INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
WORLD HEALTH ORGANIZATION
TOXICOLOGICAL EVALUATION OF SOME
FOOD COLOURS, ENZYMES, FLAVOUR
ENHANCERS, THICKENING AGENTS, AND
CERTAIN FOOD ADDITIVES
WHO FOOD ADDITIVES SERIES 6
The evaluations contained in this publication were prepared by the
Joint FAO/WHO Expert Committee on Food Additives which met in Rome,
4-13 June 19741
World Health Organization Geneva 1975
1 Eighteenth Report of the Joint FAO/WHO Expert Committee on
Food Additives, Wld Hlth Org. techn. Rep. Ser., 1974, No. 557.
FAO Nutrition Meetings Report Series, 1974, No. 54.
FUMARIC ACID
Explanation
This compound has been evaluated for acceptable daily intake by
the Joint FAO/WHO Expert Committee on Food Additives (see Annex 1,
Ref. No. 13) in 1965.
Since the previous evaluation additional data have become
available and are summarized and discussed in the following monograph.
The previously published monograph has been expanded and is reproduced
in its entirety below.
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 mg magnesium fumarate
or 432 mg disodium fumarate shortened the average time by 40%. If the
appearance of charcoal marker was taken as a guide, 15% 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 the urine or serum non-protein
nitrogen level (Bodansky et al., 1942).
TOXICOLOGICAL STUDIES
Acute toxicity
LD50
Animal Route (mg/kg bw) References
Rat Oral (sodium fumarate) approx. 8 000 Levey et al., 1946
Rabbit Oral (disodium approx. 3 600 Locke et al., 1942
fumarate) 4 800 Weiss et al., 1923
Short-term studies
Guinea-pig
Eight animals were maintained on a diet containing 0%, 1% and
10% 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 on blood levels of non-protein nitrogen or
creatinine, phensulfolphthalein excretion, or kidney and liver
histology (Bodansky et al., 1942). Six rabbits received twice weekly
i.p. injections of 60 mg/kg bw of sodium fumarate over 17-29 weeks.
Swelling and congestion of the thyroids and atrophy of testes, with
low hyaluronidase content, were found (Arai & Suchiro, 1953). A
further nine male rabbits received 60 mg/kg bw 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 bw of disodium fumarate
daily for 28 days without any deaths. A further six rabbits received
2880-3680 mg/kg bw for 17 days with three deaths. Two rabbits were fed
a daily diet containing 640 mg/kg bw for 36 days without consistent
adverse effect 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% sodium fumarate (equivalent to 5% fumaric acid)
for 150 days. There were no significant differences from controls in
body weight 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 six young dogs at 0, 1, 3
and 5% of the diet for two years without adverse effect on body weight
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).
Long-term studies
Rat
Eight groups of 14 weanling rats were kept on diets containing 0,
0.1 and 1.0% fumaric acid and 1.38% 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% of fumaric acid
for two years without toxic effects on growth or food consumption. A
further four groups of 12 male rats were kept for two years on diets
containing 0, 0.5, 1.0 and 1.5% fumaric acid. Only at the 1.5% 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).
OBSERVATIONS IN 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).
Comments:
Fumaric acid is a normal component of intermediary metabolism.
The testicular atrophy in rabbits reported after intraperitoneal
administration of high doses was not seen after oral administration of
doses as high as 6-9% in the diet in rabbits and other species.
EVALUATION
Level causing no toxicological effect
Rat: 1.2% (=12 000 ppm) in the diet equivalent to 600 mg/kg bw.
Estimate of acceptable daily intake for man
0-6 mg/kg bw
REFERENCES
Arai, T. & Suchiro, S. (1953) Wakayama med. Rep., 1, 35
Arai, T., Suchiro, S. & Okamoto, T. (1955) Wakayama med. Rep., 2, 115
Bodansky, O., Gold, H. & Zahm, 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
Harrison, 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. et al. (1946) J. Amer. pharm. Ass., sci. Ed., 35, 298
Locke, A. et al. (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. Pharmacol., 5, 163
Weiss, J. M., Downs, C. R. & Corson, H. P. (1923) Ind. Eng. Chem., 15,
628