FAO Nutrition Meetings 
    Report Series No. 48A 
    WHO/FOOD ADD/70.39


    The content of this document is the 
    result of the deliberations of the Joint 
    FAO/WHO Expert Committee on Food Additives 
    which met in Geneva, 24 June  -2 July 19701

    Food and Agriculture Organization of the United Nations
    World Health Organization


    1 Fourteenth report of the Joint FAO/WHO Expert Committee on Food
    Additives, FAO Nutrition Meetings Report Series in press; Wld Hlth
    Org. techn. Rep. Ser., in press.


    Biological Data

    Biochemical aspects

         Methanol is only slowly eliminated after ingestion or inhalation.
    In the rat excretion is mainly by the lungs as CO2 (65%) and
    unchanged methanol (14%). In the urine appears 3% unchanged methanol
    and 3% formate (Bartlett, 1950). In the rabbit 10%-20% is excreted
    unchanged in the urine and in the dog 15% methanol is excreted in the
    lungs. 10% in the urine as methanol and 20% as urinary formate (Voltz
    & Dietrich, 1912). The rabbit forms methylglucuronide (Kamil et al.,

         Man excretes methanol and formate in the urine after oral dosing.
    The urinary formate reaches a peak 2-3 days after ingestion (Williams,
    1959). Other urinary metabolites are choline and methyglycuronide
    (Browning, 1965). There is argument whether ethanol, given
    simultaneously with methanol, decreases the latter's toxicity by
    depressing the oxidation of methanol and causing increased excretion
    of unchanged methanol. But in mice ethanol increases the toxicity of
    methanol (Browning, 1965).

         Methanol is rapidly distributed to all tissues and body water
    (Yant & Schrenk, 1937). Methanol is probably oxidised by catalase and
    hydrogen peroxide and any formaldehyde is converted to methylformate
    by alcohol dehydrogenase of the liver and this slowly hydrolyses
    (Kendal & Ramanathan, 1952). As the oxidative processes in the cells
    are poisoned, organic acids accumulate with extreme acidosis (Patty,
    1958). The toxic product in man may be formaldehyde (Potts & Johnson,
    1952) and/or formic acid (Herken & Rietbrock, 1968).

         In laboratory animals such as the mouse, rat and guinea-pig, the
    oxidation of methanol proceeds through a peroxidase system involving
    catalase (Makar & Mannering, 1968a). Presumably, man like the monkey,
    uses ADH for the metabolism of methanol (Makar et al., 1968b).
    Therefore, data on the metabolism and the acute toxicity of methanol
    taken from lower animal species may not be applicable to man.

    Acute toxicity


    Animal    Route          LD100               LD50      Reference

    mouse     intragastric   10.5 - 12 mg/kg     -         Weese, 1928
              inhalation     173 000             -         Bachem, 1927
    rat       inhalation     8.71 - 12.28 g/kg   -         Loewy & van der Heide, 1914
              oral           -                   12900     Spector, 1962; 
                                                           Union Carbide, 1966
    cat       i.v.           5.9 ml/kg           -         Macht, 1920
              inhalation     65 700 ppm          -         Lehmann & Flury, 1943
    rabbit    intragastric   18 ml/kg            14200     Munch & Schwartze, 1925
              i.v.           4.2 g/kg            -         Spector, 1962
    monkey    inhalation     1 000 ppm           -         McCord & Cox, 1931

         The acute effects of irritation of mucous membraines, depression
    and drowsiness followed by death from respiratory paralysis. The
    narcotic effect of methylalcohol is weaker than ethylalcohol but the
    toxic effect of accumulated doses is greater because of slow
    elimination. Acute poisoning in man is often followed by blindness.
    Symptoms occur after a latent period and consist of dizziness, stupor,
    G.I. disturbances (Wood & Buller, 1904; Browning, 1965). Estimates of
    toxicity for man vary from 5 - 10 mg for some individuals (Lehmann &
    Flury, 1943) to 10 ml (Gleason et al., 1969) and 60 250 ml (Gleason et
    al., 1969) are probably fatal although less than 1 g/kg has been
    blamed (Williams, 1959). Poisoning followed by blindness has also
    occurred after inhalation but many reports exist of long exposure
    without symptoms (Browning, 1965), Mass poisoning episodes have
    occurred (Bennett et al., 1953; Jacobsen et al., 1945; Tanning et al.,
    1956). The TLV is 200 ppm (Amer, Conf. Gov. Ind. Hyg., 1969),
    Apparent penetration of the skin can occur in monkeys, dogs and man
    (Patty, 1958).

    Short-term studies


         Groups of 10 rats received 2.5% methanol with or without 0.9%
    salt or sodium formate for 210-225 days. 3 rats from each group were
    given C14 labelled methanol on the 120-150th day. Body weights were
    comparable with controls. Measurements of 14CO2 showed no difference
    in oxidation rate between methanol and ethanol. All methanol-treated
    rats showed greater oxygen uptake of liver slices and increased
    catalase activity but no change in alcohol dehydrogenase activity
    (Wartburg & Roethlisberger, 1961).

