FAO Nutrition Meetings
    Report Series No. 40A,B,C
    WHO/Food Add./67.29


    The content of this document is the result of the deliberations of the
    Joint FAO/WHO Expert Committee on Food Additives which met at Rome,
    13-20 December, 19651 Geneva, 11-18 October, 19662


    1 Ninth Report of the Joint FAO/WHO Expert Committee on Food
    Additives, FAO Nutrition Meetings Report Series, 1966 No. 40; 
    Wld Hlth Org. techn. Rep. Ser., 1966, 339

    2 Tenth Report of the Joint FAO/WHO Expert Committee on Food
    Additives, FAO Nutrition Meetings Report Series, 1967, in press; 

    Food and Agriculture Organization of the United Nations
    World Health Organization


    Chemical names                Trans-butenedioic acid;
                                  Trans-1,2-ethylenedicarboxylic acid

    Empirical formula             C4H4O4

    Structural formula            HOOC - CH
                                         CH - COOH

    Molecular weight              116.07

    Definition                    Fumaric acid contains not less than 99
                                  per cent. C4H4O4.

    Description                   Fumaric acid occurs as white odourless
                                  granules, or as a crystalline powder
                                  with a characteristic acid taste.

    Uses                          As an acidulant and flavouring agent.

    Biological Data

    Biochemical aspects

         Fumaric acid is a normal constituent of tissues as an
    intermediate in the tricarboxylic acid cycle. Distribution of fumaric
    acid in rat tissue has been studied by partition chromatography and it
    was found that blood contained 3 mg/l, brain tissue 150 mg/kg, kidney
    tissue 95 mg/kg, liver 78 mg/kg and muscle 23 mg/kg (Marshall et al.,

         The laxative effect of fumarates was studied in mice by
    determining the dose which shortened the average time before soft
    faeces appeared after oral administration. 433.2 mg magnesium fumarate
    or 432 mg disodium fumarate shortened the average time by 40 per cent.
    If the appearance of charcoal marker was taken as a guide, 15 per
    cent. shortening of appearance time was effected by 843.6 mg magnesium
    fumarate or 640 mg disodium fumarate (Locke et al., 1942). Twenty-six
    constipated patients suffering from a variety of chronic diseases not
    involving the gastrointestinal tract were given oral doses, of 5-30 g
    sodium fumarate, a satisfactory bowel motion resulting in 18 patients.
    There was much variability of response to a given dose between
    patients and in the same individual.  Doses above 15 g caused
    unpleasant side effects. No abnormalities were noted in urine or
    serum. non-protein nitrogen level (Bodansky et al., 1942).

    Acute toxicity


    Animal    Route                    LD50             Reference

    Rat       oral (sod. fumarate)     approx. 8 000     Levey et al., 1946
    Rabbit    oral (disod. fumarate)   approx. 3 600     Locke et al., 1942
                                       4 800             Weiss et al., 1923

    Short-term studies

         Guinea-pig. Eight animals were maintained on a diet containing
    0 per cent. and 10 on a diet containing 1 per cent. fumaric acid for
    one year without any adverse effect on growth. The second generation
    from four mated animals was treated similarly without any adverse
    effect noted regarding growth, fertility or lactation (Levey et al.,

         Rabbit. Each of five rabbits received i.v. injections of 50-500
    mg/kg sodium fumarate every second or third day for 10-32 days without
    any injurious effect an blood levels of non-protein nitrogen or
    creatinine, phenolsulfophthalein excretion, or kidney and liver
    histology (Bodansky et al., 1942). Six rabbits received twice weekly
    i.p. injections of 60 mg/kg body-weight of sodium fumarate over 17-29
    weeks. Swelling and congestion of the thyroids and atrophy of testes,
    with low hyaluronidase content, were found (Arai & Suehiro, 1953). A
    further nine male rabbits received 60 mg/kg body-weight sodium
    fumarate every second day by i.p. injection for 150 days. By the end
    of the test period, gonadotropic activity of the serum, as well as
    oestrogenic activity, was detected. There was progressive testicular
    atrophy in all animals, resulting in disappearance of seminiferous
    epithelium and survival of Sertoli cells only. Chromophobe cells were
    increased in the pituitary (Arai et al., 1955).

         Fourteen rabbits were fed 320-2080 mg/kg body-weight of disodium
    fumarate daily for 28 days without any deaths. A further six rabbits
    received 2880-3680 mg/kg body-weight for 17 days with three deaths.
    Two rabbits were fed a daily diet containing 640 mg/kg body-weight for
    36 days without consistent adverse effects on body-weight,
    haematology, non-protein nitrogen or creatinine levels, or
    histopathological findings (Locke, et al., 1942). In another
    experiment, four groups of 15 rabbits were fed diets containing 0 or
    6.9 per cent sodium fumarate (equivalent to 5 per cent. fumaric acid)
    for 150 days. There were no significant differences from controls in
    bodyweight gain, food consumption, mortality rate, blood counts, blood
    sugar, non-protein nitrogen level and urine. Organ weights were not
    significantly different between the groups and histologic examination

    showed no adverse findings attributable to the diet. In particular,
    spermatogenesis and testicular structure were unaffected (Packman et
    al., 1963).

