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.
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