1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names/trade names
   1.6 Main manufacturers/importers
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First-aid measures and management principles
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/form
      3.3.3 Description
   3.4 Hazardous characteristics
   4.1 Uses
      4.1.1 Use
      4.2.2 Description
   4.2 High risk circumstances of poisoning
   4.3 Occupationally exposed populations
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
   7.1 Mode of action
   7.2 Toxicity
      7.2.1 Human data Adults Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
      7.2.4 Workplace standards
      7.2.5 Acceptable Daily Intake (ADI) and Other Guideline Levels
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection Toxicological analyses Biomedical analyses Arterial blood gas analysis Haematological analyses Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens Toxicological analyses Biomedical analyses Arterial blood gas analysis Haematological analyses Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens Toxicological analyses Biomedical analyses Arterial blood gas analysis Haematological analyses Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material Simple Qualitative Test(s) Advanced Qualitative Confirmation Test(s) Simple Quantitative Method(s) Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens Simple Qualitative Test(s) Advanced Qualitative Confirmation Test(s) Simple Quantitative Method(s) Advanced Quantitative Method(s) Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis Blood, plasma or serum Urine Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analyses and toxicological investigations
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological Central nervous system (CNS) Peripheral nervous system Autonomic nervous system Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary Renal Others
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eyes, ears, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic Acid base disturbances Fluid and electrolyte disturbances Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks: pregnancy, breast-feeding, enzyme deficiencies
   9.5 Others
   9.6 Summary
   10.1 General principles
   10.2 Life supportive procedures and symptomatic treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.6.2 Children
   10.6 Management discussion: alternatives, controversies and research needs
   11.1 Case reports from literature
   12.1 Specific preventive measures
   12.2 Other

    International Programme on Chemical Safety
    Poisons Information Monograph G003

    1.  NAME

        1.1  Substance


        1.2  Group


        1.3  Synonyms

             Hydrogen cyanide: formonitrile, hydrocyanic
             acid, prussic acid, Blausäure

             Sodium cyanide: cyanogran

             Potassium cyanide: cyankali

        1.4  Identification numbers

             1.4.1  CAS number

                    Hydrogen cyanide:    74-9O-8
                    Sodium cyanide:      143-33-9
                    Potassium cyanide:   151-5O-8

             1.4.2  Other numbers

                    RTECS: GS7175OOO

        1.5  Main brand names/trade names

             To be added by centre using the monograph.

        1.6  Main manufacturers/importers

             Du Pont (USA); ICI (UK); Degussa (Germany).

    2.  SUMMARY

        2.1  Main risks and target organs

             Histotoxic anoxia in the brain and heart may cause early
             coma, respiratory failure and cardiovascular collapse. 
             Reduced oxygen utilization and lactate acidosis cause severe
             metabolic effects.

        2.2  Summary of clinical effects

             Symptoms appear within seconds or minutes after
             ingestion or inhalation.  Giddiness, pulsating headache,
             anxiety, palpitations, hyperventilation, confusion and
             dyspnoea are the initial signs of acute poisoning.  They are
             rapidly followed by vomiting, coma, convulsions, apnoea,
             bradycardia, hypotension and metabolic acidosis.
             Severe poisoning is characterized by convulsions, collapse,
             coma and death (apopletic form), and is fatal within minutes.
             Mild exposure only causes anxiety, headache, nausea and

        2.3  Diagnosis

             The diagnois of acute poisoning is based on:
             (a) knowledge of the patient's occupation, previous altered
             mental status and location of the incident,
             (b) rapid occurence of signs and symptoms:  headache,
             anxiety, tachypnea, drowsiness, intense metabolic acidosis,
             convulsions and coma.
             From the analytical point of view:
             Blood for toxicological analyses: Anticoagulated blood (19
             mL) should be collected before giving cyanide antidotes.  The
             sample container must be tightly closed.  If immediate
             analysis is not possible, blood samples should be stored in
             the refrigerator at 4°C.  Blood for routine biochemical
             analysis, in particular lactate, potassium and glucose. 
             Blood gas analysis.  Blood gases should be tested
             immediately.  Maethemoglobin determination is desirable in
             case of maethemoglobin forming antidotes, however most
             methods could be invalidated in cyanide poisoning because the
             cyanmaethamoglobin is not taken into account.
             A simple and fast semiquantitative analysis on cyanide in air
             or blood is the Dräger tube "Hydrocyanic acid 2/a" method
             (see Section 8).
             Urine should be collected.
             Routine biomedical analysis at the place of the accident:
             stomach contents, scene residues, suspect material. 
             Toxicological analysis; the sample containers must be tightly

