation, dose-related 
increase in cytochrome P-450 content in rats exposed to levels up 
to 4000 mg/m3 for 24 h.  When rats from this exposure group were 
pre-treated with phenobarbital prior to toluene exposure, a 
decreased induction of cytochrome P-450 was seen. 

    Korpela et al. (1983) found an increase in the haemolytic 
resistance of the rat erythrocyte in hypotonic medium, in  in vitro  
studies and in  in vivo studies, when animals were exposed to a 
toluene concentration of 7500 mg/m3.   In vitro dose levels of 200 - 
500 mg/litre were tested for the antihaemolytic effect.  A maximum 
was reached with 300 mg/litre.  Dog

    Appreciable fat in the convoluted tubules and hyaline casts in 
the collecting tubules of the kidneys and congestion in the lungs 
were observed in dogs exposed through inhalation to 750, 1500, or 
2250 mg/m3 for approximately 20 daily 8-h exposures, then for 
7 h/day, 5 days/week for 1 week, and finally to 3188 mg/m3 for 1 h 
(von Oettingen et al., 1942b). 

    At autopsy, hyperaemic renal glomeruli and albuminuria were 
observed, but no effects on the bone marrow, in 2 dogs exposed to 
7500 mg/m3 (8 h/day, 6 days/week, for 4 months), then 9975 mg/m3 
(8 h/day, 6 days/week, for 2 months) (Fabre et al., 1955). 

8.2.2.  Other animal species and routes

    Neither continuous exposure to 389 mg/m3 toluene for 90 days 
nor repeated exposure to 4095 mg/m3 for 6 weeks (8 h/day, 5 
days/week) affected the liver, kidneys, lung, spleen, heart, or 
blood composition in 30 rats, 30 guinea-pigs, 4 dogs, or 6 monkeys, 
as assessed by histopathological examination.  In addition, no 
effects of treatment were seen in the brain or the spinal cord of 
dogs or monkeys.  No significant changes were observed in any of 
the haematological parameters (haemoglobin, haematocrit, or 
leukocyte count).  All except 2 of 30 treated rats survived 
exposure, and all animals in the study gained body weight with the 
exception of the monkeys (Jenkins et al., 1970). 

    Guinea-pigs exposed to toluene at 4688 mg/m3 for 4 h/day, 
6 days/week, survived 3 weeks of exposure, though they were 
severely affected.  At 3750 mg/m3, guinea-pigs were not affected 
even after 35 exposures, though there was evidence of degenerative 
changes in the liver and kidneys (Smyth & Smyth, 1928). 

    Reversible morphological changes in the liver were noted when 
toluene was injected via the sc and ip routes in CFY male rats.  
The dose levels were 1 ml/kg body weight ip for 12 days or sc for 
3 weeks, 0.5 ml/kg body weight ip or sc for 3 weeks, and 0.25 or 
0.125 ml/kg body weight ip or sc for 4 weeks (Ungvry et al., 
1976).  The same changes were observed when toluene was given 
orally to guinea-pigs (Divincenzo & Krasavage, 1974). 

    Subcutaneous injection of rats with toluene at 0.87 g/kg body 
weight, twice daily, for 6 months, elicited repolarization 
disorders, atrial fibrillation, and in some of the animals, 
ventricular extrasystoles.  Intravenous injection of 0.4 mg 
toluene/kg body weight in rats reduced arterial blood pressure; 
however, injection of the same dosage by the ip or sc route did not 
have any effects on blood pressure (Morvai et al., 1976). 

    Rabbits administered sc 300 mg toluene/kg body weight for 
6 weeks or 700 mg/kg body weight for 9 weeks in rabbits did not 
show any effects on DNA synthesis in bone-marrow cells or 
peripheral blood elements (Speck & Moeschlin, 1968).  Braier (1973) 
found a transient slight granulopenia followed by granulocytosis in 
rabbits given 865 mg toluene/kg body weight, sc, for 6 days.  No 
changes in bone marrow were seen. 

8.2.3.  Oral  Rat

    In a short-term oral study, female rats fed up to 590 mg 
toluene/kg body weight by intubation, for periods of up to 
6 months, did not exhibit toxicological effects as determined by 
gross appearance, growth, blood counts, analysis for blood-urea 
nitrogen, final body and organ weights, bone-marrow counts, or 
histopathological examination of adrenals, pancreas, lungs, heart, 
liver, kidneys, spleen, and testes (Wolf et al., 1956). 

8.3.  Skin and Eye Irritation; Sensitization

8.3.1.  Skin

    Repeated (10 - 20) applications of undiluted solvent to the 
rabbit ear or the shaved skin of the abdomen, for 2 - 4 weeks, 
produced slight to moderate irritation (Wolf et al., 1956; Smyth et 
al., 1969a) and increased capillary permeability locally (Delaunay 
et al., 1950).  Cutaneous contact (1 ml as skin depot) in the 
guinea-pig resulted in histopathological changes, such as 
karyopyknosis, karyolysis, spongiosis, and cellular infiltration in 
the dermis, within 16 h (Kronevi et al., 1979). 

8.3.2.  Eye

    Depending on the dose level and the duration of the 
application, slight to severe irritation of the conjunctival 
membrane was reported following direct application of toluene to 
the rabbit eye (Carpenter & Smyth, 1946; Wolf et al., 1956; Smyth 
et al., 1969a). 

    The results of the different studies are summarized in more 
detail in Table 8. 

8.4.  Long-Term Exposures

8.4.1.  Inhalation  Rat

    The long-term toxicity of inhaled toluene was studied in 
Fisher-344 rats.  Four groups of 120 male and 120 female rats were 
exposed to 0, 112, 375, and 1125 mg/m3, for 6 h/day, 5 times per 
week, for 24 months.  All animals were examined for clinical 
changes throughout the course of the study and selected animals 
were used for ophthalmological, haematological and clinical 
chemistry studies, and urinalysis.  A slight, but significant 
reduction in haematocrite was observed among female rats exposed to 
375 or 1125 mg/m3.  Among the 1125 mg/m3 group only, the mean 
corpuscular haemoglobin concentration was slightly, but 
significantly, increased.  No histopathological changes were found 
in liver, kidneys, lungs, or other organ systems including spleen 
and bone marrow (Gibson & Hardisty, 1983). 

8.5.  Reproduction, Embryotoxicity, and Teratogenicity

8.5.1.  Reproduction

    No data are available.

8.5.2.  Embryotoxicity and Teratogenicity

    A number of studies have been carried out on the chicken embryo 
(McLaughlin et al., 1964; Elovaara et al., 1979), but the test is 
not considered a suitable test for teratogenicity and thus, the 
results have not been recorded in this document.  Inhalation

    (a)  Rat

    Hudk et al. (1977) exposed CFY female rats to 6000 mg 
toluene/m3 for 24 h/day during days 1 - 8, 9 - 14, or 9 - 21 of 
pregnancy.  No teratogenic effects were found.  However, a definite 
embryotoxic effect, which was related to the duration of the 
exposure was noted.  Seventeen percent of implants died or were 
resorbed in the group exposed between 7 and 14 days and, in the 
group exposed during days 9 - 21 of pregnancy, fetal and placental 
weights were decreased and the bone development was retarded. 

    In a follow-up study, Hudk & Ungvry (1978) exposed rats to 
1000 mg toluene/m3 for 8 h/day on days 1 - 21 of pregnancy, or to 
1500 mg toluene/m3 for 8 h/day on days 1 - 8 or 9 - 14 of 
pregnancy.  There were no signs of maternal toxicity at 1000 mg/m3.  
There were no significant effects in toluene-exposed groups on 
implants/dam, live fetuses/dam, dead or resorbed fetuses/dam or 
malformations.  Fetal body weight was signficiantly reduced by 13% 
when dams were exposed to 1000 mg/m3 throughout pregnancy, but not 
in the 1500 mg/m3 groups exposed in early or mid-pregnancy.  There 
was a signficant increase in retarded ossification in the 1000 
mg/m3 groups exposed throughout pregnancy and in the 1500 mg/m3
group exposed on days 1 - 8 of pregnancy.  Significant increases 
were also seen in fused and extra ribs in the fetuses, when dams 
were exposed to 1500 mg/m3 on days 9 - 14 of pregnancy. 
Table 8.  Acute effects of toluene on skin and eyes
Route/species   Dose      Duration (h)  Effect                        Reference

Rabbit          435 mg    72            mild irritation (well-        RTECS (1984)
                                        defined erythema and
                                        slight oedema)

Rabbit          500 mg    72            moderate-to-severe            RTECS (1984)
                                        erythema and moderate

Guinea-pig      1 ml      16            karyopyknosis, karolysis,     Kronevi et al. 
                                        perinuclear oedema, spong-    (1979)
                                        iosis, junctional separ-
                                        ation, cellular infiltra-
                                        tion in dermis; no liver
                                        or kidney damage

Guinea-pig      2 ml,                   completely absorbed by 5th -  Wahlberg (1976)
                covered                 7th day; no mortality up to
                                        4 weeks; weight less than
                                        controls for weeks 1 - 3;
                                        no differences at week 4

Table 8.  (contd.)
Route/species   Dose      Duration (h)  Effect                        Reference

Rabbit          0.005 ml                moderately severe injury      Smyth et al. 

Rabbit          100 mg    30 sec (then  mild eye irritation           RTECS (1984)

Rabbit          870 g    72            mild eye irritation           RTECS (1984)

Rabbit          2 mg      24 h          severe eye irritation         RTECS (1984)
    (b)  Mouse

    Hudk & Ungvry (1978) concluded from their study that toluene 
administered via inhalation at 500 mg/m3, for 24 h/day, from day 6 
to 13 of pregnancy, was not teratogenic in mice. 

    Shigeta et al. (1982) investigated the effects of maternal 
exposure to toluene at a concentration of 375 or 3750 mg/m3, for 
6 h/day, from the first to the 17th day of gestation, on mouse 
embryos, fetuses, and postnatal growth.  No significant differences 
compared with controls were found.  There was a slight increase in 
the incidence of resorbed fetuses and rudimentary 14th ribs, and an 
increase in the incidence of extra 14th ribs after exposure to 
3750 mg toluene/m3 (32.6% compared with a mean incidence in the 
control litter of 19.2%). 

    (c)  Rabbit

    In a study by Ungvry & Ttrai (l984), New Zealand rabbits were 
exposed to 500 or 1000 mg toluene/m3, for 24 h/day, on days 6 - 20 
of pregnancy.  The toluene caused spontaneous abortions at 1000 
mg/m3, but no teratogenic effects were found at either 
concentration.  Oral

    Toluene was administered, by gavage, to CD-1 mice from days 6 
to 15 of gestation at doses of 260, 430, or 870 mg/kg body weight 
per day and from days 12 to 15 at 870 mg/kg body weight per day.  
The vehicle used was cottonseed oil (0.5% of maternal body weight 
per dose).  A significant increase in embryonic lethality occurred 
at all dose levels, when toluene was administered on days 6 - 15, 
and a significant reduction in fetal weight was measured in the 430 
and 870 mg/kg groups.  Exposure to 870 mg toluene/kg on days 6 to 
15 also significantly increased the incidence of cleft palate; this 
effect reportedly did not appear to be due merely to a general 
retardation in growth rate.  When toluene was administered at 
870 mg/kg on days 12 - 15, however, decreased maternal weight gain 

was the only effect observed.  Maternal toxicity was not noted 
after exposure to toluene on days 6 - 15 at any dose level (Nawrot 
& Staples, 1979). 

