FAO Nutrition Meetings Report Series No. 48A WHO/FOOD ADD/70.39 TOXICOLOGICAL EVALUATION OF SOME EXTRACTION SOLVENTS AND CERTAIN OTHER SUBSTANCES 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. METHANOL 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., 1953). 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 mg/kg 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 Rat 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, 1931). 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, 1965). Comments 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. REFERENCES 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., Baltimore 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. 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See Also: Toxicological Abbreviations Methanol (EHC 196, 1997) Methanol (HSG 105, 1997) Methanol (ICSC) METHANOL (JECFA Evaluation) Methanol (PIM 335)