        2.4  First-aid measures and management principles

             Without immediate medical treatment, severe cyanide
             poisoning is usually fata1.  Intensive support therapy is
             important.  Urgent specific antidotal therapy is not

             indicated unless the patient is in a coma and if there are
             deteriorating vital functions of respiration and
             Severe poisoning
             Outside hospital:  stop further exposure (induce vomiting,
             wash skin immediately); give artificial ventilation with lOO%
             oxygen (mask and bag preferably with a non-return valve);
             administer O.2 to O.4 mL amyl nitrite via Ambu bag.
             Within hospital or if physician is available: give artificial
             ventilation with lOO% oxygen (mask or intubation and bag,
             preferably with a non-return value); give cardio-respiratory
             support; give O.2 to O.4 mL amyl nitrite via Ambu bag
             immediately followed (in adults) by:
             either:         sodium nitrite solution 3%, 10 mL (300 mg)
                             intravenously over 5 to 20 min. (the dose
                             must be adjusted for children).
             either:         4-dimethylaminophenol(4-DMAP) 3.25 mg/kg
                             intravenously.  Dose as exact as possible and
                             mind overdose (dose for children is unknown,
                             overdose must be avoided).
             either:         dicobalt edetate solution 1.5% (Kelocyanor),
                             20 mL (300 mg)intravenously over 1 minute,
                             followed immediately by 50 mL dextrose
                             intravenously, infusion 500 g/1.
             either:         hydroxycobalamin solution 4%, 100 mL (4 g)
                             intravenously over 20 minutes.
             AND:          50 mL of a 25% sodium thiosulfate solution
                             (12.5 g) over about 10 minutes. (preferably
                             in a separate infusion).
             Decontaminate by gastric lavage if cyanide has been
             swallowed; wash skin in cases of skin contamination.  Give
             sodium bicarbonate (intravenously) till acidosis is
             If the patient fails to respond, doses of hydroxycobalamin
             and thiosulfate may be repeated, but expert medical advice is
             required before repeating a dose of any other specific
             antidote.  Physicians must establish whether specific
             antidotal therapy was conducted at the time of the incident
             before further doses are administered, especially in the case
             of methemoglobin-forming agents.
             Moderately severe poisoning
             Short-lived period of unconsciousness, convulsions, vomiting,
             and/or cyanosis (blood cyanide concentrations 2-3 mg/litre):
             lOO% oxygen for not more than 24 hours;  observation in an
             intensive care area: 5O mL of 25% sodium thiosulfate solution
             (1.5 g) intravenously over lO minutes.
             Mild poisoning
             Nausea, dizziness, drowsiness (blood cyanide concentrations
             of less than 2 mg/L).  Give oxygen and bed rest, reassure the


        3.1  Origin of the substance

             Cyanide can be of natural or synthetic origin.
             Natural origin: cyanide is found in foodstuffs such as
             cassava, cabbage, spinach, mustard and in the kernels of
             apples, stones of peaches and plums, as well as in cherry
             stones and in almonds.  Another source of human exposure is
             tobacco smoke.
             Synthetic hydrogen cyanide: the Andrussaw process involves
             the high temperature reaction of ammonia, methane and air
             over a platinum catalyst:
                   2NH3 + 2CH4 +3O2 --------------> 2HCN + 6H2O
             The Degussa process:
                          CH4 + NH3 ----------------> HCN + 3H2
             Synthetic sodium cyanide:
                          HCN + NaOH ---------------> NaCN + H2O

        3.2  Chemical structure

             Cyanides comprise a wide range of compounds with various
             degrees of chemical complexity, all of which have the cyanide
             (CN) group.
             Major compounds are:  Hydrogen cyanide (HCN), Sodium cyanide
             (NaCN), and Potasssium cyanide (KCN).

