TOLUENE
Explanation
This extraction solvent was reviewed for the first time by the
Joint FAO/WHO Expert Committee on Food Additives.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Absorption, distribution and excretion
A number of studies using human subjects have investigated
factors which influence the uptake and distribution in the blood of
inhaled toluene under both acute and chronic conditions. The results
of these studies showed that alveolar air sampling can be used as a
measure of the uptake of toluene, and under certain conditions, there
exists a direct correlation between the toluene concentrations in the
alveolar air and blood (Astrand, 1975; Konietzko et al., 1980; Ovrum
et al., 1978; Sato & Nakajima, 1978; and Veulemans & Masschelein,
1978a, 1978b and 1979).
There were no reports on the absorption of toluene by humans
following oral ingestion.
In a study with Sprague-Dawley rats, the uptake and distribution
of toluene by the oral or inhalation routes has been compared.
Tritiated toluene was administered by inhalation or gastric
intubation, and the tissue distribution of toluene was compared at
periods of 15-246 minutes after exposure. Although higher tissue
levels were present at the beginning of the study in the rats inhaling
toluene, after several hours the tissue levels of toluene were similar
in each test group. Adipose tissue reached its maximum toluene level,
at a slower rate than other tissues, but the final level was much
higher than that observed in the other tissues (Pykko et al., 1977).
In a similar study, Sprague-Dawley rats (male) were exposed to
500 ppm (0.05%) 14C labelled (labelled at the methyl group) toluene
vapour for one hour. The greatest concentration of 14C toluene and/or
its 14C metabolites were found in the white adipose tissue with
lesser amounts being detected in the following tissues; kidney,
adrenal gland, liver, cerebrum, cerebellum. Six hours after exposure
the 14C level was reduced in all of the tissues assayed except for
the white adipose (Carlsson & Lindquist, 1977).
Mice were injected i.p with 14C toluene at a dose level of
290 µg/kg bw. The 14C toluene was distributed in the following
tissues in descending order: adipose tissue, kidney, liver, lung and
brain. The biological half-life was determined to be 25 minutes, with
blood levels declining in an exponential fashion. Non-volatile 14C
metabolites were detected in the kidney and liver soon after
administration of toluene, while a volatile 14C compound was detected
in the adipose tissue and brain. The major route of excretion of the
14C (approximately 75% of administered dose) occurred in the urine,
with only small amounts of 14C toluene and/or 14C metabolites being
excreted via the pulmonary and faecal routes (Koga, 1978a).
Metabolism
Toluene is rapidly and almost completely metabolized to hippuric
acid in experimental animals. Administration of a single oral dose of
toluene to rabbits, resulted in about 75% of the dose being excreted
in the urine as hippuric acid within 24 hours. About 18% of the dose
was eliminated unchanged in the expired air in 12 hours (Smith et al.,
1954 and El Masry et al., 1956). When male Wistar rats were dosed with
either 87, 173 or 347 mg/kg bw toluene dissolved in olive oil,
hippuric acid was shown to be the major urinary metabolite (Ogata et
al., 1979). However, in rabbits, if glycine conjugation were
overwhelmed by a high dose of orally administered toluene then
glucuronide conjugation could occur (Bray et al., 1951). In another
study in which rats were administered toluene at 100 mg/kg bw,
hippuric acid was the major urinary, metabolite, however, 0.5-1.1% of
the total dose was excreted as p- and o-cresol glucuronide or sulfate
conjugate (Bakke & Scheline, 1970).
Another minor pathway in the biotransformation of toluene has
been demonstrated in adult male Wistar rats. Toluene administered
either orally or intraperitoneally produced a decrease in hepatic
glutathione concentration, and this in turn was accompanied by an
enhanced excretion of thioether compounds in the urine. The
mercapturic acid associated with toluene administration was
benzylmercapturic acid, however, it accounted for only 0.4-0.7% of the
dose of toluene (Van Doorn et al., 1980).
Studies on industrially exposed humans have shown similar
patterns of metabolism of toluene as to those observed in laboratory
animals.
Twenty-three male volunteers who had no prior contact with
toluene were exposed to either 100 or 200 ppm (0.01 or 0.02%) in
groups of four or five for periods of three or seven hours with one
break of an hour. Sixty-eight per cent. of the absorbed toluene was
excreted in the urine as hippuric acid (Ogata et al., 1970).