    Special studies

         Repeated inhalations in animals cause small haemorrhages in the
    gastric mucosa, oedema and retinal ganglionar degeneration, blindness,
    increased haemopoiesis, oedema and necrosis of cardiac muscle,
    parenchymatous degeneration with focal necrosis in the liver and
    kidney, pulmonary inflammation, oedema and patchy neuronal
    degeneration (Browning, 1965). Dogs were exposed for 379 days to 500
    ppm methylalcohol for 8 hours per day without any ill effects on
    weight, vision, haematology or histopathology (Sayers et al., 1942).

         Skin absorption was tested on 9 rats, 12 rabbits and 8 monkeys.
    All animals died within a few days, rabbits being the least
    susceptible. Methylalcohol could be recovered from all organs and
    optic atrophy was noted. About 0.5 ml/kg body weight applied four
    times per day is the lowest dose causing adverse effects (McCord,

    Observations in man

         Conjunctivitis, headache, giddiness, G.I. disturbances and
    failure of vision with oedema of the optic nerve and retina and
    degeneration secondary to metabolites, e.g. formaldehyde or formic
    acid, occur in man (Fink, 1943). Methanol can be absorbed through the
    skin and cause eye lesions. Individual susceptibility and pre-existing
    nervous disease predispose to toxic effects of methanol (Browning,


         Ingestion by man gives rise to toxic metabolites (formaldehyde
    and/or formic acid) which may cause retinal and optic nerve
    degeneration in susceptible individuals.

    Tentative Evaluation

         The use of this solvent should be restricted to that determined
    by good manufacturing practice which is expected to result in minimal
    residues unlikely to have any significant toxicological effects.


    Amer. Conf. Gov. Ind. Hyg. (1969) Threshold limit values for 1969

    Bachem, C. (1927) Arch. Exptl. Pathol. Pharmakol., 122, 69

    Bartlett, G R. (1950) Amer. J. Physiol., 163, 614

    Bennett, I. L., Cary, F. H., Mitchell, G. L. & Cooper, M. N. (1953)
    Medicine, 32 431

    Browning, E. (1965) Toxicity and Metabolism of Industrial Solvents,
    Elsevier, Amsterdam

    Fink, W. H. (1943) Amer. J. Ophthalm., 26 802

    Gleason, M. N., Gosselin, R. E., Hodge. H. C. & Smith, R. P. (1969)
    Clinical Toxicology of Commercial Products, Williams and Wilkins, Co.,

    Herken, W. & Rieforock. N. (1968) Naunyn Schmiedeberg Arch. Pharm.
    Exp. Path., 26O, 142

    Jacobsen, B. M., Russell, H. K., Grimm, J. J. & Fox, E. C. (1945)
    U.S. Naval Med, Bull. 44, 1099

    Kamil. I. A., Smith, J. N. & Williams, R. T. (1953) Biochem. J., 121
    129, 137 and 54, 390

    Kendal, L. P. & Ramanathan, A. N. (1952) Biochem. J., 52, 430

    Lehmann, K. B. & Flury, P. (1943) Toxicology and Hygiene of Industrial
    Solvents, Williams

    Loewy, A. & van der Heide (1914) Biochem. Z., 65, 230

    Macht, D. I. (1920) J. Pharmacol., 16, 1

    McCord, C. P. (1931) Ind. Eng. Chem., 23, 931

    McCord, C. P. & Cox, N. (1931) Ind. Eng. Chem., 23, 931

    Makar, A. B. & Mannering, G. J. (1968a) Molecular Pharmacol.., 4,

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    Munch, J. C. & Schwartze, E. W. (1925) J. Lab. Clin. Med., 10, 985

    Patty, F. A. (1958) Industrial Hygiene and Toxicology, 2nd ed.,
    Interscience, N.York

    Potts, A. M. & Johnson, L. V. (1952) Amer. J, Ophthamol., 35, 107

    Sayers. R. R., Yant, W. P., Schrenk. H. H., Chornyak. J., Pearce. S.
    J., Patty, F. A. & Linn, J. G. (1942) U.S. Bur. Mines Rept. Invest.,
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    Spector, W. S. (1962) Handbook of Toxicology

    Tonning, D. J., Brooks, D. W. & Harlow, C. M. (1956) Can. Med. 
    Assoc. J., 74, 20

    Voltz, W. & Dietrich, W. (1912) Biochem. Z.,40, 15

    Wartburg, J.-P. von & Roethlisberger, M. (1961) Helv. physiol. Acta,
    19, 30

    Weese, H. (1928) Arch. Exptl. Pathol. Pharmakol., 135, 118

    Williams, R. T. (1959) Detoxication Mechanisms, Chapman and Hall,

    Wood, C. A. & Buller, F. (1904) J.A.M.A., 43, 972

    Yant, W. P. & Schrenk, H. H. (1937) J. Ind. Hyg. Toxicol., 19, 337

    See Also:
       Toxicological Abbreviations
       Methanol (EHC 196, 1997)
       Methanol (HSG 105, 1997)
       Methanol (ICSC)
       METHANOL (JECFA Evaluation)
       Methanol (PIM 335)