FAO Meeting Report No. PL/1965/10/2
    WHO/Food Add/28.65


    The content of this document is the result of the deliberations of the
    Joint Meeting of the FAO Committee on Pesticides in Agriculture and
    the WHO Expert Committee on Pesticide Residues, which met 15-22 March

    Food and Agriculture Organization of the United Nations
    World Health Organization

    1 Report of the second joint meeting of the FAO Committee on
    Pesticides in Agriculture and the WHO Expert Committee on Pesticide
    Residues, FAO Meeting Report No. PL/1965/10; WHO/Food Add./26.65.

    (including hydrogen cyanide evolved from calcium cyanide)


         Hydrogen cyanide

    Chemical name

         Hydrocyanic acid


         Hydrogen cyanide, prussic acid

    Empirical formula


    Structural formula

         H - C - N

    Relevant physical and chemical properties

    Physical state (atmospheric pressure, 20C); colourless liquid

    Boiling-point: 26C

    Odour: almond-like

    Flammability limits in air: 6-41% by volume


         Water: soluble in all proportions

         Organic solvents: infinitely soluble in alcohol and ether

    Specific gravity (liquid): 0.688

    Specific gravity (gas): 0.9


         Hydrogen cyanide has been widely employed for fumigating dry
    foodstuffs including cereals and milled cereal products, seeds,
    pulses, nuts and dried fruit and also tobacco. It has also been used
    for the disinfestation of buildings, such as flour mills, warehouses,
    and domestic houses, and ships (the latter usually directed against
    rats). For all these purposes hydrogen cyanide has been largely
    superceded by other fumigants which are more convenient or more

    efficient (in particular by methyl bromide) or other methods of
    control have taken the place of fumigation. However its use continues
    on a limited scale.

         It is not generally recommended for moist materials such as fresh
    fruit and vegetables many of which suffer damage by burning, wilting
    or discoloration (Monro, 1961).

         For fumigation the usual source of the gas is the liquid hydrogen
    cyanide either in cylinders or absorbed on a solid material.

         Various crude forms of calcium cyanide are also used as a vehicle
    for the generation of hydrogen cyanide gas by the action of water or
    moisture and some of these, in granular form, have been used as grain
    fumigants. These products generally contain not more than 50% calcium
    cyanide, Ca(CN)2 and produce about half of this weight as available
    HCN or approximately 20-25% of the weight of the crude material. The
    main impurities are lime, cyanamide, carbon and calcium carbide. The
    material is usually added continuously to the grain stream as a bin is
    filled using a dosage rate of 10 lb or 20 lb per 1000 bushels. It is
    recommended that the grain should not be moved for at least 72 hours
    and should, if possible, be allowed to remain for a week or 10 days.


         Because of its extreme solubility in water, hydrogen cyanide is
    most firmly retained by moist commodities. Generally the bulk of the
    gas escapes from drier products fairly readily and without reaction
    with the constituents, but small amounts of gas may be retained for
    long periods. Monier-Williams (1930) gives data collected from the
    literature up to 1929 for residual hydrogen cyanide found in a large
    number of treated commodities under the headings: milk and milk
    products; oils and fats, meat, fish, etc.; cereals, flour, etc.; fresh
    fruit; dried fruit; fresh vegetables; tea, coffee, cocoa; and
    miscellaneous foods, together with details of treatments.

         Cereal grains take up hydrogen cyanide during fumigation and
    small amounts of gas remain associated with the grains for long
    periods, but with moving, cleaning and milling this is progressively

         It has been suggested that a proportion of the sorbed cyanide may
    be combined with a constituent of the bran and that this compound
    slowly undergoes decomposition (Turtle, 1941).

         After fumigation with hydrogen cyanide at a measured
    concentration-time product of 60 mg h/l and subsequent aeration for
    seven days, whole wheat of 11.5% moisture content showed hydrogen
    cyanide residues of 10 ppm, bran 33 ppm and the flour 5 ppm. Wheat of
    up to 18% moisture content fumigated at a measured concentration-time
    product of 100 mg h/l and then milled to 65% extraction without

    washing or cleaning, showed residues in the flour of 10 ppm hydrogen
    cyanide, and 3 ppm in bread baked from this flour (Pest Infestation
    Laboratory, 1940).

