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

         Ethyl alcohol is rapidly and readily oxidized to CO2 and water.
    The toxicity is diminished if substances which increase tissue
    oxidation are given beforehand. The pathway is generally agreed to be
    initial oxidation to acetaldehyde, conversion to acetyl co-enzyme A
    and acetic acid, final combustion in kidney and liver to CO2 and
    water (Browning, 1965). Lung tissue can also convert ethanol to CO2
    (Masoro et al. 1953). The principal organ responsible for the
    metabolism of ethanol is the liver - it employed two enzyme systems -
    alcohol dehydrogenase and aldehyde dehydrogenase - both require NAD as
    a cofactor (Westerfeld, 1961). Alcohol dehydrogenase activity has been
    demonstrated in several other organs and tissues, including the
    stomach and intestine (Spencer et al. 1964, Mistilis et al. 1969),
    kidney (Buttner, 1965), lung (Moser et al. 1968), and brain (Raskin et
    al. 1968), but their contribution to the overall metabolism of ethanol
    is slight (Bartlett, 1949). Acetaldehyde dehydrogenase controls the
    further oxidation of acetaldehyde to acetic acid (Camps, 1968). Using
    C14 labelled alcohol it has been shown that rats exhale 75 per cent.
    as CO2 in 5 hours and 90 per cent. in 10 hours. Two per cent. is
    eliminated unchanged in the urine and expired air, while 0.5-2.0 per
    cent. is conjugated and excreted in the urine as ethylglucuronide
    (Bartlett & Barnett, 1949, Kamil et al. 1953).

         Clearance of ethanol from blood depends on the blood levels
    present. At low dosage it is proportional to the blood alcohol levels
    when liver alcohol dehydrogenase is not fully saturated. As the
    circulating blood ethanol level increases maximum metabolic conversion
    is achieved. At still higher levels the resultant CNS depression
    produced hypoventilation, hypothermia, and hypotension, with a
    consequent decrease in alcohol metabolism (Lundquist & Wolthers,
    1958). The rat metabolizes alcohol more slowly than the mouse and
    faster than the dog (Aull et al. 1956). In dogs alcohol passes through
    the kidneys by simple diffusion. During absorption from the G.I. tract
    the concentration of ethyl alcohol was a little lower in peripheral
    veins compared with arterial levels. 2-4% of total ingested alcohol
    was eliminated by kidneys and 4% in the expired air (Treon, 1958).
    Recent evidence suggests that man metabolises alcohol at a rate
    depending upon the concentration present if catalase handles oxidation
    but independent of concentration in the human body if alcohol
    dehydrogenase handles oxidation. Tetraethylthiuram disulphide inhibits
    acetaldehyde dehydrogenase and gives rise to toxic tissue accumulation
    of acetaldehyde (Goodman & Gilman, 1967). Other possibilities are the
    prevention of the oxidation of ethanol and the production of
    disulphide metabolites. Any acetic acid formed joins the body acetate
    pool (Treon, 1958). Etharel is distributed uniformly in body water
    (Camps, 1968). Ethanol has a direct effect on liver cells in vitro,
    decreases DPN and increases DPNH and therefore effects more acetate

    incorporation into fatty acids (Lieber & Schmid, 1961). Acute ethanal
    induced fatty liver differs from that induced by chronic small amounts
    in that the latter responds to choline but not the former. Hence
    hepatic fat may increase by (a) increased mobilization of fat from
    depots, (b) increased fat synthesis and esterification in the liver
    itself, (c) inducing a relative recline deficiency, all leading to the
    picture of fatty infiltration and fibrosis (Klatskin, 1961). Decreased
    fat oxidation in the liver may contribute to the fat accumulation
    (Isselbacher & Greenberger, 1964). Ethanol produces a marked increase
    in serum cholesterol in the dog, while in man a small but significant
    increase occurs after large intakes. Hyperlipaemic subjects show
    greater rise (Grande & Amatuzio, 1960). Ethanol has a moderate
    short-lasting effect on adrenal medullary secretion producing a rise
    in urinary adrenalin and noradrenalin output. This is probably due to
    a sympathetic stimulation (Perman, 1961). Alcohol is not absorbed
    through normal skin but can be absorbed through abraded areas (Camp,

    Acute toxicity


    Animal       Route         LD50          LD100         References
                               mg/kg         mg/kg
                               body-weight   body-weight

    Frog         s.c.          -             7100-7900     Spector, 1956
    Mouse        oral          9488          -             Spector, 1956
                 s.c.          8285          -             Spector, 1956
                 s.c.          -             4700          Browning, 1953
                 i.v.          1973          -             Spector, 1956
                 inhalation    -             29300 ppm     Browning, 1965
    Rat          oral          13660         -             Spector, 1956
                 i.p.          5000          -             Spector, 1956
                 inhalation    -             12700 ppm     Browning, 1965
    Guinea-pig   i.p.          5560          -             Spector, 1956
                 inhalation    -             21900 ppm     Browning, 1965
    Rabbit       oral          6300          -             Spector, 1956
                 oral          9500                        Spector, 1956
                 oral          -             7890          Spector, 1956
                 oral          -             9000-10000    Browning, 1953
                 i.p.          -             3500          Browning, 1953
                 i.v.          -             9400          Spector, 1956
    Cat          i.v.          -             3945          Spector, 1956
    Dog          oral          -             5500-6500     Spector, 1956
                 s.c.          -             6000-8000     Spector, 1956
                 i.v.          -             5365          Spector, 1956
    Man          oral          -             6000-8000     von Oettingen, 

