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    Toxicological evaluation of some food
    additives including anticaking agents,
    antimicrobials, antioxidants, emulsifiers
    and thickening agents



    WHO FOOD ADDITIVES SERIES NO. 5







    The evaluations contained in this publication
    were prepared by the Joint FAO/WHO Expert
    Committee on Food Additives which met in Geneva,
    25 June - 4 July 19731

    World Health Organization
    Geneva
    1974

              

    1    Seventeenth Report of the Joint FAO/WHO Expert Committee on
    Food Additives, Wld Hlth Org. techn. Rep. Ser., 1974, No. 539;
    FAO Nutrition Meetings Report Series, 1974, No. 53.

    CALCIUM, POTASSIUM, SODIUM FERROCYANIDE

    Explanation

         These compounds were evaluated for acceptable daily intake by the
    Joint FAO/WHO Expert Committee on Food Additives (see Annex 1, Ref.
    No. 20) in 1969.

         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

         Because of the strong chemical bond between iron and the cyanide
    groups these salts have a low toxicity. Dogs injected i.v. with sodium
    ferrocyanide (0.5 g/kg bw), excreted the salt without renal damage
    demonstrated by high urea clearance, absence of gross or microscopic
    haematuria. Repeated clearance several weeks after injection was found
    to be entirely normal without chronic haematuria, albuminuria or
    cylindruria. Sodium ferrocyanide, inulin and creatinine show the same
    excretory behaviour in respect to plasma clearance. In the dog,
    ferrocyanide is probably excreted entirely by glomerular filtration
    (Van Slyke et al., 1935; Berliner et al., 1950; Chinard, 1955). I.v.
    infusion of ferrocyanide and creatinine (20 mg%) into dogs gave an
    average clearance ratio of 0.966  0.41. Ferrocyanide clearance ratios
    showed no relationship to plasma ferrocyanide concentration (Berliner
    et al., 1950). "Instantaneous" injection into renal artery of dogs of
    combinations of inulin, creatinine and sodium ferrocyanide showed that
    there was no displacement of one glomerular substance with respect to
    another in spite of very rapid changes in serum concentration
    (Chinard, 1955).

         Rabbits injected i.v. with either sodium or calcium ferrocyanide
    (0.25 g/kg bw), showed similar rates of excretion of ferrocyanide in
    the urine. In another experiment rabbits were injected i.v. with
    either sodium, calcium or magnesium ferrocyanide and histochemical
    studies made on the kidneys to determine ferrocyanide distribution.
    Ferrocyanide appeared to be eliminated via the glomeruli. There was no
    evidence of tubular excretion. Some storage of ferrocyanide occurred
    in the proximal convoluted tubule cells after the urine was free of
    demonstrable ferrocyanide (Gersh & Stieglitz, 1934).

         Female dogs 10 to 20 kg were injected i.v. with 1000 mg of
    ferrocyanide.  94 to 98% of the administered ferrocyanide was
    recovered in the urine in 24 hours. Ferrocyanide could not be detected
    in red blood cells, gastric juice or faeces (Kleeman et al., 1955).

         Rats dosed orally with 200 mg/kg potassium ferrocyanide excreted
    about 47% unchanged in the faeces and 3% in the urine. Faecal and
    urinary excretion of ferrocyanide and thiocyanate was at a maximum
    from day 1 to day 3 after dosing, and thereafter declined to a low
    level (Gage, 1950).

    TOXICOLOGICAL STUDIES

    Acute toxicity

                                                                        
                                       LD50                Reference
         Animal         Route          (mg/kg bw)
                                                                        

         Rat            Oral           1600-3200           Fasset, 1958
                                                                        

    Short-term studies

    Rat

         Groups of 10 male and 10 female rats were maintained for 13 weeks
    on diets containing 0, 0.05, 0.5 and 5.0% sodium ferrocyanide. Growth
    rate and food consumption was normal except at the 5% level, where
    there was slight depression. Haematocrit and haemoglobin values were
    depressed at the 5% level. Kidney weight of both males and females at
    the 5% level and females at the 0.5% level was increased as were male
    adrenal and female pituitary gland weights in the 5% group. The
    kidneys of rats at the 0.5% level showed a minimal degree of tubular
    damage. The effect was more marked at the 5% level, in addition
    granular and calcified deposits were observed (Oser, 1959).

    Dog

         Groups each of eight young beagle dogs (four male, four female)
    received food containing 0, 10, 100 or 1000 ppm (0%, 0.001%, 0.01% or
    0.1%) of sodium ferrocyanide. Diets were offered 1 h/day, 6 days/week.
    The average intake of sodium ferrocyanide was approximately 0.26, 2.6
    and 26 mg/kg bw per day. Body weight and food consumption of control
    and test animals were similar. Haematologic, biochemical tests, and
    urine analysis of test and control animals were similar and within
    normal limits. There were no marked differences in absolute and
    relative organ weight of test and control animal. Histological studies
    of organs and tissues indicated chronic inflammation of the liver and
    kidney of one test animal in the 0.1% group. No effect on kidney
    histology was noted in any other test animal (Morgareidge, 1970).