         One hundred and ninety days after fumigating wheat and maize with
    hydrogen cyanide 0.3-0.5 ppm was found, and in flour 0.2 ppm after 45
    days (Desbaumes and Deshusses, 1956).

         A bag of wheatmeal (85% extraction) fumigated with hydrogen
    cyanide at a measured concentration-time product of 185 mg h/l showed
    a residue of 104 ppm at the centre of the bag after airing for two
    days, 18 ppm after seven days, 6 ppm after 14 days and 5.4 ppm after
    30 days (Pest Infestation Laboratory, 1943a).

         Much of the evidence on the retention of hydrogen cyanide by
    wheat and its milled products relates to treatments with the granular
    form of calcium cyanide, particularly with the proprietary material
    Cyanogas G which yields about 25% by weight of hydrogen cyanide.

         After application of Cyanogas to 155 tons of Manitoba wheat of
    about 12% moisture content at a rate of 20 lb per 1000 bushels the bin
    remained closed for 17 days. Residual hydrogen cyanide determined in
    31 samples collected as the bin was emptied (and therefore before
    cleaning) varied between 26 and 62 ppm (Pest Infestation Laboratory,

         Hydrogen cyanide reacts with laevulose in dried fruit to form
    laevulose cyanhydrin (Monier-Williams, 1930; Turtle, 1941; Page and
    Lubatti, 1948). This compound may be retained after prolonged aeration
    since the slight acidity in dried fruit favours its stability. Seven
    days after a normal treatment of dried fruit with hydrogen cyanide an
    average residue of 60 ppm could be expected, of which about 75% would
    exist as laevulose cyanhydrin and 25% as free hydrogen cyanide. Only
    if wet fruit is treated would residues up to 250 ppm be expected
    (Turtle, 1941).

    Effect of fumigant on treated crop

    (a) HCN naturally occurring in food

         Some foodstuffs of vegetable origin contain HCN, generally as
    glucoside. From glucoside, free HCN is liberated by enzymatic action
    in plants or in the digestive tract. The best characterized
    cyanogenetic glucoside is perhaps amygdalin, which is present
    especially in the seeds and leaves of the cherry, almond, peach, etc.
    Cherry kernels yield about 170 mg per 100 g and bitter almond pulps
    about 250 mg per 100 g (Sollman, 1944).

         Feeding amygdalin to a small group of rats at a level of 1000 ppm
    (equivalent of 60 ppm HCN in the diet) for 12 weeks was without
    effect. Since amygdalin in the digestive tract is only partly

    hydrolysed, the level of cyanogenetic glucosides up to 500 ppm in
    foods is considered to be of no health hazard (Lehman, 1959).

         Lima beans contain linamarin. After enzymatic hydrolysis 42 ppm
    HCN was found in lima beans; some specimens of lima beans yield as
    much as 180 ppm HCN (Lehman, 1959; Malkus, 1957). HCN in canned whole
    apricots, cherries and prunes was found to be 0.13, 0.048 and 0.012
    ppm respectively (Luh and Pinochet, 1959).

         In some samples of sec wine as high as 0.140 ppm free HCN was
    detected; combined HCN amounted to 0.230 ppm. In alcoholic
    fermentation a soluble substance, possibly vitamin B12, is formed,
    which readily eliminates HCN at normal temperatures as proved in
    experiments with yeast (Mestres, 1961).

    (b) HCN added for fumigation purposes

         Wheatmeal (85% extraction) fumigated with hydrogen cyanide at
    measured concentration-time products of 54-185 mg h/l showed damage to
    baking quality in the form of decrease in loaf volume, coarsening of
    crumb and decreased spring figure and increased extensibility in
    extensometer tests (Pest Infestation Laboratory, 1943a).

         In wheat fumigated at a wide range of dosage levels and at
    moisture contents of 11, 15 and 18% no damage to milling quality was
    noted but damage to the baking quality of 65% extraction flour
    prepared from this wheat was observed at all levels of treatment
    especially at the higher dosage and moisture contents. After thorough
    aeration of the flour for one month no damage to baking quality was
    observed, showing that the previous damage was due to unaired hydrogen
    cyanide (Pest Infestation Laboratory, 1940).