    Kostas & Hotchin (1981) studied the effects of toluene in the 
drinking-water on mice exposed prenatally, postnatally, or 
continuously.  The test animals were the offspring of dams given 
drinking-water containing 16, 80, or 400 mg toluene/litre during 
pregnancy and lactation.  After weaning, the test mice were exposed 
to the same toluene concentrations as the dams.  No effects of 
toluene exposure were seen on maternal fluid consumption, offspring 
mortality rate, development of eye or ear opening, or surface-
righting response.  At 35 days of age, the offspring exposed to 
400 mg toluene/litre showed decreased habituation of open-field 
activity.  Rotorod performance measured at 45 - 55 days of age was 
depressed in all exposed groups.  Postnatal exposure alone did not 
produce similar results. 

    Although it is generally accepted that toluene readily crosses 
the placenta, it does not appear to be teratogenic in mice, rats, 
or rabbits (Hudk et al., 1977; Hudk & Ungvry, 1978, Litton 
Bionetics, Inc., 1978b; Ttrai et al., 1980; Shigeta et al., 1982; 
Ungvry et al., 1983; Ungvry, 1984; Ungvry & Ttrai, 1984).  It 
is fetotoxic, causing a reduction in fetal weight in mice and rats 
and retarded ossification with some increase in minor skeletal 
anomalies at doses that are below those toxic for the dam as well 
as at toxic doses (Hudk & Ungvry, 1978; Nawrot & Staples, 1979). 

8.6.  Mutagenicity and Related End-Points

     The genetic activity of toluene has been tested in an array 
of microbial, isolated mammalian cell, and whole organism test 
systems.  The results have usually been negative.  In the few 
studies in which a positive result was found, the purity of the 
toluene was not stated. 

8.6.1.  DNA damage

    The ability of toluene to induce DNA damage was evaluated in 2 
studies by comparing its differential toxicity for wild-type and 
DNA repair-deficient  E. coli and  S. typhimurium (Matsushita et 
al., 1971; Fluck et al., 1976; Mortelmans & Riccio, 1980).  Toluene 
did not produce any differential toxicity in these tests. 

8.6.2.  Mutation

    Toluene has been reported to be non-mutagenic in the Ames 
 Salmonella assay when tested with strains TA 1535, TA 1537, TA 
1538, TA 98, and TA 100 (Litton Bionetics, Inc., 1978a; Mortelmans 
& Riccio, 1980; Nestmann et al., 1980; Bos et al., 1981; Snow et 
al., 1981), and in the  E. coli WP2 reversion to trp+ prototrophy 
assay (Mortelmans & Riccio, 1980). 

    Toluene (0.05 - 0.30 l/ml, with and without mouse liver S-9 
activation) failed to induce specific locus forward mutations in 
the L5178y Thymidine Kinase (TK) mouse lymphoma cell assay (Litton 
Bionetics, Inc., 1978a). 

    Toluene, with and without metabolic activation, was tested  for 
its ability to induce reversions to isoleucine independence in 
 S. cerevisiae strain D7 (Mortelmans & Riccio, 1980), mitotic gene 
conversion to tryptophan independence in strains D4 (Litton 
Bionetics, Inc., 1978a) and D7 (Mortelmans & Riccio, 1980), and 
mitotic crossing over at the ade2 locus in strain D7 (Mortelmans & 
Riccio, 1980).  Toluene did not elicit a positive mutagenic 
response in any of these tests. 

    Donner et al. (1981) reported that pure liquid toluene in doses 
of 500 and 1000 mg/kg fed to  Drosophila melanogaster males (white 
strain), for 24 h, did not induce recessive lethal mutations. 

8.6.3.  Chromosomal effects

    Evans & Mitchell (1980) concluded that toluene did not alter 
sister chromatid exchange (SCE) frequencies in cultured Chinese 
hamster ovary (CHO) cells.  In this study, CHO cells without rat 
liver S-9 activation were exposed to 0.0025 - 0.04% toluene for 
21.4 h, and CHO cells with activation were exposed to 0.0125 - 
0.21% for 2 h. 

    In an analysis of 720 metaphases from the bone marrow of 5 male 
rats that had been injected sc with 0.8 g toluene/kg body weight 
per day, for 12 days, chromosomal aberrations were observed in 13% 
of the preparations.  Sixty-six percent of the aberrations were 
chromatid breaks, 24% were chromatid "fractures", 7% were 
chromosome "fractures", and 3% involved multiple injuries.  The 
frequency of spontaneous aberrations in 600 marrow metaphases from 
5 control rats injected with vegetable oil averaged 4.16% (34.2% 
were chromatid aberrations; 65.8% were breaks); no chromosomal 
"fractures" or multiple injuries were recorded.  The significance 
of the positive clastogenic effects attributed to toluene is 
difficult to assess, however, because the purity of the sample 
employed was not stated, and because the distinction between 
chromatid breaks and "fractures" was not clear (Dobrokhotov, 

    Lyapkalo (1973) administered 1 g toluene/kg body weight per day 
to 6 rats, by sc injection, for 12 days.  Treatment with toluene 
resulted in chromosome aberrations in 11.5% of the bone-marrow 
cells examined (84 aberrant metaphases/724 cells) compared with 
3.87% (40/1033) in olive oil-injected controls.  The types of 
aberrations that were found consisted of "gaps" (60.47%), chromatid 
breaks (38.37%), and isochromatid breaks (1.16%).  The purity of 
the toluene used in this study was not stated.

    Dobrokhotov & Enikeev (1976) exposed rats to 610 mg toluene/m3 
via inhalation, for 4 h daily (presumably 6 days/week).  After 4 
months of exposure, damaged metaphase chromosomes were seen in 

21.6% of the bone-marrow cells analysed.  The percentage of 
metaphases with damaged chromosomes in bone-marrow cells from 
control rats was 4.02%.  Chromosome damage was observed in the 
group with toluene 1, 2.5, and 4 months after the initial exposure.  
However, Donner et al. (1981) did not find an increased frequency 
of chromosome aberrations in the bone-marrow cells of male Wistar 
rats following inhalation exposure to toluene at 1125 mg/m3, for 
6 h/day, 5 days/week for 15 weeks.  The frequency of SCEs was 
significantly increased in rats exposed for 11 and 13 weeks, but 
the frequency was in the control range after 15 weeks of exposure. 

    Pure toluene injected ip into Charles River rats, did not 
induce bone-marrow chromosomal aberrations (Litton Bionetics, Inc., 
1978b).  Toluene was injected at dosages of 22, 71, and 214 mg/kg 
body weight in 2 different studies.  In one study, 5 rats were 
sacrificed at 6, 24, and 48 h following injection of each dose; in 
a second study, 5 rats were dosed daily at each level for 5 days, 
and the rats were sacrificed 6 h after injection of the last dose.  
Approximately 50 cells per animal were scored for damage.  Dimethyl 
sulfoxide (the vehicle) was administered ip at 0.65 mg/kg body 
weight per rat and served as a negative control, while 
triethylenemelamine (TEM) in saline administered at 0.3 mg/kg body 
weight was used as a positive control. 

    Gad-El-Karim et al. (1984) treated 5 male and 5 female CD-1 
mice with 1720 mg toluene/kg body weight by oral gavage.  An equal 
number of control animals was treated with olive oil.  The mice 
were killed 30 h after dosing.  Toluene did not cause any 
clastogenic effects (micronuclei or chromosome aberrations) in the 
bone marrow of the animals. 

    Feldt & Zhurkov (1984) studied the clastogenic effect in bone-
marrow cells and the inducibility of dominant lethal mutations in 
germ cells of randomly bred SHR male mice treated with different 
doses of toluene by gavage.  They found a dose-related increase in 
the rate of polychromatophilic erythrocytes with micronuclei.  The 
minimum effective dose was 200 mg toluene/kg body weight.  Toluene 
did not induce chromosome aberrations in bone-marrow cells or 
dominant lethal mutations in germ cells. 

    The ip administration of toluene to male Swiss mice did not 
cause an increase in micronucleated polychromatophilic erythrocytes 
in the bone marrow (Kirkhart, 1980).  Two doses (separated by 24 h) 
of 250, 500, or 1000 mg/kg body weight were administered to groups 
of 32 mice.  The animals were sacrificed at 30, 48, and 72 h after 
the first dose (8 mice/time interval).  Five hundred polychromatic 
erythocytes per animal were evaluated for the presence of 

    Toluene was evaluated for its ability to induce dominant lethal 
mutations in the sperm cells of CD-1 male mice (Litton Bionetics, 
Inc., 1981).  Test mice were exposed, via inhalation, to exposure 
levels of 375 and 1500 mg/m3 for 6 h/day, 5 days/week, for 8 weeks.  
Following treatment, the males were mated sequentially with 2 
females/week for each of 2 weeks.  Toluene did not cause any 

significant reduction in the fertility of the treated males, and 
did not cause increases in either pre- or post-implantation loss of 
embryos, compared with the controls.  A significant induction of 
dominant lethal mutations was observed in the positive control mice 
that received triethylene melamine (TEM). 

8.7.  Carcinogenicity

8.7.1.  Inhalation

    The carcinogenicity of inhaled toluene (purity 99.98%) was 
assessed in Fisher-344 rats (Gibson & Hardisty, 1983).  Groups of 
120 males and 120 females were exposed to toluene at concentrations 
of 112.5, 375, or 1125 mg/m3 for 6 h/day, 5 days/week, for 24 
months.  No increased incidence of neoplastic lesions was observed 
in males or females.  Neoplasms were observed in the lungs and 
liver, endocrine organs, lympho-reticular system, mammary glands, 
skin, testes, and uterus, but the lesions occurred with equal 
frequency in both control and treated groups.  There were no 
differences in mortality between the groups. 

8.7.2.  Oral

    Preliminary results of a study that is still in progress were 
reported by Maltoni et al. (1983).  Groups of 40 male and 40 female 
7-week-old Sprague Dawley rats were given 500 mg toluene/kg body 
weight (98.34% purity) by stomach tube in olive oil, 4 - 5 
days/week, for 2 years.  Results were reported after 92 weeks and 
indicated no increase in the incidence of Zymbal-gland, oral-
cavity, nasal-cavity, liver, or mammary-gland tumours, compared 
with controls. 

    Carcinogenicity studies on mice and rats are in progress in 
which toluene is being administered orally.  The studies fall 
within the US National Toxicology Program (no details are 

8.7.3.  Dermal

    Toluene has been used as a solvent for lipophilic chemicals 
such as polycyclic aromatic hydrocarbons, in tests for their 
carcinogenic potential, when applied topically to the shaved skin 
of animals.  The results in mice have been mainly negative for 
toluene itself (Poel, 1963; Coombs et al., 1973; Doak et al., 

    Lijinsky & Garcia (1972) reported a skin papilloma in one mouse 
and a skin carcinoma in a second mouse from a group of 30 animals 
subjected to topical applications of 16 - 20 l of toluene, twice a 
week, for 72 weeks. 

    Frei & Kingsley (1968) examined the promoting effect of toluene 
on skin tumour induction in Swiss mice following initiation with 
7,12-dimethylbenz[ a]anthracene (DMBA).  Results showed that, in 
11 out of 35 mice, DMBA plus toluene gave 6 permanent and 5 

regressing skin papillomas.  With toluene alone, one permanent and 
one regressing tumour were observed in 14 mice.  It was concluded 
from this study that toluene had some weak promotor activity, but 
these results were not confirmed by Frei & Stephens (1968). 