         Dogs intoxicated by ingestion showed liver injury consisting of
    cellular oedema at the periphery of lobules and increase in lipid
    which regressed subsequently (MacNider, 1933). Inhalation of high
    concentrations caused reversible fatty infiltration of the liver
    (Weese, 1928).

    Short-term studies

         Mouse. Groups of 10 mice were fed for 5 weeks on a control diet
    but drinking water was either normal water or 0.8 per cent., 4 per
    cent. and 20 per cent. ethyl alcohol. Mortality increased with dose
    but there was little effect on the mean weight of survivors (College
    Pharmaceutical Society, (1962).

         Groups of male and female mice were given ethyl alcohol (unknown
    composition) i.p. for 6 months. No tumours were noted (Larson &
    Heston, 1945).

         Rat. Five female rats received orally 1 ml 40 per cent. aqueous
    alcohol 3 times per week for 41 days. No tumours were observed
    (Russell et al. 1941).

         Nine groups of rats containing 5-25 animals received 20 per cent.
    alcohol in their drinking water and additional cystine with or without
    choline in their diet. Observation extended from 8 to 24 weeks. No
    tumours were observed (Wanscher, 1953).

         15 rats received 15 per cent. alcohol in water for up to 14
    weeks. No tumours were observed (Baumann et al. 1942).

         Groups of male rats received 15 per cent. alcohol in their
    drinking water. After 177 days there were no tumours (Best et al.

         24 rats were given 15 per cent. alcohol in their drinking water.
    After 120 days there were no tumours (Klatskin et al. 1951).

         In another experiment rats were given ethyl alcohol in their food
    for 300 days without any pathological changes having been observed
    (Nakahara & Mori, 1939).

         Rabbit. 64 rabbits were given 20 per cent. alcohol in water by
    stomach tube in quantities from 20-100 ml daily for 304 days. Thirteen
    died of infection but no tumours were seen in the rest (Connor, 1940).

         Dog. Twenty-three dogs received a 40 per cent. aqueous solution
    at a rate of 10 ml/kg body-weight daily for 6 to 26 months without any
    signs of tumour development (McNider & Donnelly, 1932).

    Observations in man

    Ethylalcohol acts principally on the brain whether ingested or
    inhaled, first as an inhibitor of the higher functions and then as an
    anaesthetic. The lethal dose for man is 8-10 ml per kg body-weight or
    one quart of whisky or a blood level of 0.5% or more (Haag et al.
    1951, von Oettingen, 1943). Death occurs from severe and probably
    irreversible injury to CNS. Acute intoxication affects visual acuity,
    fields of vision, eye co-ordination and distance judgement. The vapour
    is slightly irritant to the eye and respiratory tract mucosa. Animals
    as well as man develop tolerance. Inhalation concentrations up to 3500
    ppm caused no irritation nor any subjective symptoms nor any rise in
    blood alcohol levels (Treon, 1958). The TLV is 100 ppm (Amer, Conf.
    Gov, Ind. Hyg., 1969). Moderate doses stimulate the appetite and food
    absorption. Higher concentrations irritate the gastric mucosa (Jacobs,
    1947). Ingestion of less than 0.5 g/kg does not affect the behaviour
    of man, 0.5 - 2.0 g/kg cause some disturbance and doses above 2 g/kg
    cause serious drunkenness (von Oettingen, 1943). Chronic ingestion
    causes visual impairment and incoordination of voluntary muscles
    (Browning, 1965). Chronic intake of alcohol amounting to over 160 g
    pure alcohol per day for more than 10 years leads to hepatic cirrhosis
    (Thaler, 1969). The preferential oxidation of ethanol in the liver
    diverts NAD from other sites, leading to alteration of cellular
    biochemistry and pathological damage despite enzyme inhibition of
    alcohol dehydrogenase activity (Mistilis & Birchall, 1969). In man,
    secondary nutritional inadequacies, along with electrolyte and mineral
    imbalance may and do occur. The cardiotoxic effects could arise from
    hypomagnesemia and hypozincemia. Ethanal is a diuretic and when it is
    consumed with relatively large volumes of water magnesuria and
    zincuria will result. If prolonged, cardiac damage, secondary to low
    cardiac magnesium (Heggtveit et al. 1964) or zinc (Wendt of al. 1966)
    can appear. 20% w/u i.p. ethanol produce a chemical peritonitis,
    pancreatitis and peritoneal adhesions (Wiberg et al. 1969).