         The damage to baking can also be largely reversed by treatments
    with certain of the chemicals used as "improvers" including nitrogen
    trichloride (Agene) (now no longer permitted), and potassium bromide
    (Turtle, 1941; Desbaumes and Deshusses, 1956). Wholemeal flour treated
    at a measured concentration-time product of 80 mg h/l showed no
    destruction of vitamin B1 (Pest Infestation Laboratory, 1940).


    Biochemical aspects

         Hydrogen cyanide is extremely toxic and the intoxication can be
    caused not only by ingestion and inhalation, but also by percutaneous
    resorption of liquid HCN and its vapours. Death of the organism
    results from inhibition of the iron (ferric) containing cell
    respiratory enzymes. The cytochromoxydase is the most sensitive. The
    inhibition is reversible.

         Cyanides in the organism are in their greatest part metabolized
    to thiocyanate and excreted in this form in urine (Lang, 1894). In
    rabbits 80% is excreted in 24-48 hours; in dogs the excretion is
    slower; in sheep, 60% is excreted within three days (Baumann et al.,
    1933; Mukerji and Smith, 1943; Blakley and Coop, 1949).

         There are other metabolites as well as thiocyanate. To a slight
    extent cyanide can be oxidized to carbon dioxide and formate (Boxer
    and Richards, 1952). From the urine of rats
    2-iminothiazolidine-4-carboxylic acid was isolated and formed 15% of
    the injected dose of KCN, thiocyanate accounting for 80%. The above
    acid is formed in vivo from cystine and HCN and, from the metabolic
    of view, it is inert (Wood and Cooley, 1956).

         Thiocyanate is present normally in human saliva in a
    concentration of about 0.01% (Shohl, 1939). In serum and urine, the
    average values for thiocyanate, as KCNS, are reported as follows: in
    non-smokers 0.54 mg % and 0.65 mg/24 hours, in smokers 1.52 mg % and
    10 mg/24 hours (Lawton et al., 1943).

         The conversion of cyanide to thiocyanate occurs by means of the
    specific enzyme rhodanase, which catalyses the formation of
    thiocyanate from cyanide in the presence of sodium thiosulfate or
    colloidal sulfur. Rhodanase activity in the liver decreases in the
    order rat>rabbit>man>dog. In vitro, the whole liver from one dog
    is capable of detoxicating 4015 g of cyanide in 15 minutes (Lang,
    1933; Himwich and Saunders, 1948). Rhodanase is present in large
    amounts in all tissues but not in blood. In the detoxication mechanism
    of the organism an important role is played by the availability of
    sulfur. With high concentrations of thiocyanate in the organism,
    cyanide can be liberated. This accounts for some of the toxic symptoms
    observed after the injection of large doses of thiocyanate. The
    formation of cyanide from sodium thiocyanate was seen both in dogs and
    men when NaCNS was injected in doses of 300 or 700 mg/kg per man,
    respectively (Goldstein and Rieders, 1951). Partial conversion of
    thiocyanate to cyanide in the presence of erythrocytes was confirmed
    by in vitro experiments (Pines and Crymble, 1952). This conversion
    is evidently dependent on the presence of an enzyme found only in
    erythrocytes and called thiocyanate oxidase (Goldstein and Rieders,

    Acute toxicity
    Compound     Animal      Route               LD50 mg/kg         Reference

    Potassium    Mouse       subcutaneous       6.02 + 0.33    Spector, 1956
    cyanide                  intravenous          2.5 (LD)             "
                 Rat         oral                10-15 (MLD)           "
                             intravenous          2.5 (MLD)            "

    Acute toxicity (continued)
    Compound     Animal      Route               LD50 mg/kg         Reference

    Potassium    Dog         oral                 5.3 (LD)        Gettler &
    cyanide                                                       Baine, 1938

