FAO Nutrition Meetings
Report Series No. 40A,B,C
WHO/Food Add./67.29
TOXICOLOGICAL EVALUATION OF SOME
ANTIMICROBIALS, ANTIOXIDANTS, EMULSIFIERS,
STABILIZERS, FLOUR-TREATMENT AGENTS, ACIDS AND BASES
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
1967
FUMARIC ACID
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.,
1949).
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
(mg/kg
body-weight)
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.,
1946).
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,
1962).
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).
Comments
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.
Evaluation
This is based on the rat, bearing in mind the 2-year study in the
dog.
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
REFERENCES
Arai, T. & Suehiro, S. (1953) Wakayama Med. Reps., 1, 35
Arai, T., Suehiro, S. & Okamoto, T. (1955) Wakayama Med. Reps., 2,
115
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)