8.8.  Special Studies

8.8.1.  Central nervous system (CNS)

    Earlier studies on the distribution of toluene demonstrated the 
affinity of the compound for organs with a high lipid content, so 
it is not surprising that CNS effects have been observed.  A 
biphasic response to toluene exposure has been found with initial 
excitability followed by a depression in response, which is dose 
related.  This response is typical of a narcotic drug.  Toluene has 
also been shown to produce seizures in the limbic system, which 
identifies it as a CNS stimulant according to the 
neuropharmacological scheme of Winters et al. (1972). 

8.8.2.  Effects on electrical activity in the brain

    Studies that were carried out to study the influence of toluene 
on electroencephalogram (EEG) changes and sleep rhythms are 
summarized in Table 9.  These studies were mainly carried out on 
rats and the route of administration was by inhalation or ip 
injection.  In essence, high levels of exposure (above 3750 mg/m3) 
produced initial excitability with subsequent depression of 
cortical activity resulting in coma (Contreras et al., 1979).  
Seizure activity was found with high exposure levels (Takeuchi & 
Suzuki, 1975; Takeuchi & Hisanaga, 1977; Contreras et al., 1979).  
Short-term exposure to 7500 mg/m3 for 24 weeks caused interruption 
of the sleep cycle in rats (Takeuchi et al., 1977, 1979). 

8.8.3.  Effects on neurotransmitters

    Studies on changes in the concentrations of various 
neurotransmitters in rat brain following inhalation exposure to 
high concentrations of toluene have been reported and details are 
summarized in Table 10.  The significance of the changes found and 
their relationship to behavioural changes is not known. 

    Repeated exposure of male Sprague Dawley rats to high 
concentrations of toluene vapour (1875 - 3750 mg/m3, 6 h/day, for 
3 days) led to increased noradrenaline levels in the subependymal 
layer of the median eminence (SEL) and to an increase in 
noradrenaline turnover within the subependymal layer, and the 
paraventricular hypothalamic nucleus (PVI).  Increased dopamine 
(DA) levels in the lateral palisade zone of the medial palisade 
zone (MPZ) were also produced.  Measurement of the anterior 
pituitary hormone secretion showed a significant increase in 
follicle-stimulating hormone (FSH) and delayed increase in 
corticosterone secretion, following toluene exposure (Andersson et 
al., 1980).  The toluene-induced increase in catecholamine turnover 
in the MPZ could, in part, reflect an increase in DA turnover in 
the MPZ (Fuxe et al., 1978; Andersson et al., 1980). 

8.8.4.  Behaviour

    A number of behavioural studies were carried out on rats and 
mice.  The exposure route was mainly inhalation.  The dose levels 
that were studied were in the range of 3.75 - 86 250 mg/m3 during 
periods ranging from a few hours to many weeks (Table 11). 

    The results of some studies suggest that low levels (3.75 mg 
toluene/m3) of exposure may have behavioural effects (decreased 
wheel-turning activity) in mice (e.g., Horiguchi & Inoue, 1977), 
but most have only shown effects with higher concentrations (Table 

    Repeated exposure of a male mouse to a high concentration of 
toluene (22 500 mg/m3) for 30 min/day, 7 days/week, for 7 weeks, 
did not result in the development of tolerance to the acute 
behavioural effects of toluene.  However, by 3 days after cessation 
of exposure, responses had returned to baseline levels indicating 
that there were no residual effects of toluene (Moser & Balster, 

8.8.5.  Liver

    In a long-term study on rats exposed to 112, 375, or 1125 
mg/m3, for 6 h/day, 5 days/week, for 24 months, no 
histopathological evidence of liver damage was observed (Gibson & 
Hardisty, 1983).  Jenkins et al. (1970) reported that there were no 
histopathological liver changes in a variety of species exposed to 
4069 mg toluene/m3 during a 6-week inhalation period.  Short-term 
studies, generally using biochemical and morphological methods to 
study the effects of toluene on the liver, have been carried out on 
different animal species (rats, mice, guinea-pigs, rabbits, dogs, 
and monkeys) using different routes of application, i.e., 
inhalation (Gut, 1971, 1983; Reynolds, 1972; Thti et al., 1977; 
Ungvry et al., 1980, 1982; Tftgard et al., 1982), oral (Wolf et 
al., 1956; Reynolds, 1972; Mungikar & Pawar, 1976a; Pyykk, 1980, 
1983; Ungvry et al., 1980, 1982), dermal, sc, and ip (DiVincenzo & 
Krasavage, 1974; Hudk et al., 1975; Ungvry et al., 1976, 1981; 
Wahlberg, 1976; Chand & Clausen, 1982). 

    Alterations observed in the short-term studies of Ungvry et 
al. (1980, 1982) are more or less representative of those often 
observed in rats and mice exposed to toluene.  Though Ungvry and 
coworkers did not find any specific histological changes, two 
general types of alteration were identified. These included:  (a) 
biochemical responses such as proliferation of smooth endoplasmic 
reticulum; increased enzymatic activity, e.g., succinate 
dehydrogenase (EC, aniline hydroxylase (EC, and 
aminopyrine  N-demethylase activities; increased cytochrome P-450 
(EC and cytochrome b5 (EC concentrations; and 
alterations in liver weight (increased), liver glycogen 
(decreased), and BSP retention (decreased); and (b) morphological 
changes such as non-specific subcellular changes (in 10 - 15% of 
hepatocytes); dilatation of rough endoplasmic reticulum (RER), 
separation of ribosomes, variability in shape of mitochondria, and 
increase in number of mitochondria and autophagous bodies. 

Table 9.  Central nervous system effects of toluene
Species  Route       Dose     Duration     Effects                       Reference
Cat      inhalation  25 500   10 min/day   restlessness, tachypnoea,     Contreras et al. (1979)
                              x 40 days    coughing, sneezing, 
                                           salivation, mydriasis,

                     153 500  10 min/day   ataxia, collapse; EEG 
                              x 40 days    changes in cerebellum,
                                           amygdala, and visual cortex;
                                           seizures with repeated high-
                                           level exposure; recovery
                                           occurred 12 min after

Rat      inhalation  3750;    4 h/day      EEG changes (decreased        Takeuchi & Hisanaga (1977)
                     7500                  cortical and hippocampal

                     15 000   4 h/day      increased excitability
                                           followed by depression and
                                           inability to stand; changed
                                           sleep cycle myoclonic
                                           seizures; increased pulse

Rat      inhalation  7500     8h/day x     decreased threshold for       Takeuchi & Suzuki (1975)
                              8 weeks      Bemegride-induced

Rat      inhalation  3750     6 h/day x    increased spontaneous         Ikeda et al. (1981)
                              6 days/week  activity during light period
                              x 4 weeks    after repeated exposure;
                                           single exposure did not
                                           influence circadian rhythm

Rat      inhalation  7500     4 h/day x    interrupted sleep cycle;      Takeuchi et al. (1979)
                              24 weeks     decreased duration of REM

Table 9.  (contd.)
Species  Route       Dose     Duration     Effects                       Reference
Rat      inhalation  26 250   15 min x 1,  hind-limb abduction, resting  Yamawaki et al. (1982)
                              7, or 14     tremor, head weaving; 
                              days         ataxia, tachypnoea, 
                                           salivation, diarrhoea, and
                                           convulsions; frequency
                                           unchanged after 2 weeks of

Rat      inhalation  15 000   4 h/day x    changes in sleep cycle and    Hisanaga & Takeuchi (1983)
                              4 weeks      EEGs continued 1 week after

Rat      inhalation  3750     24 h         increased REM sleep           Fodor et al. (1973)

Rat      ip          200,     single dose  no effect on circadian        Nakagaki et al. (1983)
                     400,                  sleep-waking rhythm; rhythm 
                     or 600                of paradoxical sleep and
                     mg/kg                 wakefulness were changed; at
                     body                  600 mg/kg, EEG was abnormal;
                     weight                on second day, 200 mg/kg-
                                           exposed group showed 
                                           increase in paradoxical 
                                           sleep phase during dark 
                                           period; sleep-waking rhythm 
                                           returned to normal by third 

Table 10.  Changes in neurotransmitters after toluene exposure
Species   Route       Dose     Duration        Effects                        References
Rat       inhalation  26 250   15 min/14 days  decrease in 5HTa binding in    Yamawaki et al. (1982)
                                               whole brain, especially
                                               hippocampus, pons, and 
Rat       inhalation  375;     8 h             increased DAb levels           Rea et al. (1983)

Rat       inhalation  3750     8 h             increased DAb levels in
                                               striatum; increase NAc in
                                               medulla and midbrain; 
                                               increased 5HTa in cerebellum,
                                               medulla, and striatum

Rat       inhalation  750,     continuous      increased DAb in striatum      Honma et al. (1983)
                      1500,    exposure for    (dose-dependent); reduced
                      3000     30 days         5HTa in cortex and hippo-
                                               campus, NAc in hypothalamus,
                                               cortex, and hippocampus;
                                               reduced AChd in striatum and
                                               whole brain; cAMPe in 
                                               striatum; amino acids:  GABAf 
                                               increased by mid- and highest 
                                               doses while glycine was 
                                               reduced by the 750 mg/m3 

Rat       inhalation  15 000   8 h             glutamine levels in mid-brain  Honma et al. (1982)
                                               increased significantly

Rat       inhalation  3750 -   8 h             Achd increased at low dose     Honma (1983)
                      30 000                   and reduced at high dose;
                                               AchEg elevated at both 
                                               exposures; ChATh activity 
                                               reduced; dose-dependent

Table 10.  (contd.)
Species   Route       Dose     Duration        Effects                        References
Rat       inhalation  1875     6 h/day x       increase in catecholamines     Andersson et al. (1980)
(Sprague                       3 days; killed  (DAb + NAc) in lateral 
Dawley)                        16 - 18 h       palisade zone of median 
                               after exposure  eminence 

                      3750     6 h/day x 5     increase in catecholamines  
                               days; decap-    (DAb + NAc) in subependymal
                               itated 4 h      layer of median eminence;
                               after exposure  increase in FSHi in plasma
                                               and delayed increase in
                                               corticosterone secretion
Rat       inhalation  300      6 h/day x 3     decreased DAb levels in        Fuxe et al. (1982)
                               days            marginal zone of nucleus,
                                               caudatus, and anterior
                                               nucleus accumbens; DAb
                                               turnover significantly
                                               reduced in all parts of
                                               anterior caudate nucleus

Rat       inhalation  1875     6 h/day x 3     reduction in DAb turnover in   Fuxe et al. (1982)
                               days            anterior nucleus accumbens

          inhalation  5625     6 h/day x 3     effects on DAb in anterior     Fuxe et al. (1982)
                               days            nucleus accumbens dis-
                                               appeared, while a selective
                                               increase in DAb in the DAb-
                                               CCKj immunoreactive nerve 