    Sodium       Rabbit      subcutaneous         2.2 (MLD)       Spector, 1956
    cyanide      Guinea-pig  subcutaneous         5.8             Ghiringhelli,
                 Dog         intravenous          2.8 (LD)        Spector, 1956

    Sodium       Mouse       oral              598.4 + 18.3       Spector, 1956
    thiocyanate              intravenous       483.5 + 9.3            "
                 Rat         oral              764.7 + 50.9           "
                             intra-peritoneal  540   + 42.5           "
         The minimum lethal absorbed dose of HCN after administration of
    cyanide to the dog was 1.1-1.5 mg/kg by inhalation and 1.06-1.4 mg/kg
    by mouth. The same figures in man obtained from cases of suicide are
    0.5-1.4 mg/kg by mouth and in one case 3.6 mg/kg (Gettler and Baine,

         For man, the acute toxic oral dose of HCN is usually given as
    50-90 mg, for potassium or sodium cyanide 200 mg, representing 81 and
    110 mg HCN, respectively (Lehman, 1959). Data on the oral lethal dose
    of cyanide for man in four cases of suicide, calculated from the total
    amount of HCN absorbed in the body at the time of death, and from the
    amount of HCN found in the digestive tract, differed considerably
    (calculated as mg HCN): 1450 (62.5 kg body-weight), 556.5 (74.5 kg),
    296.7 (50.7 kg), and 29.8 (51 kg) (Gettler and Baine, 1938).

         By inhalation an HCN concentration of 135 ppm (150 mg/m3) is
    given as lethal after 30 minutes, 270 ppm (300 mg/m3) as immediately
    lethal (Patty, 1942).

         The American TLV (threshold limit value) for HCN (1964) in eight
    hours' exposure in industry is 10 ppm (11 mg/m3) (Anon, 1964).

         No cases of chronic intoxication in industry have been diagnosed.
    The possibility of chronic intoxication with HCN or cyanides is
    usually considered to be improbable. Reports of single cases of
    "chronic cyanide poisoning" after repeated occupational exposure are
    considered to represent thiocyanate intoxication (Hamilton and Hardy,
    1949). In one case the symptoms were reproduced by daily intravenous
    injection of 1.4 g of sodium thiocyanate (Wtherich, 1954). Two other
    cases with thyroid changes following occupational exposure to cyanide
    have been described (Hardy et al., 1950).

    Short-term studies

         Dog.    Three males and two females were fed for 30 days on a
    diet containing 150 ppm of sodium cyanide. One male and one female
    served as controls. No unusual signs or symptoms were noted, and
    general behaviour or appearance, and food consumption were not
    affected. Total and differential leucocyte counts, haemoglobin and
    haematocrit were determined prior to the start of the experiment and
    four weeks later. The results were similar, organ weights fell within
    the normal range. In comparison to the controls and after elimination
    of histopathological changes induced by infection, it was concluded
    that feeding 150 ppm of sodium cyanide to dogs for 30 days did not
    induce any gross or microscopical pathology (American Cyanamid Co.

         Three female dogs were given NaCN in gelatin capsules every day
    in doses of 0.5, 2 and 2  2 mg/kg body-weight for 14-1/2 months,
    always in the morning when their stomachs were empty. The fourth bitch
    in the group was the control. The two experimental dogs which were
    given doses of 2 and 2  2 mg/kg body-weight, showed toxic symptoms
    immediately after dosing, which did not last more than 30 minutes. In
    the dog which was given doses of 0.5 mg/kg, toxic symptoms of
    temporary character only began to appear after 53 weeks. After one of
    the doses she died suddenly in anoxaemic convulsions. In the course of
    the experiment, a complete haematological examination was carried out
    at intervals of 1-2 months, as well as determination of plasma
    proteins, residual nitrogen, blood sugar, potassium, sodium,
    chlorides, calcium, thiocyanate, cholesterol, bicarbonate
    concentration, functional liver tests with tetrabromphenolphthalein,
    examination of urine for protein, and examination of the sediment.
    Only elevated erythrocyte counts up to the eighth month of the
    experiment, and a little lowering of the level of albumin towards the
    end of the experiment were found. The concentration of thiocyanate in
    plasma stabilized towards the end of the experiment at a level of
    under 1 mg %. Such a low level of thiocyanate could not have any toxic
    effect. Degenerative changes of ganglion cells in the central nervous
    system were found post mortem. The Purkinje cell system of the
    cerebellum was especially affected, as a consequence of repetitive
    attacks of acute hypoxia (Hertting et al., 1960).