Urinary metabolites of toluene were studied in a group of 34
printing workers industrially exposed to toluene at an average
workroom concentration of 23 ppm (0.0023%). Hippuric acid was shown to
be a major urinary metabolite with lesser amounts of o-cresol. It was
estimated that approximately 0.5% of the toluene retained by the
subjects was metabolized to o-cresol (Angerer, 1979).
In another study on male workers who were exposed to toluene at
an average workroom concentration of 280 ppm (0.028%), it was shown
that besides hippuric acid and o-cresol, both m- and p-cresol were
formed (Woiwade et al., 1979).
Biliary excretion of toluene and its metabolite appears to be
minor. In a study in which female, Wistar albino rats were dosed with
(14C) toluene at a dose equivalent to 50 mg/kg bw biliary and urinary
samples were collected. Less than 2% of the administered radioactivity
appeared in the bile, primarily as conjugates of the metabolites of
toluene (Abou-El-Makarem et al., 1967).
The mixed function oxidase system of the liver is the major
enzymatic system involved in the metabolism of toluene.
The administration of 75 mg/kg bw of sodium phenobarbital daily
for four days to young, female Wistar rats markedly enhanced the
in vivo metabolism of toluene, as shown by the decreased narcotic
effect of toluene and in increased rate of disappearance of toluene
from the blood (Ikeda & Ohtsuji, 1971).
In another study, pretreatment of mice with 75 mg/kg bw of
phenobarbital, protected the mice from the central nervous system
depressant action of toluene. In contrast, pretreatment with a number
of hepatic enzyme inhibitors (e.g., carbon tetrachloride) enhanced the
central nervous system activity of toluene as measured by the
induction and length of sleep and toxicity of toluene (Koga & Ohmiya,
1978b).
Effects on enzyme system
Groups of six-week-old male mice (North Carolina Department of
Health strain) received daily i.p. injections of toluene for three
days at a dose of 100 mg/kg bw per day. No significant effect was
noted on liver weight microsomal N- and O-demethylase activity and a
number of spectral characteristics of microsomal cytochrome P-450
(Fabacher & Hodgson, 1977).
A single oral dose of toluene (2600 µmoles/100 g bw) had no
effect on the function and composition of the liver endoplasmic
reticulum of young, male rats (Reynolds, 1972).
Toluene may influence the metabolism of other compounds. For
example, when rats were dosed with a combination of toluene and
trichloroethane, the rate of metabolism of the trichloroethane was
reduced (Ikeda, 1974). Similarly when rats were dosed with a
combination of toluene and benzene, the rate of metabolism of both
compounds was reduced (Andrews et al., 1977; Ikeda et al., 1972; and
Sato & Nakajima, 1979).
TOXICOLOGICAL STUDIES
Special studies on carcinogenicity
Several studies in mice involving topical application of toluene
with and without a number of organic compounds have been reported.
None of these studies could demonstrate that the percutaneous
application of toluene resulted in either a carcinogenic or
promotional effect (Coombs et al., 1973; Doak et al., 1976; Frei &
Stephens, 1968a; and Frei & Kingsley, 1968b).
Special studies on mutagenicity
Toluene was inactive in the Ames test using the following four
strains of S. typhimurium, TA-98, TA-100, TA-1535, TA-1538, with and
without activation (Purchase et al., 1978).
Toluene was inactive in mammalian cell transformation culture
systems utilizing Syrian hamster kidney cell (BHK 21/c 113), or human
diploid lung fibroblast (WI-38) or human derived liver cells (Purchase
et al., 1978).
Chromosomal studies have been carried out on peripheral blood
lymphocytes of workers industrially exposed to toluene. The mean
ambient air concentrations of toluene in the work areas ranged from 0
to 240 ppm (0 to 0.024%). The individuals exposed to toluene
demonstrated a somewhat higher rate of unstable chromosome changes and
of calculated breaks in comparison with the controls, however, none of
these differences were significant (Forni et al., 1971).