         Dog. Fumaric acid was fed to four groups of 6 young dogs at 0,
    1, 3 and 5 per cent. of the diet for two years without adverse effect
    on bodyweight gain, development, haematology, blood sugar and urea
    levels, haemoglobin and urine. Organ weights and gross and
    histopathological examination of all principal organs and tissues
    revealed no effects attributable to the treatment (Harrisson & Abbott,

         Man. Seventy-five chronically disabled subjects ranging in age
    from 29-91 years received 500 mg fumaric acid daily for one year
    without any toxic manifestations in haemoglobin level, RBC and WBC,
    non-protein nitrogen level, creatinine level, bromosulfonphthalein
    excretion and phenolsulfonphthalein excretion (Levey et al., 1946).

    Long-term studies

         Rat. Eight groups of 14 weanling rats were kept on diets
    containing 0, 0.1 and 1.0 per cent. fumaric acid and 1.38 per cent.
    sodium fumarate for one year (half the groups) or two years. No
    adverse effect was noted on rate of weight gain, haemoglobin, blood
    picture, calcium balance as shown by bone histology, or on the
    histology of liver, kidney, spleen and stomach (Levey et al., 1946).

         In another experiment five groups of 12 male and 12 female rats
    were fed diets containing 0, 0.1, 0.5, 0.8 and 1.2 per cent. of
    fumaric acid for 2 years without toxic effects on growth or food
    consumption. A further four groups of 12 male rats were kept for 2
    years on diets containing 0, 0.5, 1.0 and 1.5 per cent. fumaric acid.
    Only at the 1.5 per cent. level was there a very slight increase in
    mortality rate and some testicular atrophy. Gross and microscopic
    examination of major organs revealed no abnormalities and tumour
    incidence was not significantly different between the groups (Fitzhugh
    & Nelson, 1947).


         Fumaric acid is a normal component of intermediary metabolism. A
    human intake of 500 mg per day over one year had no apparent
    deleterious effects. Gonadal effects in male animals were reported on
    intraperitoneal administration of high doses, and should be
    investigated further.


         This is based on the rat, bearing in mind the 2-year study in the

    Level causing no toxicological effect

         Rat. 1.2 per cent. = 12 000 ppm of fumaric acid in the diet,
    equivalent to 600 mg/kg body-weight per day. 1.38 per cent. = 13 800
    ppm of sodium fumarate in the diet equivalent to 690 mg/kg body-weight
    per day. 

         Man 500 mg per day, equivalent to 10 mg/kg body-weight per day.

    Estimate of acceptable daily intakes for man

                                       mg/kg body-weight

       Unconditional acceptance              0-6
       Conditional acceptance                6-10


    Arai, T. & Suehiro, S. (1953) Wakayama Med. Reps., 1, 35

    Arai, T., Suehiro, S. & Okamoto, T. (1955) Wakayama Med. Reps., 2,

    Bodansky, O., Gold, H. & Zabm, W. (1942) J. Amer. Pharm. Ass. Sci.
    Ed., 31 1

    Fitzhugh, O. G. & Nelson, A. A. (1947) J. Amer. Pharm. Ass. Sci.
    Ed., 36 217

    Hall, R. L. (1960) Food Techn., 14, 488

    Harrisson, J. W. E. & Abbott, D. D. (1962) Unpublished report of
    LaWall and Harrisson Research Laboratories, submitted to WHO

    Innes, J. M. (1936) Biochem. J., 30, 2040

    Levey, S., Lasichak, A. G., Brimi, R., Orten, J. M., Smyth, C. J. &
    Smith, A. H.(1946) J. Amer. Pharm. Ass. Sci. Ed., 35, 298

    Locke, A., Locke, R. E., Schlesinger, H. & Carr, H. (1942) J, Amer.
    Pharm. Ass., 31 12

    Marshall, L. M., Orten, J. M. & Smith, A. H. (1949) J. Biol. chem.,
    179, 1127

    Packman, E., W., Abbott, D. D. & Harrisson, J. W. E. (1963) Toxicol.
    appl. Pharm., 5, 163

    Weiss, J. M., Downs, C. R. & Corson, H. P. (1923) Ind. Eng. Chem.,
    15, 628

    See Also:
       Toxicological Abbreviations
       Fumaric acid (ICSC)
       Fumaric acid (WHO Food Additives Series 6)
       FUMARIC ACID (JECFA Evaluation)