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    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


    MALIC ACID

    Chemical names                DL-Malic acid; Hydroxysuccinic acid

    Empirical formula             C4H6O5

    Structural formula            HO-CH-COOH
                                     '
                                     CH2-COOH

    Molecular weight              134.09

    Definition                    Malic acid after drying for 5 hours at
                                  105 contains not less than 99 per cent.
                                  C4H6O5.

    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.

    Biological Data

    Biochemical aspects

         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.

    Acute toxicity

                                                                       

    Animal    Route     Lethal Dose              References
                        (mg/kg body-weight)
                                                                       

    Rabbit    oral      5 000 (L(+)-malic)       Weiss et al, 1923
    Dog       oral      1 000 (Sodium malate)    Underhill & Pack, 1925
                                                                       

    Short-term studies

         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
    (Rose, 1925).

    Long-term studies

         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).

    Comments

         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.

    Evaluation

    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
    for man

                                  mg/kg body-weight

       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.

    REFERENCES

    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.,
    17(3), 522

    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.,
    25, 467

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

    Worthen, H. G. (1963) Lab. invest., 12, 791
    


    See Also:
       Toxicological Abbreviations