Table 10.  (contd.)
Species   Route       Dose     Duration        Effects                        References
                      11 250   6 h/day         significantly-increased DAb 
                               x 3 days        turnover in tuberculum
                                               olfactorium; significant
                                               increases in amine levels in 
                                               DAb-CCKj immuno-reactive-
                                               nerve terminals in the 
                                               nucleus accumbens, especially 
                                               in the tuberculum olfactorium
a 5HT = 5-hydroxytryptaline.                   
b DA = dopamine. 
c NA = noradrenaline.                          
d ACh = acetylcholine.                                                
e cAMP = cyclic 3',5'-adenosine monophosphate.  
f GABA = gamma-aminobutyric acid.                       
g AChE = acetylcholinesterase.
h ChAT = choline acetyltransferase. 
i FSH = follicle-stimulating hormone. 
j CCK = cholecystokinin.
Table 11.  Behavioural effects of different doses of toluene
Species     Route       Dose    Duration     Effects                     Reference
Rat         inhalation  563     0.5, 1,      initial stimulation         Geller et al. (1979)
(Sprague                        2, or 4 h    followed by depression
Dawley)                                      in multiple FR-FI response
                                             schedule performance

Rat         inhalation  375,                 no-observed-adverse-effect  Wood et al. (1983)
                        668,                 level

                        3750,   4 h          deficit in conditioned
                        6675,                reflex; less when external
                        11 250               signal cued response

Rat (male)  inhalation  2063 -  4 h/day x    no effect on avoidance      Battig & Grandjean (1964)
                        3000    3 weeks      response

Rat (male)  inhalation  7500    8 h/day x    process of extinction in    Maeda (1970)
                                52 days      conditioned behaviour

Rat (male)  inhalation  11 250  4 h          deficit in conditioned      Shigeta et al. (1978)
                                             avoidance response

                        3750    4 h          no effect

Rat (male)  inhalation  12 000  4 h          deficit in conditioned      Krivanek & Mullin (1978);
                        and                  avoidance response          Mullin & Krivanek (1982)
                        24 000

Rat (male)  inhalation  3000    4 h          no effect                   Krivanek & Mullin (1978);
                        and                                              Mullin & Krivanek (1982)

Rat (male)  inhalation  3000    4 h          deficit in unconditioned    Krivanek & Mullin (1978);
                                             reflexes and simple         Mullin & Krivanek (1982)

Table 11.  (contd.)
Species     Route       Dose    Duration     Effects                     Reference
Rat         inhalation  15 000  2 h/day x    multiple response           Ikeda & Miyake (1978)
                                60 days      schedule; no effect on CRF 
                                             or FR30; deficit in DRL in 
                                             12-second schedule

Rat         inhalation  86 250  30 min/day   induced forced turning      Ishikawa & Schmidt (1973)
(Sprague                        x 7.6 days

Mice        inhalation  3.75,   6 h/day x    deficit in wheel-turning    Horiguchi & Inoue (1977)
(male)                  37.5,   10 days

Mice        inhalation  15 000  3 h          deficit in visual placing,  Peterson & Bruckner (1978)
                        40 000  10 min       grip strength, wire 
                                             manoeuvre tail pinch, 
                                             righting reflex

Mice        inhalation  45 000  3 h/day, 5   deficit in performance      Bruckner & Peterson (1976)
                                days/week    tests
                                for 8 weeks

    Ungvry et al. (1980, 1982) observed these changes in both 
sexes and found such alterations to be dose-related and reversible.  
Alterations in various liver cell enzyme activities have been 
reported.  No relationship to exposure time was observed.  No 
changes were noted in the activities of alanine aminotransferase 
(SGPT) (EC 2.6.l.2) or aspartate aminotransferase (SGOT) (EC 

    A dose-dependent induction of the total liver microsomal 
concentration of cytochrome P-450 was observed after exposure to 
1875, 5625, and 11 250 mg toluene/m3 for 3 days for 6 h/day 
(Tftgard et al, 1982).  The increase was significant at the 2 
highest exposure levels.  The authors also reported that the liver 
weights and liver to body weight ratio were significantly 

    In oral, ip, and sc studies, adaptive responses comparable to 
those observed in inhalation studies were seen.  Toluene induction 
of liver enzymes appeared to be less in adult females than in males 
(Pyykk, 1983).  Induced enzyme levels in young rats (13 days old) 
of both sexes were comparable to those in adults.  Reversible 
morphological changes were noted, when toluene was injected sc and 
ip in rats (Ungvry et al., 1976) and when toluene was given orally 
to guinea-pigs (DiVincenzo & Krasavage, 1974). 

8.9.  Factors Modifying Toxicity; Toxicity of Metabolites

8.9.1.  Effects of combined exposure to toluene and other chemicals

    Occupational groups and, to a minor extent, the general 
population are mostly exposed to mixtures of chemicals rather than 
to pure toluene.  The main exposure route is inhalation.  Oral 
exposure occurs to a much less extent, and is generally to very low 
levels of toluene in the form of contaminants in food and drinking-

    This criteria document will not include details of the studies 
carried out with mixtures, but they will be mentioned in a general 
sense and the available literature referred to for those who would 
like to know more.  Benzene and toluene

    It is clear that, in general, the older studies were mainly 
carried out using toluene containing variable quantities of 
benzene.  Simultaneous administration of benzene and toluene will 
result in interference in the metabolism of each chemical in the 
liver.  The conversion of benzene to its metabolites (such as 
phenol) is suppressed by toluene in rats and mice, and the 
disappearance of benzene from the blood is delayed.  The hippuric 
acid excretion metabolites of toluene are reduced by benzene. 

    Simultaneous sc administration of toluene and benzene in mice 
and rats had an ameliorating effect on benzene toxicity.  Toluene 
decreased the toxic effect of benzene on bone marrow.  Furthermore, 

toluene diminished the clastogenic effect of benzene but produced 
an additive effect on chromosome damage (Ikeda & Ohtsuji, 1971; 
Dobrokhotov, 1972; Ikeda et al., 1972; Dobrokhotov & Enikeev, 1976; 
Mungikar & Pawar, 1976b; Pawar et al., 1976; Andrews et al., 1977; 
Sato & Nakajima, 1979b; Ttrai et al., 1980; Gut et al., 1981; 
Tunek et al., 1982; Gut, 1983; Gad-El-Karim et al., 1984).  Xylenes and toluene

    From the study of Ogata & Fujii (1979), it appears that these 
solvents do not significantly interfere with each other. 

    Riihimaki (1979) studied the possible kinetic interactions 
between toluene and xylene and their metabolites and found that 
full conjugation capacity with benzoic acid and methylbenzoic acid 
was reduced during inhalation of toluene and/or xylene.  This 
suggests that the body has a relatively large capacity for the 
conjugation reaction of toluene and xylene metabolism.  However, 
the consumption of a large amount of easily-metabolized glycine may 
impair the conjugation and hence the excretion of poorer 
substrates.   n-Hexane and toluene

    It seems from a number of animal studies that toluene decreases 
the neurotoxicity of  n-hexane.  Toluene interfered in the 
metabolism of  n-hexane in rats with a resulting decrease in the 
urinary excretion of  n-hexane metabolites.  The biotransformation 
of toluene to  o-cresol and hippuric acid was not affected by 
 n-hexane, as assessed by the urinary concentrations of these 
toluene metabolites (Takeuchi et al., 1981a; Honma, 1983; 
Perbellini et al., 1982).  Toluene and other chemicals

    The ability of toluene to interfere with the biotransformation 
of several solvents has been reported by numerous authors.  It 
interferes with the metabolism of styrene (Ikeda & Ohtsuji, 1969), 
acrylonitrile (Gut et al., 1981), trichloroethylene (Ikeda, 1974; 
Withey & Hall, 1975), and methylethylketone (Iwata et al., 1983). 

    Further studies have been carried out with toluene and carbon 
tetrachloride (Tatrai et al., 1979), ethanol (Morvai & Ungvry, 
1979; Sato et al., 1981; Waldron et al., 1983), acetylsalicylic 
acid (Ungvry, 1984), and a mixture of paraffins, naphthenes, and 
aromatic compounds (Carpenter et al., 1944, 1976a,b; Carpenter & 
Smyth, 1946; Wolf et al., 1956; Taylor & Harris, 1970). 


9.1.  Acute Toxicity

    The acute effects of single doses of toluene in man are 
summarized in Table 12.  The lowest dose level of 9.4 mg/m3 seems 
to be the odour threshold, while dose levels of 37 500 and higher 
are associated with narcosis. 

9.2.  Effects of Short- and Long-Term Exposure Including Controlled 
Human Studies

    Many studies are available on the effects of short- and long-
term exposure to toluene including toluene abuse. 

    It is important to recognize that studies of intentional abuse 
and occupational studies have generally involved exposures to 
complex mixtures with toluene as the principal constituent.  Prior 
to 1950-60, benzene was a common contaminant of commercial toluene.  
Thus, when evaluating the effects of toluene on human beings, the 
purity of the compound must be considered.  In instances involving 
exposure to complex mixtures, no unequivocal cause-effect 
relationship with regard to toluene can be established. 

9.2.1.  Controlled human studies

    Odour thresholds and sensory responses to inhaled vapours of 
toluene concentrate were investigated by May (1966) and Carpenter 
et al. (1976b).  The most probable concentration for odour 
threshold, determined in 2 trials on 6 volunteers, was 9.4 mg/m3 
(Carpenter et al., 1976b).  Mild eye and throat irritation was 
noted after an 8-h exposure to 750 mg/m3 and lachrymation at 
1500 mg/m3.  Based on sensory thresholds for irritation (eye, nose, 
throat), dizziness, taste, and olfactory fatigue, 6 out of 6 
volunteers indicated their willingness to work for 8 h in a 
concentration of 825 mg toluene/m3. 

    Ogata et al. (1970) reported that 23 Japanese volunteers 
exposed to 750 mg/m3 toluene for 3 h or 3 h and 1 h break followed 
by an additional 4-h exposure showed a prolonged eye-to-hand 
reaction time, but no effect on critical flicker fusion frequency.  
No changes in either reaction time or flicker value were observed 
after exposure to toluene at 375 mg/m3.  Gamberale & Hultengren 
(1972) studied the effects of toluene on psychophysiological 
functions in 12 healthy male volunteers.  There was significant 
impairment of reaction time at 1125 mg/m3, which was further 
impaired at 1875 and 2625 mg/m3.  No impairment was observed at 
375 mg/m3.  Perceptual speed was unaffected at exposure levels 
below 2625 mg/m3. 

Table 12.  Dose-response relationships for the acute effects in 
human beings of single short-term exposures to toluene vapour
Dose             Effect
9.4 mg/m3        odour threshold
(2.5 ppm)

138.8 mg/m3      probably perceptible to most human beings
(37 ppm)                        

188 - 375 mg/m3  subjective complaints (fatigue, drowsiness, or 
(50 - 100 ppm)   very mild headache) but probably no observable 
                 impairment of reaction time or coordination

750 mg/m3        mild throat and eye irritation; prolonged eye-to-
(200 ppm)        hand reaction time; some impaired cognitive 
                 function; slight headache, dizziness, sensation of 
                 intoxication; after effects: fatigue, general
                 confusion, moderate insomnia

1125 mg/m3       detectable signs of incoordination may be expected
(300 ppm)        during exposure periods up to 8 h

1500 mg/m3       irritation of the eyes and throat and 
(400 ppm)        lachrymation; skin paraesthesia, gross signs of 
                 incoordination, and mental confusion expected 
                 during exposure periods up to 8 h

1875 - 2250      anorexia, staggering gait, nausea, nervousness
mg/m3 (500 -     (persist to next day), momentary loss of memory,
600 ppm)         significant reduction in reaction time

3000 mg/m3       pronounced nausea (after 3-h exposure); confusion,
(800 ppm)        lack of self-control; extreme nervousness,
                 muscular fatigue, and insomnia lasting for several 

5625 mg/m3       probably not lethal for exposure periods of up to 
(1500 ppm)       8 h; incoordination likely; extreme weakness

15 000 mg/m3     would probably cause rapid impairment of reaction
(4000 ppm)       time, and coordination exposures of 1 h or longer
                 might lead to narcosis and possibly death

37 500 -         onset of narcosis within a few min; longer 
112 500 mg/m3    exposures may be lethal
(10 000 -  
30 000 ppm)

    Winneke (1982) noted that exposure to 375 mg toluene/m3 for 
3.5 h did not affect psychophysiological performance in 18 
volunteers.  Simple reaction time began to increase at 1125 mg/m3.  
Complex reaction time did not change until vapour concentrations 

had reached 1875 mg/m3.  The parameters evaluated in this study 
included performance in a bisensory (auditory and visual) vigilance 
task, psychomotor performance, critical flicker fusion frequency, 
and auditory-evoked potentials. 