    Long-term studies

    Mouse. 16 mice received 0.1 ml of a 50 per cent. alcoholic solution
    every two days rectally for 547 days. Two animals developed tumours of
    which one was a sarcoma. In another experiment, 10 male and female
    mice received 0.1 ml of a 50 per cent. alcoholic solution every two
    days orally for 554 days. Two tumours of the back were observed
    (Krebs, 1928).


         Ethanol is a common component in the diet and it is not
    appropriate to consider it in the same way as other extraction
    solvents. As a solvent residue it will probably constitute no more
    than 0.5% of any food.


         The use of this solvent should be restricted to that determined
    by good manufacturing practice. There is less urgency to ensure the
    minimum amount of residues because of its dietary role, but residues
    resulting from good manufacturing practice are unlikely to have any
    significant toxicological effects.


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

    Aull, J. S. Jr., Roberts, W. J. Jr, & Kinard, F.W. (1956) Amer. 
    J. Physiol., 186, 38O

    Bartlett, G. R. & Barnet, H. N (1949) Quart. J. Stud, Alcohol, 10,

    Baumann, C. A., Foster, E. G. & Moore, P. R. (1942) J. biol. Chem.,
    142, 597

    Buttner, H. (1965) Biochem. Z. 341, 300

    Best, C. H. et al (1949) Brit. med. J., 2, 1001

    Browning, E. (1953) Medical Res. Council Report No. 80, Her
    Majesty's Stationery Office, London

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

    Camps, F. E. (1968) J. Roy. Coll. Phycns. Lond., 2, 311

    College of the Pharmaceutical Society (1962) Report to BEMA

    Connor, C. L. (1940) Arch. Path., 30, 165

    Goodman, L. S. & Gilman, A. (1967) The Pharmacological Basis of
    Therapeutics, Macmillan, New York

    Grande, F. & Amatuzio, D. S. (1960) Minn. Mad., 43, 731

    Haag, H. B., Silverman, T. & Kaye, S. (1951) J. Pharmacol. exp.
    Ther., 103, 344

    Heggtveit, H. A., Herman, L. & Mishra, R. K. (1964) Amer. J. Path.,
    45, 757

    Isselbacher, K. J. & Greenberger, N. J. (1964) New Engl. J. Med.,
    270, 351 and 402

    Jacobs, M. B. (1947) Synthetic Food Adjuncts, D. van Nostrand Co.

    Kamil, I. A., Smith, J. N. & Williams, R. T. (1953) Biochem. J., 53,
    129 & 54, 390

    Klatskin, G., Gewin, H. M. & Krehl, W. A. (1951) Yale J. Biol. Med.,
    23, 317

    Klatskin, G. (1961) Amer. J. clin. Nutr., 9, 439

    Krebs, C. (1928) Ztsch. Immun. exp. Therap , 59, 203

    Larsen, C D. & Heston, W. E.(1945) Cancer Research, 5, 592

    Lieber, C. S. & Schmid, R. (1961) J. clin. Invest., 40, 394, 1355

    Lundquist, F. & Wolthers, H. (1958) Acta Pharmacol. Toxicol., 14,

    MacNider, W. de B. & Donnelly, G. L. (1932) Proc. Soc. exp. Biol.
    N.Y.), 29, 581

    MacNider, W. de B. (1933) J. Phamacol. exp. Ther., 49, 100

    Masoro, E. T., Abramovitch, H. & Birchard, T. R. (1953) Amer. J.
    Physiol., 173, 87

    Mistilis, S. P. & Birchall, A. (1969) Nature, 223, 199

    Moser, K., Papenberg, J. S. & von Wartburg, J. P. (1968)
    Enzymol. biol. clin.,6, 447

    Nakahara, W. & Mori, K. (1939) Proc. Imp. Acad. Jap., 15, 278

    von Oettingen, W. F, (1943) Pub. Hlth Bull. No. 281, US Pub. Hlth

    Perman, E. S. (1961) Acta. Physiol. Scand., 62 & 68

    Raskin, N. H. & Sokoloff, L. (1968) Science, 162, 131

    Russell, H. K. et al. (1941) Endocrinology, 28, 897

    Spector, W. S. (1956) Handbook of Toxicology, W. B. Saunders & Co

    Spencer, R. P., Brody, K. R., & Lutters, B. M. (1964)
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    Thaler, H. (1969) Dtsch Med. Wschr.  94, 1A3

    Treon, J. F. (1958) in F. A. Patty, Industrial Hygiene & Toxicology
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    Wanscher, O. (1953) Acta Path. microbiol. scand., 32, 348

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

    Wendt, V. E. et al (1966) In Zinc Metabolism, Thomas, Springfield,

    Westerfeld, W. W. (1961) Amer. J. clin. Nutr., 9, 426

    Wiberg, G. S.  Coldwell, B. B. & Trenholm, H. L. (1969) J. Pharm.
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    See Also:
       Toxicological Abbreviations
       ETHANOL (JECFA Evaluation)