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