    Three human volunteers were exposed repeatedly to toluene 
(benzene < 0.01%) for 8-h periods at concentrations ranging from 
188 to 3000 mg/m3, in an exposure chamber.  A maximum of 2
exposures a week was maintained to allow sufficient time for 
recovery between exposures; a total of 22 exposures was performed 
over an 8-week period.  The design of the study is complex and not 
clear.  For instance, the number of h per day is different for the 
several groups.  Seven of the 22 exposures were controls (exposed 
to air only) and exposures to particular levels of toluene were 
replicated only 1 - 4 times.  The effects that were observed at 
each toluene concentration are summarized in Table 13.  Subjective 
complaints of fatigue, muscular weakness, confusion, impaired 
coordination, enlarged pupils, and accommodation disturbances were 
reported at 750 mg/m3.  These effects increased in severity with 
increases in toluene concentration until, at 3000 mg/m3, the 
subjects experienced severe fatigue, pronounced nausea, mental 
confusion, considerable incoordination and staggering gait, 
strongly impaired pupillary light reflex, and after-effects 
(muscular fatigue, nervousness, and insomnia), which lasted for 
several days (von Oettingen, 1942a,b). 

    Sixteen healthy volunteers were exposed to increasing 
concentrations of toluene ranging from 37.5, 150, to 375 mg/m3, by 
inhalation, for 6 h/day, for 4 days.  At the 375 mg/m3 exposure, 
the multipication errors, Landolt's rings, and screw plate tests 
were significantly affected in addition to the occurrence of 
headache, dizziness, and a reported sensation of intoxication.  The 
two lower levels did not result in any adverse effects (Andersen et 
al., 1983). 

    Suzuki (1973) found an effect on heart rate, a mean decrease 
of 7 beats/min in 5 male volunteers exposed to 750 mg toluene/m3 
for 6 h compared with controls.  Other studies have shown that 
exposure to toluene at levels of 375 - 750 mg/m3 for up to 30 min 
(Astrand et al., 1972; Gamberale & Hultengren, 1972) or 188 - 3000 
mg/m3 for 8 h (von Oettingen et al., 1942a,b) did not cause any 
definite effects on heart rate or blood pressure. 

    Thti et al. (1981) studied 46 workers exposed to various 
concentrations of toluene in air ranging from 75 to 750 mg/m3, for 
10 - 20 years and found no correlation between the occurrence of 
chronic diseases and toluene exposure. 

    No studies have demonstrated a cause-effect relationship 
between toluene exposure and teratogenic effects in human beings.  
There are, however, a few publications, such as those of Euler 
(1967) and Holmberg (1979), in which cases of children with 
malformations and central nervous system defects have been 
reported, but the studies were all concerned with exposures to 
mixtures of solvents.  In a study in which 132 women exposed to 

mixtures containing toluene were compared with 201 female controls, 
the exposed women recorded high percentages of menstrual disorders, 
effects on the duration of labour, perinatal mortality, or adverse 
effects on the newborn infant (Syrovadko, 1977). 

Table 13.  Effects of controlled 8-h exposures to pure toluene on
3 human subjectsa,b
Concentration  Number of  Effects
0 mg/m3        7          no complaints or objective symptoms, except
                          occasional moderate tiredness toward the 
                          end of each exposure, which was attributed 
                          to lack of physical exercise, unfavorable 
                          illumination, and monotonous noise from 

188 mg/m3      2          drowsiness with a very mild headache in 1
                          subject; no after effects

375 mg/m3      4          moderate fatigue and sleepiness (3), and a
                          slight headache on one occasion (1)

750 mg/m3      3          fatigue (3), muscular weakness (2),
                          confusion (2), impaired coordination (2),
                          paraesthesia of the skin (2), repeated
                          headache (1), and nausea (1) at the end 
                          of the exposure; in several instances, the
                          pupils were dilated, pupillary light reflex
                          was impaired, and the fundus of the eye was
                          was engorged; after-effects included 
                          fatigue, general confusion, moderate 
                          insomnia, and restless sleep in all 3 

1125 mg/m3     2          severe fatigue (3), headache (2), muscular 
                          weakness and incoordination (1), and slight 
                          pallor of the eyeground (2); after-effects 
                          included fatigue (3) and insomnia (1)
1500 mg/m3     2          fatigue and mental confusion (3), headache, 
                          paraesthesia of the skin, muscular 
                          weakness, dilated pupils, and pale 
                          eyeground (2); after effects were fatigue 
                          (3), skin paraesthesia (1), headache (1), 
                          and insomnia (2)

Table 13.  (contd.)
Concentration  Number of  Effects
2250 mg/m3     1        extreme fatigue, mental confusion,
                        exhilaration, nausea, headache, and dizziness 
                        (3), and severe headache (2) after 3 h of 
                        exposure; after 8 h exposure, the effects 
                        included considerable incoordination and 
                        staggering gait (3), and several instances of 
                        dilated pupils, impaired pupillary light 
                        reflex, and pale optic discs; after-effects 
                        included fatigue and weakness, nausea, 
                        nervousness, and some confusion (3), severe 
                        headache (2), and insomnia (2); fatigue and 
                        nervousness persisted on the following day

3000 mg/m3     1        rapid onset of severe fatigue and, after 3 h, 
                        pronounced nausea, confusion, lack of self-
                        control, and considerable incoordination and 
                        staggering gait in all 3 subjects; also, 
                        pupillary light reflex was strongly impaired 
                        (1), and optic discs were pale (2); all 3 
                        subjects showed considerable after-effects, 
                        lasting at least several days, which included 
                        severe nervousness, muscular fatigue, and 
a From:  von Oettingen et al. (1942a,b).
b Exposures were twice weekly for 8 weeks.  The number of subjects 
  affected is noted in parentheses.

9.2.2.  Short- and long-term abuse in the general population

    It is important to recognize that studies of intentional abuse 
are generally concerned with exposures to complex mixtures in which 
toluene is usually the principal constituent.  Benzene is one of 
the most important contaminants in commercial toluene. 

    Solvent abuse is a major problem throughout the world.  As an 
example, in Scotland alone, 1300 new cases of solvent abuse had 
been reported to the police between 1977 and 1980 in a secondary 
school population of almost half a million (King, 1982).  In the 
same period, 6 deaths following glue sniffing were recorded in 
Scotland (King et al., 1981).  King (1982) and King et al. (1981) 
diagnosed a series of 20 cases of acute encephalopathy in children 
aged 8 - 14 years following toluene abuse; 5 presenting in coma, 5 
with ataxia and dysarthria, 3 with convulsions, and 2 with diplopia 
and behaviour disturbance.  In 6 of these subjects, the diagnosis 
of solvent-induced encephalopathy was made solely by a blood-
toluene assay (0.8 - 8.0 mg/litre).  Six of these children left 
hospital with neurological impairment and one, seen 1 year later, 

had persistent cerebellar signs.  Thirteen children recovered 
completely.  The authors emphasized the importance of diagnosis, if 
further damage due to continued abuse is to be prevented. 

    The extent of "sniffing" solvents containing toluene has been 
extensively reviewed (Massengale, et al, 1963; Barman et al., 1964; 
Press & Done, 1967a,b; Gellman, 1968; Wyse, 1973; Linder et al., 
1975; Faillace & Guynn, 1976; Oliver & Watson, 1977; Walter et al., 
1977; Watson, 1979).  The concentrations of toluene inhaled under 
these conditions can approach 112 500 mg/m3, i.e., saturation 
concentration at 20 C.  Such severe exposures can result in gross 
disorientation and unconsciousness (Hayden et al., 1977). 

    Episodes of toluene abuse are characterized by the progressive 
development of CNS symptoms of dysfunction.  Toluene sniffers 
experience an initial excitatory stage that is typically 
characterized by drunkenness, dizziness, euphoria, delusions, 
nausea, and vomiting, and, less commonly, visual and auditory 
hallucinations (Press & Done, 1967a,b; Wyse, 1973; Lewis & 
Patterson, 1974; Hayden et al., 1977; Oliver & Watson, 1977; Tarsh, 
1979; Streicher et al., 1981).  As the duration of exposure 
increases, symptoms indicative of CNS depression become evident 
including confusion and disorientation, headache, blurred vision 
and reduced speech, drowsiness, muscular incoordination, ataxia, 
depressed reflexes, and nystagmus.  In extreme cases, there is loss 
of consciousness possibly associated with convulsions (Helliwell & 
Murphy, 1979).  The duration and severity of these effects vary 
greatly, depending on the intensity of exposure; the duration may 
range from 15 min to a few hours (Press & Done, 1967b).  There are 
reports of seizures including status epilepticus occurring as the 
primary presentation of acute intoxication in toluene sniffers 
(Helliwell & Murphy, 1979; King et al, 1981). 

    A case of permanent encephalopathy from repeated, prolonged 
exposure (14 years) to pure toluene vapour was reported.  A 33-
year-old man purchased approximately 4 litres of toluene from a 
paint store every 4 - 6 weeks for 14 years to satisfy his addiction 
to toluene vapour.  The result of this addiction was permanent 
cerebral atrophy.  The clinical signs were ataxia, tremulousness, 
unsteadiness, emotional lability, marked snout reflex (distorted 
nostrils on subjection to sniff test), and positive Babinski sign 
on the right side.  The brain (cerebral hemispheres) damage was 
confirmed by EEG and pneumoencephalography.  This same individual 
was the subject of a report published by Grabski (1961) who 
reported cerebellar degeneration, hepatomegaly, and impaired liver 
function after 6 years of toluene vapour inhalation (Knox & Nelson, 

    O'Brien et al. (1971) reported reversible hepatorenal damage, 
confirmed by biochemical tests, in a 19-year-old male who sniffed 
glue while employed as a sign painter.  The blood-toluene level was 
0.61 mg/litre. 

    These findings lead to the conclusion that should adverse 
effects result from the abuse of toluene-based products, the 
effects are likely to be transient and to follow closely on 
intensive solvent exposure. 

    Schikler et al. (1982) reported the findings on 11 out of 42 
cases of toluene abuse, who were examined by computed tomography 
(CT) scan because of neurological abnormalities; 6 out of the 11 
were found to have cerebellar cortical atrophy; 2 of the 6 had 
cerebellar atrophy.  The mean age of the patients was 22 years 
(range 14 - 31 years) with a mean exposure of 10 years (range 4 - 
16 years). 

