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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    WORLD HEALTH ORGANIZATION



    TOXICOLOGICAL EVALUATION OF SOME
    FOOD COLOURS, EMULSIFIERS, STABILIZERS,
    ANTI-CAKING AGENTS AND CERTAIN
    OTHER SUBSTANCES



    FAO Nutrition Meetings Report Series 
    No. 46A WHO/FOOD ADD/70.36




    The content of this document is the result of the deliberations of the
    Joint FAO/WHO Expert Committee on Food Additives which met in Rome,
    27 May - 4 June 19691





    Food and Agriculture Organization of the United Nations

    World Health Organization



                   
    1 Thirteenth report of the Joint FAO/WHO Expert Committee on Food
    Additives, FAO Nutrition Meetings Report Series, in press;
    Wld Hlth Org. techn.  Rep. Ser., in press.


    CALCIUM, POTASSIUM AND SODIUM FERROCYANIDE

    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 body weight), excreted the salt without renal
    damage demonstrated by high urea clearance, absence or gross or
    microscopic hematuria. Repeat clearance several weeks after injection
    was found to be entirely normal without chronic hematuria, 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 g/cent) 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
    gm/kg body weight), 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 per cent, 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 per cent. 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 g of ferrocyanide.
    94-98 per cent. 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 g/kg potassium ferrocyanide excreted about
    47 per cent. unchanged in the feces and three per cent. in the urine.
    Faecal and urinary excretion of ferrocyanide and thiocyanate was at a
    maximum from day one to three 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 per cent (68-87
    per cent.) 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 no half time value
    (T 1/2) was 135 minutes. The rate of disappearance was slower in
    patients with renal damage. There was 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. Ten ml five per
    cent. 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).

    Acute toxicity

                                                                     

    Animal    Route         LD50            Reference
                        (mg/kg body weight)
                                                                     

    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 per cent. sodium
    ferrocyanide. Growth rate and food consumption was normal except at
    the five per cent. level, where there was slight depression.
    Haematocrit and haemoglobin values were depressed at the five per
    cent. level. Kidney weight of both males and females at the five per
    cent. level and females at the 0.5 per cent. level was increased as
    were male adrenal and female pituitary gland weights in the five per
    cent. group. The kidneys of rats at the 0.5 per cent. level showed a

    minimal degree of tubular damage. The effect was more marked at the
    five per cent, level, in addition granular and calcified deposits were
    observed (Oser, B. L. 1959).

    Long-term studies

    No data are available.

    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.

    EVALUATION

    Level causing no toxicological effect in the rat

    0.05 per cent. (= 500 ppm) in the diet equivalent to 25 mg/kg body
    weight/day

    Estimate of acceptable daily intake for man

    Temporary acceptance                    mg/kg body weight

                                                0 - 0.00125

    Further work required by June 1974

    A long-term study in one species and a two-year study in a non-rodent
    mammalian species with particular emphasis on kidney function.

    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 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. lnvest., 15, 489-492

    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, 611-628
    


    See Also:
       Toxicological Abbreviations