         Pig.    Two pigs remained healthy after being fed for 11 days
    upon a diet of wheatfeed treated at a very high dosage with calcium
    cyanide (equivalent to 1500 ppm of hydrogen cyanide) and partially
    aired before feeding. The amount of recoverable hydrogen cyanide in
    the diet fell, during the period of the feeding experiment from 318
    ppm to 206 ppm (Pest Infestation Laboratory, 1944).

    Long-term studies

         Rat. Two groups of 20 rats (10 males and 10 females) were fed a
    diet fumigated with hydrogen cyanide, containing residual HCN in the
    concentration of 100 and 300 ppm, for two years. Another group of 20
    rats was fed a control diet. Growth, food consumption and survival in

    both groups were comparable. Haematological values determined
    initially and at the end of the experiment appeared to be within
    normal limits. Organ-body-weight ratios for the liver, kidneys,
    spleen, brain, heart, adrenals and testes or ovaries did not show any
    substantial differences from controls. Histological examination of
    tissues was carried out for the heart, lung, liver, spleen, stomach,
    small and large intestines, kidneys, adrenals, thyroid, testes or
    uterus and ovary, and the cerebrum and cerebellum of the brain. In the
    tissues examined no changes due to hydrogen cyanide feeding were
    found. At the end of the experiment the amount of free cyanide and
    thiocyanate in blood, liver and kidney was determined. In the group
    fed 100 ppm HCN free cyanide was found only in red blood cells with an
    average of 5.40 g per 100 ml, thiocyanate was found in plasma with an
    average of 936 g per 100 ml, in the liver and kidney 719 and 1023 g
    per 100 g of tissue, respectively.

         In the group fed 300 ppm HCN, free cyanide was found in the liver
    of one rat and in the erythrocytes of less than 50% of animals
    (average 1.97 g per 100 g tissue). Average values for thiocyanate in
    plasma and erythrocytes were 1123 and 246 g per 100 ml, respectively,
    in the liver and kidney 665 and 1188 g per 100 g tissue,
    respectively. The average thiocyanate values in the controls were as
    follows: plasma 361 g, red blood cells 73 g per 100 ml; liver 566
    g, kidney 577 g per 100 g (Howard and Hanzal, 1955).

    Comment on the experimental studies reported

         Lethal doses of cyanide are of about the same order of magnitude
    for most species of mammals. For attaining critical concentration in
    tissues and for inducing acutely toxic effect, the intensity and
    rapidity of absorption of the HCN dose is decisive. In the short-term
    experiments in dogs, the diet contained 150 ppm of sodium cyanide; in
    long-term experiments rats 300 ppm HCN, and in neither case was any
    sign of intoxication detected except that there was a more than
    three-fold increase in the level of thiocyanate in plasma and
    erythrocyte in the rat. The lack of other signs of toxicity can be
    explained by the fact that HCN administered in food is diluted and for
    this reason it is absorbed only slowly, so that the rapidity of the
    enzymatic conversion to thiocyanate does not allow the toxic level of
    CN' in tissues to be attained. It cannot be excluded that the low
    toxicity observed in these cases was due to the chemical reaction of
    HCN with other components of the food, or to its chemical
    transformation in the gastrointestinal tract.

         Long-term experiment in rats in the course of their whole
    life-span can be taken as a basis for determining the acceptable daily
    dose for man. This dose (100 ppm) does not increase the level of
    thiocyanate in the blood to the same extent as reported in smokers,
    which is about three-fold of that of non-smokers, so that effects of
    thiocyanate produced in the organism from the consumption of food
    treated with HCN are improbable.


    Level causing no toxicological effect in the rat

         The maximum no-effect level in the rat was 100 ppm as residue in
    the diet after fumigation with HCN, equivalent to 5 mg/kg body-weiglat
    per day.