    Fornazzari et al. (1983) noted a marked impairment of 
neurological and neuropsychological test performance in 65% of 24 
solvent abusers.  Cerebellar symptoms were particularly prominent.  
The impairment was significantly correlated with CT scan 
measurements of cerebral and cerebellar atrophy. 

    Chronic neurological damage from solvent abuse (Table 14) has 
been sporadically reported in patients who have abused toluene for 
from 1.5 to 14 years and takes the form of dementia with cerebellar 
ataxia (Satran & Dodson, 1963; Kelly, 1975; Hnninen et al., 1976; 
Boor & Hurtig, 1977; Sasa et al., 1978; Malm & Lying-Tunell, 1980; 
Lewis et al., 1981; Metrick & Brenner, 1982; Fornazzari et al., 
1983; Lazar et al., 1983). 

    Pathologically, in a post-mortem analysis of a 27-year-old man 
addicted to a thinner containing approximately 40% toluene for 12 
years, the most striking feature was diffuse cerebral and 
cerebellar cortex atrophy.  There was a 70% loss of cerebellar 
Purkinje cells and giant axonal degeneration in the posterior and 
lateral columns of the spinal cord (Escobar & Aruffo, 1980). 

    Other effects attributed to chronic glue sniffing (different 
types of mixtures) besides cerebellar dysfunction include optic 
atrophy with blindness (Keane, 1978; Ehyai & Freemon, 1983), 
sensorineural hearing loss (Ehyai & Freemon, 1983), and convulsions 
(Helliwell & Murphy, 1979; Allister et al., 1981).  Evidence of 
chronic neurological damage after a much shorter duration of glue 
sniffing has appeared recently.  Channer & Stanley (1983) reported 
the case of a 16-year-old boy presenting with persistent visual 
hallucinations after cessation of glue sniffing for several months, 
who had evidence of a diffuse encephalopathy characterized by an 
abnormal EEG and delayed visual evoked responses (VERs) to 
checkerboard pattern reversal.  In another study (Cooper et al., 
1985), VERs were studied in 12 young asymptomatic glue sniffers who 
had abused glue for several months, but not on the day of the 
recordings.  The mean latencies of the VERs in the sniffers were 
significantly prolonged in all compared with 27 controls and 
outside the normal range in nine.  In 2 subjects, the recordings 
were repeated after abstinence for 6 months and remained abnormal.  
The recovery process after damage has occurred seems to be slow if 
the sniffing is stopped.  The time scale is at least 6 months and 
it may be that the damage is permanent. 

Table 14.  Summary of chronic toluene-abuse cases
Subject       Inhala-              Clinical and pathological manifestation                 Reference
(age)         tion     cerebel-  mental   abnormal  brain    visual   liver    others
              period   lar dys-  retard-  EEG       atrophy  impair-  impair-
              (years)  function  ation                       ment     ment
Pure toluene

Male (25)      6       +         +                           -        +                    Grabski (1961)
     (33)      14      +         +        +         +        -        +                    Knox & Nelson 
Female (18)    6       +         +        +         -                 +                    Takeuchi et al.
Male (21)      12                +                  +        +        -                    Lazar et al. (1983)

99% Toluene

Male (25)     10       +         +        -         +                 -                    Boor & Hurtig
Male (59)     long     +         +        -         -                 -                    Boor & Hurtig


Male (30)     10       +         +        +         -                 -                    Satran & Dodson
Male (25)     0.3                +        -         -                                      Escobar & Aruffo
Male (11)     < 1      +         +        +         -                 -                    King (1982)

Male (25)     5        +         -                  +        +                 hearing     Lazar et al. (1983)
Male (18)     3                  -                  -        +        -        poly-       Ehyai & Freemon
                                                                               neuro-      (1983)
Male (23)     7                  +                  -        -                             Ehyai & Freemon

Table 14.  (contd.)
Subject       Inhala-              Clinical and pathological manifestation                 Reference
(age)         tion     cerebel-  mental   abnormal  brain    visual   liver    others
              period   lar dys-  retard-  EEG       atrophy  impair-  impair-
              (years)  function  ation                       ment     ment
68-30% Toluene

Male (19)     0.8      +         +        +         -        +        +        hallu-      Suzuki et al. 
                                                                               cination,   (1983)
Male (23)     12       +         +        +         +        +        -        haematuria  Metrick & Brenner
                                                                               brainstem   (1982)

Aromatic hydrocarbon

Female (30)   5        +         +        +                  +        -                    Prockop (1977)


Male (?)      ?                  +        +         +        -        -                    Weisenberger (1977)
Male (28)     10                                    +                 -        hearing     Lazar et al. (1983)

Female (19)   1.5      +         -        -         -                 -                    Kelly (1975)
Male   (20)   3        +         +                           +                             Keane (1978)
Male   (28)   16       +         +                  +        +                haematuria  Metrick & Brenner
                                                                               brainstem   (1982)

Glue or thinner

Male (27)     10       +         +                  -        +        -                    Sasa et al. (1978)
Male (29)     12       +         +        +         +                 -        grand       Allister et al.
                                                                               mal         (1981)

Table 14.  (contd.)
Subject       Inhala-              Clinical and pathological manifestation                 Reference
(age)         tion     cerebel-  mental   abnormal  brain    visual   liver    others
              period   lar dys-  retard-  EEG       atrophy  impair-  impair-
              (years)  function  ation                       ment     ment

Male (15)     ?                           +                          -        micro-      Lazar et al. (1983)
Male (16)     0.25                        +         -        -                 hearing     Lazar et al. (1983)
Male (27)     5        +                  -         +        +                             Ehyai & Freemon
    Haematological abnormalities have been occasionally reported in 
sniffers of toluene-based glues.  In a clinical survey of 89 glue 
sniffers (aged 8 - 18 years), abnormalities of the blood were found 
in 68 of the cases (Sokol & Robinson, 1963).  An effect on the 
white blood cells was indicated by findings of eosinophilia (25 
subjects), leukocytosis (12 cases), and lymphopenia (4 subjects).  
They also reported low haemoglobin values in 20 subjects and 
basophilic stippling of erythrocytes in 42 of the patients, and 
noted the frequent occurrence of poikilocytosis (25 cases), 
anisocytosis (20 cases), hypochromia (14 cases), and polychromasia 
(10 cases). 

    Examination of peripheral blood samples from 24 solvent 
abusers, admitted to hospital, showed that 5 had lymphopenia, 3 
lymphocytosis, and 3 normochromic normocytic anaemia (including 2 
females) (Fornazzari et al., 1983). 

    In a total of 90 cases surveyed by 4 groups of investigators, 
there were no instances of anaemia or lymphopenia, a single report 
of neutropenia, and 6 cases characterized by an eosinophilia 
greater than 5% were described (Christiansson & Karlsson, 1957; 
Massengale et al., 1963; Barman et al., 1964; Press & Done, 1967b).  
Powars (1965) diagnosed 1 fatal case of acute aplastic anaemia 
associated with pancytopenia and 5 patients with homozygous sickle 
cell anaemia that showed a reversible erythrocytic aplastic crisis 
associated with glue sniffing. 

    Despite occasional reports to the contrary, Assennato et al. 
(1977) and Trevisan & Chiesura (1978) came to the conclusion that 
there appears to be a low incidence of hepatorenal injury in 
persons who abuse toluene-based products.  Litt et al. (1972) found 
modest elevations in serum glutamic pyruvic transaminase (SGPT) (EC levels in only 2% and increased alkaline phosphatase (EC levels in 5% of a group of 982 glue sniffers.  Press & 
Done (1967b) observed slight but transient abnormalities in the 
urinalysis of a small percentage of the glue sniffers they 
examined.  Liver function tests were normal.  Weisenberger (1977) 
observed some disturbances of aspartate aminotransferase (EC and LDH in a toluene addict who was hospitalized in a 
catatonic state.  These abnormalities disappeared early in the 
patient's hospital stay.  Fornazzari et al. (1983) found transient 
elevations of serum alkaline phosphatase in 13, and SGOT in 7, 
solvent abusers.  These changes returned to normal after 2 weeks' 

    Russ et al. (1981) reported irreversible renal failure in a 
20-year-old male who had sniffed glue containing 16.5% toluene 
twice a week for 9 months.  Repeated renal biopsies showed 
progressive tubular damage. 

    It appears that deliberate inhalation of glues and paint is 
associated with renal tubular defects documented by the presence of 
metabolic acidosis (Taher et al., 1974; Fischman & Oster, 1979; 
Bennett & Forman, 1980; Kroeger et al., 1980; Moss et al., 1980; 
Voigts & Kaufman, 1983).  The cases of acidosis described by these 

investigators are characterized by serious electrolyte 
abnormalities (hypokalemia, hypophosphatemia, hyperchloremia), and 
may be related to impaired hydrogen ion secretion in the distal 
renal tubule (distal renal tubular acidosis).  Other metabolic 
abnormalities include pyuria, haematuria, and proteinuria (Voigts & 
Kaufman, 1983).  The role of toluene in the causation of renal 
damage in these cases is unclear, since solvent mixtures were 

    Toutant & Lippman (1979) reported the outcome of pregnancy in a 
woman addicted to solvents containing toluene for 14 years.  In 
addition to her heavy solvent abuse, she had a 3-year history of 
alcohol intake (6 packs of beer/week).  The male child born at term 
was at the 10th percentile for weight and the 5th percentile for 
head size.  It had similar features to fetal alcohol syndrome 
(microcephaly, flat nasal bridge, hypoplastic mandible, etc.).  The 
authors suggested that there might be an analogous "fetal solvents 
syndrome" or that excessive solvent intake might enhance the 
toxicity of alcohol.  Recently, Streicher et al. (1981) reported 
that of 3 women who continued to sniff paint throughout pregnancy, 
one had a child with cerebellar dysfunction.

    Reisin et al. (1975) published a report regarding the 
development of severe myoglobinuria and non-oliguric acute renal 
failure in a paint factory worker who was exposed to pure toluene 
by skin contact and aspiration when a hose burst.  The patient had 
inhaled sufficient amounts of toluene to cause loss of 
consciousness for 18 h and subsequent development of chemical 
pneumonitis.  He also sustained superficial burns on approximately 
10% of his body surface area.  Acute renal failure apparently 
developed from the lack of fluid intake accompanied by heavy 
myoglobinuria rather than from a direct effect of toluene.  The 
early administration of intravenous fluids and diuretics, and the 
use of haemodialysis, led to complete recovery. 

    Askergren (1981) and Askergren et al. (1981a,b) observed that 
exposure of rotogravure workers to toluene was associated with an 
elevated excretion of erythrocytes and leukocytes in the urine.  
Exposure levels in the work-place were reported to be below 
300 mg/m3, though some subjects were exposed for short periods to 
levels 2 - 3 times as high.  Franchini et al. (1983) reported that 
renal function impairment indicators such as total proteinuria, 
albuminuria and urinary excretion of muramidase (EC and 
beta-glucuronidase (EC provided some evidence of renal 
damage due to occupational exposure to organic solvents and 
suggested that the kidney lesions are tubular rather than 
glomerular and mild. 

9.2.3.  Epidemiological studies

    No epidemiological studies on populations exposed to toluene 
are available. 

9.3.  Occupational Exposure

    Using data obtained from a survey conducted in the USA by the 
US Bureau of Occupational Safety and Health in 1977, US NIOSH 
estimated that 1.6 million persons in the work force could have 
potential exposure to toluene. 

