FAO Nutrition Meetings
Report Series No. 40A,B,C
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
Chemical names DL-Malic acid; Hydroxysuccinic acid
Empirical formula C4H6O5
Structural formula HO-CH-COOH
Molecular weight 134.09
Definition Malic acid after drying for 5 hours at
105° contains not less than 99 per cent.
Description Malic acid occurs as white crystals or a
crystalline powder; it is odourless and
has a characteristic acid taste.
Uses As an acidulant and flavouring agent.
The metabolism of L(+)-malic acid is well understood, but little
is known about the fate of D(-)-malic acid in the body. It has been
suggested that L(+)-malic acid is more easily oxidized in the animal
body (Pohl, 1896) and of parenterally administered DL-malic acid in
rabbits and dogs only D(-)-malic acid was recovered in the urine
(Tomita, 1921). Incubation of DL-malic acid with muscle enzyme
preparations removes the L(+)-isomer preferentially (Dakin, 1922).
Rabbits were injected with 1.7 or 2.0 g L(+)-malic acid and 1, 1.5 and
3 g DL-malic acid. The L(+)-isomer was practically non-toxic, having a
negligible effect on rate or over-all renal output of
phenolsulfonphthalein and no effect on non-protein nitrogen and
chloride level of the blood. The DL-isomer produced a reduction in the
excretion rate and total output of the phthalein dye and a rise in
non-protein nitrogen. Neither forms altered the blood creatinine level
(Rose, 1925) The addition of DL-malic, acid to diets poor in
carbohydrate led to an increase of glycogen in the liver of rats
(Ponsford & Smedley-MacLean, 1932).
Malic acid is an intermediate in the Krebs cycle.
Animal Route Lethal Dose References
Rabbit oral 5 000 (L(+)-malic) Weiss et al, 1923
Dog oral 1 000 (Sodium malate) Underhill & Pack, 1925
A rabbit was killed after subcutaneous injections of DL-malic
acid of 3 and 5 g on successive days and 1.5 g after omitting 1 day.
Renal histology revealed small areas of cortical haemorrhages, some
tubular epithelial degeneration and scattered glomerular obliteration
No studies in animals are available. Foods containing malic acid
have been consumed by man for centuries without any apparent adverse
effects. The daily human consumption of malic acid from vegetables,
fruits and their juices is calculated to be in the order of 1.5 to 3 g
(Hartman & Hillig, 1934).
Special studies on maleic acid
The need to impose a severe limitation on the content of maleic
acid in malic acid arises from the established nephrotoxicity of
maleic acid. In male rats diets containing 1 per cent. or more of
malic acid brought about growth retardation, increased mortality and
changes in the renal proximal convoluted tubules (Fitzhugh & Nelson,
1947). Intraperitoneal administration of 0.1 M sodium maleate in
daily doses of 1-2 ml/kg for 2-3 weeks produced glucosuria,
phosphaturia and aminoaciduria. There was no evidence of permanent
renal damage (Harrison & Harrison, 1954). Graded doses of sodium
maleate produced the same effects, together with proteinuria, polyuria
and deficient acidification of urine, the severity depending on the
dose. Succinic dehydrogenase activity was decreased, especially in the
renal cortex. Morphological changes in the proximal convoluted tubules
accompanies the functional defect (Worthen, 1963).
In evaluating the acceptance of malic acid, emphasis is placed on
its well-established metabolic pathway and the daily consumption of
malic acid-containing food. However, there is some doubt concerning
the utilization in the body of the D(-)-isomer of malic acid.
Estimate of acceptable daily intake of the L(+)-isomer for man
No limit need to be set for the acceptable daily intake for man
of the L(+)-isomer of malic acid.
Estimate of acceptable daily intake of the D(-)-isomer
Conditional acceptance 0-100
Limitation of use
Neither the D(-) nor DL-malic acid should be added to food for
very young infants except for therapeutic purposes.
For adults the acceptable daily intake of DL-malic acid is
calculated from the D(-)-malic acid content.
Further work required
Metabolic studies on the utilization of D(-) and DL-malic acids
in infants and adults.
Dakin, H. D. (1922) J. Biol. Chem, 52, 183
Fitzhugh, O.G. & Nelson, A. A. (1947) J. Amer Pharm. Ass., 36, 217
Harrison, H.E. & Harrison, Helen, C. (1954) Science, 120, 606
Hartmann B. G. & Hillig, F. (1934) J. Ass. Off. Agric. Chem.,
Pohl, J. (1896) Arch. esp. Path. Pharmak., 37, 413
Ponsford, A. P. & Smedley-MacLean, A. (1932) Biochem, J., 26, 1340
Rose, W.C. (1925) J. Pharmacol. exp. Ther., 24, 123
Tomita, N. (1921) Biochem. Z., 123, 231
Underhill, F. P, & Pack, G. C. (1925) J. Pharmacol. exp. Ther.,
Weiss, J. M., Downs, C. R. & Corson, H. P. (1923) Ind. Eng. Chem.,
Worthen, H. G. (1963) Lab. invest., 12, 791