         Estimate of acceptable daily intake for man of cyanide
    resulting from the fumigation of food: 0-0.05 mg HCN/kg body-weight.

    Further work considered desirable

         Reproduction studies on the rat.


    Anon, (1964) Threshold limit values for 1964. Arch. environm.
    Hlth., 9, 545

    American Cyanamid Company (1959) Report No. 59-14, 10 August, p. 199

    Baumann, E. J., Sprinson, D. B. & Metzger, N. (1933) J. biol. Chem.,
    102, 773

    Blakley, R. L. & Coop, I. E. (1949) N.Z. J. Sci. Tech., 31A, 1

    Boxer, G. E. & Rickards, J. C. (1952) Arch. Biochem., 39, 7

    Desbaumes, P. & Deshusses, J. (1956) Mitt. Lebensmitt. Hyg., 47,

    Gettler, A. O. & Baine, J. O. (1938) Amer. J. med. Sci., 195, 182

    Ghiringhelli, L. (1956) Med. d. Lavoro, 47, 192

    Goldstein, F. & Rieders, F. (1951) Amer. J. Physiol., 167, 47

    Goldstein, F. & Rieders, F. (1953) Amer. J. Physiol., 173, 287

    Hamilton, A. & Hardy, H. L. (1949) Industrial toxicology, Second
    ed., New York, Paul B. Hoeber. Cited in Wolfsie, J. H. & Shaffer C.
    Boyd (1959) J. occup. Med., 1, 282

    Hardy, H. L., Jeffries, W. McK., Wasserman, M. M. & Waddell, W. R.
    (1950) New Engl. J. Med., 242, 968

    Hertting, G., Kraupp, O., Schnitz, E. & Wuketich, S. (1960) Acta
    pharmacol., 17, 27

    Himwich, W. A. & Saunders, J. P. (1948) Amer. J. Physiol., 153,

    Howard, J. W. & Hanzal, R. F. (1955) Agric. Food Chem., 3, 325

    Lang, K. (1933) Biochem. Z., 259, 243

    Lang, S. (1894) Arch. exp. Pathol. Pharmacol., 34, 247

    Lawton, A. H., Sweeney, T. R. & Dudley, H. C. (1943) J. industr.
    Hyg., 25, 13

    "Lehman, A. J." (1959) Quart. Bull. Ass. Food Drug Offic., 23, 55
    (article signed A.J.L.)

    Luh, B. S. & Pinochet, M. F. (1959) Food Res., 24, 423

    Malkus, Z. (1957) Czech. Hyg., 2, 251

    Mestres, R. (1961) Ann. Falsif. Expert. Chim. 54, 284

    Monier-Williams, G. W. (1930) Rep. Publ. Hlth Med. Subj. No. 60,
    London, H.M. Stationery Office

    Monro, H. A. U. (1961) Manual of fumigation for insect control, FAO,
    Agric. Studies, 56

    Mukerji, B. & Smith, R. G. (1943) Ann. Biochem., 3, 23

    Page, A. B. P. & Lubatti, O. F. (1948) Chem. and Ind., November 13,

    Patty, F. A. (1942) J. industr. Hyg., 2, 631

    Pest Infestation Laboratory (1940) Unpublished Report No. 37

    Pest Infestation Laboratory (1943a) Unpublished Report No. 87

    Pest Infestation Laboratory (1943b) Unpublished Report No. 100

    Pest Infestation Laboratory (1944) Unpublished Report No. 107

    Pines, K. L. & Crymble, M. M. (1952) Proc. Soc. exp. Biol., 81,

    Shohl, A. T. (1939) Mineral metabolism, Reinhold, New York, p. 62

    Spector, W. S. (1956) Handbook of Toxicology, vol. 1, Saunders,

    Sollman, T. (1944) A manual of pharmacology, p. 826, Saunders,

    Turtle, E. E. (1941) (Ph.D. Thesis, University London)

    Wood, J. L. & Cooley, S. L. (1956) J. biol. Chem., 218, 449

    Wtherich, F. (1954) Schweiz med. Wschr., 84, 105

    See Also:
       Toxicological Abbreviations