9.3.1.  Skin and mucous membranes

    Repeated or prolonged skin contact with liquid toluene will 
remove natural lipids from skin, causing dryness, fissures, and 
contact dermatitis (Gerarde, 1960; Browning, 1965) or an injury to 
the epidermal stratum corneum (Malten et al., 1968). 

    Parmeggiani & Sassi (1954) reported irritation of the upper 
respiratory tract and conjunctiva in male subjects who were exposed 
to 750 - 3000 mg toluene/m3 for "many" years.

    Transient epithelial injury to the eyes, which consisted of 
moderate conjunctival irritation and corneal damage, with no loss 
of vision, was observed in workers who were accidentally splashed 
with toluene (McLaughlin, 1946; Grant, 1962).  Complete recovery 
generally occurred within 48 h.  The results of opthalmological 
examinations of 106 spray painters who were exposed to toluene in 
mixtures at levels of 375 - 4125 mg/m3 for periods ranging from 2 
weeks to more than 5 years were reported to be without clear 
symptoms (Greenburg et al., 1942).  Loss of visual acuity, optical 
neuropathy, and nystagmus in toluene or solvents- and thinner-
sniffers have been reported by Prockop (1977), Keane (1978), Malm & 
Lying-Tunell (1980), Takeuchi et al. (1981b), and Kimura et al. 

9.3.2.  Central nervous system

    Wilson (1943) described the effects of exposure to "commercial" 
toluene vapour on 100 workers (out of a total of 1000 workers) who 
showed symptoms severe enough to seek examination at a hospital.  
The workers were exposed daily to toluene concentrations ranging 
from 188 to 5625 mg/m3 for periods of 1 - 3 weeks.  The 
concentration of toluene was determined shortly after each exposed 
person appeared at the hospital with symptoms, and the patients 
were classified into groups according to extent of exposure.  The 
following effects were reported: 

    at 188 - 750 mg/m3 (approximately 60% of the patients):
    headache, lassitude, and loss of appetite; these symptoms
    were so mild that they were considered to be due primarily
    to psychogenic and other factors rather than to toluene

    at 750 - 1875 mg/m3 (approximately 30% of the patients):
    headache, nausea, bad taste in the mouth, anorexia,
    lassitude, slight but definite impairment of coordination
    and reaction time, and momentary loss of memory; and

    at 1875 - 5625 mg/m3 (approximately 10% of the patients):
    nausea, headache, dizziness, anorexia, palpitation, and
    extreme weakness; loss of coordination was pronounced and
    reaction time was definitely impaired.

    No clear distinction has been made between the effects 
attributable to the direct depressant action on the nervous system 
of toluene present in the organism, and those that may be 
persisting functional (or even morphological) sequelae of past 
exposure.  Psychological examinations, carried out 16 h after the 
working shift, revealed some impairment in psychological 
performance, which suggests the possibility that the functional 
changes may persist for some time after the direct narcotic effect 
(Hnninen et al., 1976).  The impaired mental functions included 
visual intelligence, sensory and vestibular function, memory 
functions, and verbal intelligence (Lindstrom, 1973, 1982; de Rosa 
et al., 1974; Rouskova, 1975; Hnninen et al., 1976; Sepplinen et 
al., 1978; Elofsson et al., 1980; Husman & Karli, 1980; Biscaldi et 
al., 1981; Iregren, l982; Sepplinen, 1982; Coscia et al., 1983). 

    Narcosis is the likely result of acute toluene exposure at high 
concentrations.  A number of accounts of workers who were rendered 
unconscious by toluene vapour have been published (Lurie, 1949; 
Browning, 1965; Longley et al., 1967; Reisin et al., 1975).  Most 
of these cases involved the exposure of workmen to high levels of 
toluene during maintenance operations in confined areas with poor 

9.3.3.  Peripheral nervous system

    There have been no reports of peripheral neuropathy occurring 
in association with exposure to toluene alone.  Most of the 
reported cases have involved exposures to mixtures containing 
either  n-hexane or methyl ethylketone, which are known to cause 
damage to peripheral nerves (Herskowitz et al., 1971; Goto et al., 
1974; Shirabe et al., 1974; Korobkin et al., 1975; Towfighi et al., 
1976; Alkenkirch et al., 1977; Boor & Hurtig, 1977). 

    Peripheral biopsy of radial cutaneous nerves showed distention 
of axons, thinning of the myelin sheath, and widening of the nodes 
of Ranvier (Korobkin et al., 1975); and axonal degeneration of 
large diameter fibres in sural nerve (Shirabe et al., 1974; 
Towfighi et al., 1976).  Neurological examination revealed 
autonomic vascular dysfunction in 28% (15% in control) and spinal 
root syndrome in 9% (0.05% in control) (Syrovadko, 1977).  The 
author attributed the spinal root syndrome and also uterine 
prolapse to the working posture; other changes (neurological, 
haematological, and gynaecological) were considered to be due to 
the action of toluene. 

9.3.4.  Blood and haematopoietic system

    Early reports of occupational exposures (generally prior to the 
1950s) ascribed myelotoxic effects to toluene exposure (Ferguson et 
al., 1933; Greenburg et al., 1942; Wilson, 1943).  However, most of 

the recent evidence indicates that the chemical is not toxic to the 
blood or bone marrow (Parmeggiani & Sassi, 1954; Capellini & 
Alessio, 1971; Matsushita et al., 1975; Thti et al., 1981).  The 
myelotoxic effects previously attributed to toluene are now 
generally regarded to be the result of concurrent exposure to 
benzene, present as a contaminant. 

    Banfer (1961) examined 112 rotogravure printers and helpers who 
were exposed to the vapours of toluene-containing printing inks for 
at least 3 years.  Controls included 478 unexposed persons from 2 
groups.  The available commercial toluene used in these inks 
reportedly contained only traces of benzene (< 0.3%).  Analysis of 
the room air for toluene by infrared spectroscopy was limited to 
samples taken on a single day from 5 different locations in the 
machine room (750 - 1500 mg/m3).  Haematological examinations of 
the workers and controls did not reveal any significant changes in 
the total number of leukocytes, lymphocytes, granulocytes, or 
erythrocytes, or in haemoglobin levels.  Matsushita (1966) 
investigated 97 painters exposed to toluene (up to 6750 mg/m3) and 
xylene for an average of 6.2 years and 49 control workers.  No 
significant differences were found in the specific gravity of whole 
blood, erythrocyte counts, haemoglobin concentration, and leukocyte 
counts between the exposed workers and the controls, except for a 
significant increase in Mommsen's toxic granules in the exposed 

9.3.5.  Liver and kidney

    Liver enlargement (palpation) was reported in 61 aeroplane 
painters exposed to 375 - 4125 mg toluene/m3 for up to 5 years.  
Urinalysis and bilirubin in serum did not show any abnormalities 
(Greenberg et al., 1942). 

    Waldron et al. (1982) examined liver function in 59 males, who 
had been exposed to toluene for various periods, in comparison with 
59 controls.  At the time of the study, levels of exposure were 
about 375 mg/m3; however, in previous years, the levels had been 
considerably higher (up to 1875 mg/m3).  Exposed males had 
significantly lower levels of alanine aminotransferase (EC  There was no evidence of a trend towards higher levels 
with increasing duration of exposure.  None of the men had any 
symptoms of liver dysfunction on clinical examination. 

    Szilard et al. (1978) reported the results of periodic 
observation of 170 persons working in toluene-containing 
atmospheres (duration of exposure 2 - 14 years at concentrations of 
200 - 300 mg/m3 rising at times to 3000 mg/m3).  They found 
hepatomegaly and increased SGOT activity in 20 - 50% of workers.  
Twenty-two of the 170 workers had liver biopsies.  Routine 
histology revealed no pathological changes.  Electron microscopy 
revealed changes in the shape of mitochondria and degranulation of 
the RER. 

    Abnormalities in the glycoprotein, serum mucoid, and 
haptoglobin patterns were reported among 53 women with histories of 
occupational exposure to toluene (Kowal-Gierczak et al., 1969), and 
51 showed changes in the serum levels of iron and copper, and 
urinary excretion of porphyrin (Cieslinska et al., 1969), while 
exposed to toluene at about 250 mg/m3 for 2 - 17 years. 

    In an examination of 94 rotogravure printers with a history of 
exposure to 68 - 1875 mg toluene/m3 and of a reference group of 30 
municipal clerks, Szadkowski et al. (1976) found a significant 
reduction in bilirubin and alkaline phosphatase levels in the 
exposed group, but no difference from controls in SGOT, SGPT, 
leucine aminopeptidase (EC, or cholinesterase (EC 

9.3.6.  Menstruation

    Michon (1965), Matsushita et al. (1975), and Syrovadko (1977) 
described studies concerning the complaints of women exposed to 
toluene, mainly in combination with other aromatic hydrocarbons.  
These complaints included menstrual disturbances such as prolonged 
and intensive menstrual bleeding.  From the available data, it was 
emphasized that a specific effect of toluene could not be 

9.3.7.  Chromosome damage


    There are discrepancies in findings related to chromosome 
damage in peripheral lymphocytes among workers exposed to toluene.  
An unequivocal evaluation of the genetic effects of occupational 
toluene exposure, based on available studies, cannot be made 
because of the relatively small number of subjects analysed, 
variation in the extent of exposure between these studies, and 
insufficient information on possible exposure to other chromosome-
damaging agents (benzene, tobacco smoke, etc.). 

    Conventional chromosome aberration analyses from 24 rotogravure 
workers (exposed only to toluene after 1953) (Forni et al., 1971) 
and SCEs and chromosome aberration analyses from 32 rotogravure 
workers (average length of exposure = 14 years) (Mki-Paakkanen et 
al., 1980) revealed no increase in the rate of chromosome damage in 
cultured blood lymphocytes compared with controls.  In the former 
study, the concentration of toluene, containing traces of xylene, 
was generally below, but occasionally above, 750 mg/m3, in the 
working zone.  However, between the working machines, it was well 
over 750 mg/m3.  In the second study, individual exposures varied 
from 26 - 420 mg toluene containing < 0.05% benzene/m3. 

    Haglund et al. (1980) reported negative findings from 17 
workers in the paint industry exposed to a mixture of organic 
solvents, mainly containing xylene and toluene.  In the chromosome 
aberration analyses, no differences were found between 5 workers 
(employed from 0.8 to 44 years with the highest exposure to toluene 
concentration > 100 mg/m3), and their matched controls. 