Toluene was inactive in an in vitro system used to assess the
number of sister-chromated exchanges (SCE) and chromosomal aberrations
in human lymphocytes (Gerner-Smidt & Friedrich, 1978). Toluene was
negative in Rabin's test degranulation of endoplasmic reticulum from
rat liver (Purchase et al., 1978).
Special studies on teratogenicity
Chicken embryo
Toluene was injected into the air space of fertilized chicken
eggs (5, 25, 50 and 100 µmol/egg) at day 2, 3 or 6 of incubation.
Embryotoxicity was dose related. Toluene also elicited a threefold
increase in the frequency of malformations as compared to the
controls. However, its teratogenic potential was less than five
aliphatic hydrocarbons, 1,1,1-trichloroethane, trichloroethylene,
ethylene chloride, tetrachloroethylene and 1,1,2-trichloroethane which
were tested in the same assay (Elovaara et al., 1979).
Mouse
Groups of pregnant mice (CFLP strain) were exposed to 500 mg/m3
(133 ppm (0.0133%)) for 24 hours per day from days 6 to 13 of
gestation. An additional group of mice was exposed to 1500 mg/m3
(399 ppm (0.0399%)), however, all of the animals succumbed within 24
hours. In the group exposed to 500 mg/m3 the number of foetuses with
reduced body weights was increased (Hudak & Ungvary, 1978).
Rat
Groups of pregnant female rats (CFY strain) were exposed to
either 1500 mg/m3 (399 ppm (0.0399%)) for 24 hours per day from days
9 to 14 of gestation, 1500 mg/m3 for 24 hours per day from days 1 to
8 of gestation or 1000 mg/m3 (266 ppm (0.0266%)) for 8 hours per day
from days 1 to 21 of gestation. Irregular sternebrae and extra ribs
were noted in those rats exposed to 1500 mg/m3 on days 9 to 14 of
gestation, but no other treatment-related anomalies were noted. In the
group of rats exposed to 1500 mg/m3 on days 1 to 8 of gestation, no
abnormalities were observed, except for a reduction of foetal weight
and a higher incidence of retarded skeletal growth. The latter effect
was also noted in the rats exposed to 1000 mg/m3, however, no
teratogenic effects were noted (Hudak & Ungvary, 1978).
Acute toxicity
Animal Route LD50 Reference
Rat Oral 7.0 g/kg bw Wolf et al., 1956
Rat (14-
day-old) Oral 2.6 g/kg bw Kimura et al., 1971
Rat Oral 5.5 g/kg bw Kimura et al., 1971
(immature)
Rat
(mature) Oral 6.4 g/kg bw Kimura et al., 1971
Mouse Inhalation 5300 ppm (0.53%) Svirbely et al., 1943
(LC50)
Rat Inhalation 8800 ppm (0.88%) Carpenter et al., 1976
(LC50)
Acute inhalation studies with toluene have demonstrated
pronounced effects on the cardiovascular system including the
myocardium (Chenworth, 1946 and Taylor & Harris, 1970). Alterations of
the central nervous system by toluene have also been demonstrated and
include such effects as decreased learning ability, behavioural
disturbances, reduction of convulsion threshold and petit and grand
mal seizures (Furnas & Hine, 1958; Contreras et al., 1979; Ikeda &
Miyake, 1978; Shigeta et al., 1978; Takeuchi & Hisanaga, 1977;
Svirbely et al., 1943; Carpenter et al., 1976 and Takeuchi & Susuki,
1975).
Short-term studies
Groups of 10 female Wistar rats were given toluene in olive oil
by stomach tube at dose levels equivalent to 118, 354 and 590 mg/kg
bw, five times per week for 193 days. No adverse effects were reported
on growth, mortality, appearance and behaviour, organ/body weight,
blood urea nitrogen levels, bone marrow counts, peripheral blood
counts, or the morphology of major organs (Wolf et al., 1956).
Groups of 30 Fischer-344 rats equally divided by sex were exposed
to toluene vapour at concentrations of 30, 100, 300 or 1000 ppm
(0.003, 0.01, 0.03 or 0.1%) for six hours per day, five days per week
for a period of 90 days. The only effect reported was a slight weight
reduction in the highest exposure group. Clinical and haematological
analyses and urinalysis as well as histological studies of tissues and
organs did not show any other compound-related effects (Rudy et al.,
1978).
