IPCS INCHEM Home


    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.

    CALCIUM, POTASSIUM AND SODIUM FERROCYANIDE

    Explanation

         These compounds have been evaluated for acceptable daily intake
    by the Joint FAO/WHO Expert Committee on Food Additives (see Annex 1,
    Refs Nos 20 and 34) in 1969 and 1973.

         Since the previous evaluation additional data have become
    available and are summarized and discussed in the following monograph.
    The previously published monographs have been expanded and are
    reproduced in their 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 gm/kg bw), excreted the salt without renal damage
    demonstrated by high urea clearance, absence of gross or microscopic
    haematuria. Repeat 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; and Chinard, 1955).
    I.v. infusion of ferrocyanide and creatinine (20 mg/litre) only dogs
    gave an average clearance ratio of 0.9660.41. 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 gm/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 (Gersch & Stieglitz, 1934).

         Following i.v. injections of sodium ferrocyanide in amounts
    ranging from 0.55-6.2 gm 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).

         Female dogs 10-20 kg were injected (i.v.) with 1000 mg of
    ferrocyanide. 94-98% 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 days 1 to 3 after dosing, and thereafter declined to a low level
    (Gage, 1950).

         A group of nine human subjects, which included patients with
    liver and kidney damage were injected (i.v.) with 30-50 mg of Fe59-
    labelled ferrocyanide. In the normal subject an average of 80%
    (68-87%) of the administered radioactivity was recovered in 24-48
    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 40-50 minutes. No significant radioactivity
    was found in the pooled faeces, saliva or gastric juices of dogs
    (Kleeman & Epstein, 1956).

         Glomerular function was studied in 115 humans, 45 healthy, 70
    patients with glomerulonephritis, hypertension and amyloidoris. 10 ml
    5% sodium ferrocyanide was non-toxic in adults and 0.0077 g/kg
    tolerated in infants. Twenty-five per cent. 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).

    TOXICOLOGICAL STUDIES

    Acute toxicity
                                                        

                        LD50
    Animal    Route     (mg/kg bw)          Reference
                                                        

    Rat       Oral      1 600-3 200         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 were 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

         Four groups of four male and four female beagles received in 
    their diet 0, 10, 100 and 1000 ppm of sodium ferrocyanide for 13 
    weeks. No abnormalities were noted regarding appearance, behaviour, 
    body weight change, physical condition, haematology, biochemical 
    parameters, urinary pathology, gross and histopathology. No compound-
    related effects were seen (Morgaridge, 1970).

    Long-term studies

         No data are available.

    Comments:

         Human studies have demonstrated that i.v. injected ferrocyanide 
    is excreted by glomerular filtration. Some tubular reabsorption 
    occurs in man but not in dogs. High levels were nephrotoxic in the 
    short-term study in rats, but studies in dogs and man showed no 
    adverse effects. No long-term studies are available. Evaluation can be
    based on the animal studies and human observations.

    EVALUATION

    Level causing no toxicological effect

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

    Estimate of acceptable daily intake for man

         0-0.025* mg/kg bw

    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. (1955) In: Patty F. A. Industrial Hygiene and
         Toxicology, New York, John Wiley & Sons, Vol. II, p. 2036

    Forero, A. & Koch, M. y 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. et al. (1955) Amer. J. Physiol., 182, 548-552

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

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

    Morgaridge, K. (1970) FDRL Report No. 91015 dated 10.9.1970 submitted
         by International Salt Co. Inc.

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

    Van Slyke, D. D., Hiller, A. & Miller, B. F. (1935) Amer. J. Physiol.,
         113, 61].-628

              

    *    Calculated as sodium ferrocyanide.


    See Also:
       Toxicological Abbreviations