    Funes-Cravioto et al. (1977) presented data on 14 workers who 
were exposed to toluene (possibly containing a low percentage of 
benzene) in a rotogravure factory.  Length of exposure ranged from 
1.5 to 26 years and air measurements of toluene showed time-
weighted average values of 375 - 750 mg/m3 with occasional rises to 
1875 and 2655  mg/m3.   In most cases, the exposures were 
sufficient to cause frequent headaches and fatigue, and occasional 
vertigo, nausea, and feelings of drunkenness.  Analyses of cultured 
blood lymphocytes showed an excess of chromosome aberrations in the 
14 toluene-exposed workers compared with a control group of 49 

    Bauchinger et al. (1982) reported a statistically-significant 
increase in the mean number of SCEs and structural chromosomal 
aberrations in cultured blood lymphocytes from a group of 20 male 
rotogravure workers exposed to 750 - 1125 mg toluene/m3 (benzene 
content < 0.3%) for more than 16 years, in comparison with 24 
unexposed persons.  Their results were similar to the observations 
of Funes-Cravioto et al. (1977).  For the statistical evaluation of 
SCEs data, the subjects of both groups were subdivided into smokers 
and non-smokers.  Such an analysis revealed significantly higher 
SCE values for non-smoking rotogravure workers than for non-smoking 
controls.  This was also true for smoking rotogravure workers 
compared with smoking controls.  In both groups, smokers had 
significantly higher SCE values than non-smokers.  Later, Schmid & 
Bauchinger (1984) repeated the chromosome aberration and SCEs 
analyses from 27 workers of the same plant with earlier exposure to 
toluene.  The workers had not been exposed for between 4 months and 
5 years.  In a subgroup of 13 workers without toluene exposure for 
up to two years, a significantly higher number of cells with 
aberrations was found (mainly chromatid types) compared with 
controls, whereas the frequency of gaps was not elevated.  A 
subgroup of 14 workers without toluene exposure for between 2.5 and 
5 years did not show any increase in the number of cells with 
structural chromosome aberrations.  In both subgroups, the SCE 
values for smoking and non-smoking workers were unchanged compared 
with the corresponding controls.  The authors concluded that 
structural chromosome changes induced by toluene exposure could 
persist for up to 2 years after exposure, but that after this time, 
the number of gaps and SCEs dropped to the control level. 

    According to Bauchinger et al. (1982), a weak clastogenic 
effect of toluene can only be detected if there is a sufficiently 
large number of subjects exposed to high toluene concentrations 
(> 750 mg/m3) and a large number of cells are scored.  The authors 
state that in the previously published studies too few metaphases 
(100 cells per individual) were analysed and that the negative 
result of Forni et al. (1971) and Mki-Paakkanen et al. (1980) may 
be explained by the lower toluene exposure of the workers. 

    The work of Vijayalaxmi & Evans (1982) and that of Obe et al. 
(1982) quite clearly showed that the frequency of chromosome 
aberrations (and also of SCEs) is increased in cultured blood 
lymphocytes of smokers as compared with non-smokers.  Moreover, 

Mki-Paakkanen et al. (1984) have found that smoking causes the 
same type of damage (chromatid-type) observed by Bauchinger et al. 
(1982) and Schmid & Bauchinger (1984). 


10.1.  Evaluation of Human Health Risks

    The major route of human exposure is through inhalation. 
Toluene is readily absorbed from the respiratory tract with an 
uptake of approximately 40 - 60% in human beings.  Smaller amounts 
are rapidly absorbed via the skin and complete absorption occurs in 
the gastrointestinal tract, but at a slower rate.  However, the 
presence of small amounts of toluene in drinking-water and food 
adds only minor quantities to man's total daily uptake.  Once 
absorbed, toluene is rapidly metabolized to benzoic acid and 
excreted in the urine as hippuric acid and its conjugates.  In the 
case of daily exposure to high concentrations, for instance, under 
occupational conditions, significant uptake of toluene into lipid-
rich tissues, such as adipose tissue and the central nervous 
system, occurs. 

10.2.  Acute and Short-Term Effects on Man

    Based on the available studies, the odour threshold for toluene 
in human beings is estimated to be 9.4 mg/m3 (2.5 ppm).  The acute 
and short-term effects of toluene can be summarized as follows: 

    -   levels up to 375 mg/m3 for a few hours showed subjective
        complaints of fatigue and drowsiness, but no observable 
        impairment of reaction time or coordination;

    -   up to 750 mg/m3 for 8 h resulted in mild throat and
        eye irritation, some impairment of cognitive function,
        headache, dizziness, and sensation of intoxication;

    -   up to 1500 mg/m3 for 8 h, besides the symptoms already 
        mentioned, caused lachrymation, skin paraesthesia, gross 
        signs of incoordination, and mental confusion.

These effects are reversible on cessation of exposure, but become 
increasingly severe and persistent with increasing concentration 
and/or duration of exposure.  No toxicity was observed in human 
beings repeatedly exposed to toluene levels of less than 188 mg/m3 
for short periods of time or exposed once to a level of 375 mg/m3 
for a few hours. 

    The critical target organs for toluene are the central nervous 
system, probably because of the accumulation of toluene in the 
lipid-rich tissues, from which it is slowly released (toluene 
concentrations are higher in brain and adipose tissues than in the 

    Effects on the central nervous system begin to appear with an 
inhalation exposure of 375 mg/m3, for 6 h/day, over 4 days.  Gross 
signs of incoordination, depression of the central nervous system, 
and mental confusion are produced with exposure to a toluene 
concentration of approximately 1500 mg/m3 for more than 8 h.  

Convulsions, nausea, and coma have been noted in human beings at 
concentrations of 2250 mg/m3 and higher.  Exposure to very high 
concentrations (above 15 000 mg/m3) leads to narcosis and death. 

    The toxic effects of toluene in human beings after long-term 
exposure are, in principal, the same.  The CNS effects may be 
depressant or excitatory, with euphoria preceeding disorientation, 
tremulousness, hallucinations, ataxia, and coma.  Human beings are 
more sensitive than certain animal species.  Effects induced in 
human beings at 750 mg/m3 were seen in rats only after exposure to 
1875 mg/m3.  Animal studies showed that sensitivity to toluene 
varies with species.  Differences were also found according to the 
sex and age of the animals.  The acute LC50 for mice and rats has 
been reported to be higher than 20 000 mg/m3.

    A proper multiple generation reproduction study is not 
available.  From the teratogenicity studies on mice, rats, and 
rabbits, toluene can be considered negative after inhalation 
exposure.  In rats, given high doses of 1000 - 1500 mg/m3, for 
8 h/day, during the period of organogenesis, no maternal toxicity 
was noted, but an influence on fetal weight and delayed 
ossification was observed.  An embryotoxic effect cannot be 
excluded.  No adverse effects were noted in mice at 375 mg/m3.  
Toluene caused spontaneous abortions in rabbits at 1000 mg/m3 and 
embryolethality and fetotoxicity in rats administered a dose level 
of 6000 mg/m3 for 24 h/day, on days 4 - 21 of gestation. 

    A significantly increased incidence of cleft palate was induced 
in mice after oral administration of 870 mg toluene/kg body weight 
on days 6 - 15 of gestation, but not with a dose level of 430 mg/kg 
body weight. 

    The effects of toluene on human male reproduction have not been 
examined; however, degeneration of germinal cells in the rat testes 
has been observed in one study after exposure to 750 mg/m3 for 
8 h/day, 6 days/week, for one year.  This finding was not confirmed 
in other studies at much higher dose levels. 

    Numerous studies on experimental animals and studies of groups 
of workers exposed to different concentrations of toluene, 
sometimes for more than 10 years failed to demonstrate effects on 
the haematopoietic system.  At exposure levels exceeding 4000 
mg/m3, cardiac arrhythmia was seen in rats and, at a dose level of 
7500 mg/m3, kidney damage was found in dogs.  Renal function 
impairment was also seen in workers exposed to levels exceeding 
300 mg toluene (mixtures)/m3 air.  Indicators studied were 
proteinuria, albuminuria, and excretion of muramides and beta-
glucuronidase.  Effects on the liver were seen only at very high 

    In long-term carcinogenicity studies on rats, inhalation of 
concentrations of 112.5, 375, and 1125 mg/m3 did not show clear 
effects, with the exception of a reduction in haematocrite and 
increase in mean corpuscular haemoglobin concentration at the 

highest dose level.  No increase in tumour incidence was observed.  
Two long-term studies concerning the oral administration of toluene 
to rats and mice are in progress. 

    Pure toluene does not seem to have any, or only negligible, 
mutagenic effects in different test systems.  However, the 
potential mutagenic effects of mixtures cannot be assessed at this 

    No epidemiological studies have been carried out following 
exposure to toluene. 

    Assessment of the toxicity of toluene in the workplace is 
frequently complicated by the impurity of the technical toluene 
used and/or the presence of other solvents that may themselves be 
toxic.  A similar situation exists in relation to solvent abuse.  
Other solvents that complicate the evaluation are benzene and 

    Although data are fairly conclusive for the evaluation of human 
health risks from pure toluene, no evaluation can be made for 
exposure to solvent mixtures containing toluene.  Data on persons 
exposed to high levels of mixtures are available and indicate a 
difference in target organs; an increased risk of liver damage or 
toxic effects on the haemopoietic tissue, the immune system and 
endocrine system.  However, no quantitative risk evaluation can be 
made at present. 

    Persons involved in long-term abuse routinely exceed 
concentrations of 3750 mg/m3, which causes a significant incidence 
of solvent-induced morbidity or permanent neurological deficit.  
Irreversible neurological sequelae may present as encephalopathy, 
optic atrophy, equilibrium disorders, diencephalic syndrome, and 
cerebellar ataxia.  These have been described in adults, as well as 
in children of 8 - 14 years of age. 

10.3.  Evaluation of Environmental Hazards of Toluene

    In areas without wind, toluene vapour can concentrate in 
depressions.  A potentially serious safety hazard can result where 
the explosive limits (1.17 - 7.10% volume in air) are exceeded. 

    Present evidence indicates that toluene concentrations in 
natural waters seldom exceed 0.1 mg/litre, though higher 
concentrations may be found near spills.  Toluene is non-persistent 
and is rapidly volatilized or biodegraded.  It is unlikely that 
toluene is bioaccumulated in fish and the food chain. 

    Toluene is of moderate to low toxicity for water organisms.  
The LC50 ranges from 3.7 to 1180 mg/litre.  The LC50s for most of 
the fish and invertebrates studied have been of the order of 15 - 
30 mg/litre.  Photosynthesis and respiration by marine plankton 
communities are inhibited at concentrations of 30 mg/litre.  The 
first effects on aquatic communities including inhibition of 
reproduction and growth may be experienced at concentrations of 
toluene in water of 2 mg/litre. 

    Toluene probably exists in soils in the adsorbed state and may 
participate in chemical reactions and biological degradation and 
transformation.  Volatilization takes place and is dependent on the 
nature of the soil.  Transfer of toluene from soil to groundwater 
takes place and this will result in contamination of sources of 

    Toluene is easily degraded by activated sludge in sewage and 
biodegraded by a variety of soil microorganisms. 


    The average daily maximum allowable concentration (MACad) and 
the highest momentary (single-occasion MAChm) for toluene in the 
ambient air of residential areas in the USSR is 0.6 mg/m3, and the 
maximum acceptable limits of toluene in bodies of water for 
sanitary-domestic uses is 0.5 mg/litre (IRPTC, 1982). 

    Examples of occupational exposure limits as time-weighted 
averages (TWA) for an 8-h day and a 40-h week include:  200 mg/m3 
in Czechoslovakia and the German Democratic Republic; 375 mg/m3 in 
Ireland, Japan, and the USA (NIOSH); 750 mg/m3 in the Federal 
Republic of Germany and the USA (OSHA); and 300 mg/m3 in Sweden.  
Other limits include:  100 mg/m3 as a ceiling concentration in 
Hungary; and 50 mg/m3 as the maximum allowable concentration in the 


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    See Also:
       Toxicological Abbreviations
       Toluene (ICSC)
       Toluene (WHO Food Additives Series 16)
       TOLUENE (JECFA Evaluation)
       Toluene (IARC Summary & Evaluation, Volume 71, 1999)