In another study four different species (NMRI:015D) Sprague-
Dawley or NMRI:(LE) Long-Evans derived rats, NMRI:(ASH) Princeton
guinea-pigs, squirrel monkeys (Saimiri scuirea) and beagle dogs,
were used to assess the short-term toxicity of toluene vapour. The
dose and exposure of toluene was either 107 ppm (0.0107%) of
continuous exposure for 90 days or 1085 ppm (0.1085%) which was
administered daily for eight hours per day, five days per week for a
six-week period. Each group was comprised of 15 animals for the rats
and guinea-pigs, and two and three animals for the dogs and monkeys,
respectively. The control group had equivalent numbers for the rats
and guinea-pigs, however, 10 and 12 animals were used for the dogs and
monkeys, respectively. During the course of the studies, no compound-
related effects were noted on the body weights, haematological data
and histopathological examination (Jenkins et al., 1970).
Long-term studies
Groups of 240 F-334 albino rats, equally divided by sex, were
exposed to toluene vapour at concentrations of 0, 30, 100 or 300 ppm
(0, 0.003, 0.01 or 0.03%) for six hours per day, five days per week,
for a period of 106 weeks. The only compound-related effects noted in
this study were significantly higher body weights and weight gains in
the treatment groups. No unusual clinical signs or mortality rates
were noted, nor were there any compound-related histopathological
changes (CIIT, 1981).
OBSERVATIONS IN MAN
There have been a number of studies on the health effects of
occupational or abusive exposure to toluene. The effects noted include
nonspecific neuropsychiatric disorders, anaesthesia, permanent
encephalopathy, glomerulonephritis, acidosis, recurrent urinary
calculi, hepatomegaly, hepatorenal dysfunction, macrocytosis,
moderately decreased erythrocyte counts, lymphocytosis increased
frequency of chromated and isochromated breaks, and abnormal tendon
reflex (Axelson et al., 1976; Beirne & Brennan, 1972; Fischman, 1979;
Funes-Cravioto et al., 1977; Greenburg et al., 1942; Knox & Nelson,
1980; Kroeger et al., 1980; Longley et al., 1967; Matsushita et al.,
1975; O'Brien et al., 1971; Taher et al., 1974; and Zimmerman et al.,
1975).
A historical prospective study of workers exposed to toluene was
undertaken to analyse the mortality information on these individuals.
The results of this analysis indicated that there was no clear
evidence of a cancer hazard in these workers (Alderson & Rattan,
1980).
Comments
Toluene is relatively non-toxic to experimental animals. The
major toxic effect following acute exposure (inhalation) is a
depressant or inhibitory effect on the CNS and cardiovascular system.
These effects are readily reversible. In both man and experimental
animals, toluene is rapidly metabolized and excreted from the body.
The major route of excretion is in the urine, with hippuric acid as
the major metabolite, and lesser amounts of benzoyl glucuronide and
o-, m- and p-cresol as conjugates of sulfate and glucuronide. Repeated
long-term exposure to toluene did not cause any liver damage. Most of
the available toxicity studies relate to exposure via inhalation.
However, the absorption of ingested toluene is slower than that of
inhaled toluene. Since toluene absorbed from oral ingestion must pass
through the liver, it is likely that at low levels of exposure,
metabolism will occur before it can pass to other tissues.
Thus, residues of toluene occurring in foods when this solvent is
used in accordance with good manufacturing practice would not pose any
toxicological hazard.
EVALUATION
ADI not specified.*
* The statement "ADI not specified" means that, on the basis of the
available data (toxicological, biochemical, and other), the total
daily intake of the substance, arising from its use or uses at
the levels necessary to achieve the desired effect and from its
acceptable background in food, does not, in the opinion of the
Committee, represent a hazard to health. For this reason, and for
the reasons stated in individual evaluations, the establishment
of an acceptable daily intake (ADI) in mg/kg bw is not deemed
necessary.
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See Also:
Toxicological Abbreviations
Toluene (EHC 52, 1986)
Toluene (ICSC)
TOLUENE (JECFA Evaluation)
Toluene (IARC Summary & Evaluation, Volume 71, 1999)