    Long-term studies

         No data are available.

    OBSERVATIONS IN MAN

         Glomerular function was studied in 115 humans, 45 healthy,
    70 patients with glomerulonephritis, hypertension and amyloidosis.
    10 ml 5% sodium ferrocyanide was nontoxic in adults and 0.0077 g/kg
    tolerated in infants. 25% was excreted in 80 minutes and the remainder
    in the next 90 minutes by glomerular filtration. Patients had slower
    rates of excretion (Forero & Koch, 1942).

         Following i.v. injections of sodium ferrocyanide in amounts
    ranging from 0.55 to 6.2 g into humans ferrocyanide and urea clearance
    rates were found to be essentially similar suggesting that
    ferrocyanide was excreted like urea with about 40% reabsorption.
    Subjects receiving excessive doses of ferrocyanide (5X recommended)
    developed a marked albuminuria accompanied by numerous granular casts,
    white cells, epithetical cells and rare red blood cells. Symptoms
    disappeared within two weeks. There was no change in urea clearance
    during this period (Miller & Winkler, 1936). 0.1% sodium ferrocyanide
    was administered by i.v. infusion to six infants, nine days to 14
    months of age. The comparative rate of glomerular filtration of inulin
    and sodium ferrocyanide suggested tubular reabsorption of the latter
    substance in infants. There was no evidence of urinary disturbance in
    infants given sodium ferrocyanide (Calcagno et al,, 1951).

         A group of nine human subjects, which included patients with
    liver and kidney damage were injected (i.v.) with 30 to 50 mg of
    Fe59-labelled ferrocyanide. In the normal subject an average of 80%
    (68 to 87%) of the administered radioactivity was recovered in 24 to
    48 hours. There was no significant radioactivity detected in pooled
    faeces, saliva or gastric juice. In normal subjects the half time
    value (T 1/2) was 135 minutes. The rate of disappearance was slower in
    patients with renal damage. There was some evidence of in vivo
    binding of ferrocyanide to plasma albumin. In dogs the T 1/2 of
    labelled ferrocyanide was 40 to 50 minutes. No significant
    radioactivity was found in the pooled faeces, saliva or gastric juices
    of dogs (Kleeman & Epstein, 1956).

    Comments:

         Human studies have demonstrated that i.v. injected ferrocyanide
    is excreted by glomerular filtration. Tubular reabsorption occurs in
    man but not in dogs. High levels were nephrotoxic in the single short-
    term study available but no renal function tests were performed.

         The material is unstable in acid solution.

    EVALUATION

    Level causing no toxicological effect

         Rat: 500 ppm (0.05%) in the diet equivalent to 25 mg/kg bw.

    Estimate of acceptable daily intake for man

         0-0.025 mg/kg bw.*

    FURTHER WORK OR INFORMATION

    Required by June 1974.

         Metabolic studies in man. If these reveal any untoward effects, a
    long-term study in one species will be required.

    REFERENCES

    Berliner, W. R., Kennedy, T. J. & Hilton, J. G. (1950) Amer. J.
         Physiol., 160, 325-329

    Calcagno, P. L., Husson, G. S. & Rubin, M. I. (1951) Proc. Soc. exp.
         Biol. & Med., 77, 309-311

    Chinard, F. P. (1955) Amer. J. Physiol., 180, 617-619

    Fassett, D. W. (1958) In: Patty, F. A., Industrial hygiene and
         toxicology, New York, John Wiley & Sons, Vol. II, p. 2036

    Forero, A. & Koch, M. M. (1942) Rev. de med. y alimentacion, 5, 34-46

    Gage, J. C. (1950) Unpublished report submitted by I.C.I. Ltd.,
         Industrial Hygiene Research Laboratories

    Gersh, I. & Stieglitz, E. J. (1934) Anatomical Record, 58, 349-364

    Kleeman, C. R. & Epstein, F. H. (1956) Proc. Soc. exp. Biol. & Med.,
         93, 228-233

    Kleeman, C. R. et al. (1955) Amer. J. Physiol., 182, 548-552

    Miller, B. F. & Winkler, A. (1936) J. clin. Invest., 15, 489-492

    Morgareidge, K. (1970) Unpublished report by Food and Drug Research
         Lab. Inc., submitted by International Salt Co. Inc. to WHO

              

    *    Temporary

    Oser, B. L. (1959) Unpublished report by Food and Drug Research Lab.
         Inc., submitted by International Salt. Co. Inc.

    Van Slyke, D. D., Hiller, A. & Miller, B. F. (1935) Amer. J. Physiol.,
         113, 611-628


    See Also:
       Toxicological Abbreviations