This extraction solvent was reviewed for the first time by the
    Joint FAO/WHO Expert Committee on Food Additives.



    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).


         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

         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,

    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).


    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).


         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).


         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

    (mature)    Oral          6.4 g/kg bw         Kimura et al., 1971

    Mouse       Inhalation    5300 ppm (0.53%)    Svirbely et al., 1943

    Rat         Inhalation    8800 ppm (0.88%)    Carpenter et al., 1976

         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,

    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.,

         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).


         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.,

         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,


         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.


    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


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    See Also:
       Toxicological Abbreviations
       Toluene (EHC 52, 1986)
       Toluene (ICSC)
       TOLUENE (JECFA Evaluation)
       Toluene (IARC Summary & Evaluation, Volume 71, 1999)