        3.3  Physical properties

             3.3.1  Colour

                    Clear liquid (hydrogen cyanide)

             3.3.2  State/form

                    See Table 1, Section 3.3.3.

             3.3.3 Description
             Table I
    Compound      State     Mol.Wt.     M.P.       B.P.        V.P.        V.Dens
                                        (°C)       (°C)       (mm Hg)     (Air = 1)
    Hydrogen        G       27.04        -13         26         807       0.94
    Sodium          S       49.01        564       1496           1         -
    Potassium       S       65.12        635          -           -         -
    Abbreviations:  G = gas, S = solution, Mo1.Wt. = molecular weight,
                    M.P. = melting point, B.P. = boiling point,
                    V.P. = vapour pressure, V.Dens = vapour density
             Table I (contd.)
    Compound                 H2O         Ethanol         Ether
    Hydrogen cyanide         Misc            Sol            Sol
    Sodium cyanide           Sol             Sl             Sl
    Potassium cyanide        Sol             Sl             -
    Abbreviations: Sol = soluble, Sl = slightly soluble

        3.4  Hazardous characteristics

             Hydrogen cyanide has a distinct odour of bitter almonds,
             which can be detected at 2 to 5 ppm.  But the sense of smell
             is easily fatigued and some individuals may not perceive it.
             Potassium and sodium salts have a lighter odour.


        4.1  Uses

             4.1.1  Use

                    Chemical used in synthesis; not otherwise specified
                    Other industrial/commercial product

             4.2.2  Description

                    Cyanide is mainly used in industry and for pest
                    Hydrogen cyanide is used in fumigation of ships, large
                    buildings, flourmills, private dwellings, freight cars
                    or airplanes that have been infested by rodents or
                    insects.  It is bound to a carrier, mostly diatomic in
                    nature and blended with a perfume or an irritating
                    product as an indicator.
                    Cyanide salts are utilized in metal cleaning,
                    gardening, in ore-extracting processes, dyeing,
                    printing and photography, electroplating, various
                    organic reactions, manufacture of adiponitril (for
                    nylon production).  Also used in great quantities for
                    production of resin monomers (e.g. acrylates).
                    Halogenated cyanides (chloro-, bromo- and iodocyanide)
                    produce the non-toxic cyanacid when they come into
                    contact with water.  Hydrogen cyanide is liberated as
                    a result of contact with strong acids.
                    Nitriles (see Section 12.3) are cyano-derivatives of
                    organic acids.  Acetonitrile is used as a solvent and
                    is less toxic (LD50.= l2O mg/kg) than hydrogen
                    cyanide (LD50 = O.5 mg/kg) but often contains toxic
                    admixtures.  Acrylonitrile is the raw material used
                    for the manufacture of plastics and synthetic fibres. 
                    Contact with skin causes bullae formation.  Pyrolysis
                    generates hydrogen cyanide.  Acrylonitrile and
                    proprionitrile  are less toxic (LD50 = 35 mg/kg)
                    than butyronitrile (LD50 = lO mg/kg).

                    Trichloroacetonitrile (LD50 = 2OO mg/kg) is used as
                    an insecticide.  The aromatic nitriles bromoxynil
                    (LD50 = l9O mg/kg) and ioxynil (LD50 = llO mg/kg)
                    are used as herbicides.
                    Cyanamide, cyanoacetic acid, ferricyanide and
                    ferrocyanide do not release cyanide and are therefore
                    less toxic (LD50 = lOOO to 2OOO mg/kg) than the
                    cyanogenic compounds above.

        4.2  High risk circumstances of poisoning

             Suicide attempts with cyanide products.
             Occupational exposure - a list of occupations at risk of
             exposure is fumigation of ships, large buildings, flourmills,
             private dwellings, freight cars or airplanes that have been
             infested by rodents or insects.
             Fire-fighters or victims of fires involving materials such as
             wood, silk, horsehair, tobacco, and polyurethane,
             polyacrylonitrile and other N-containing synthetic materials
             (see Table 2)(Alarie, l985; Lowry et a1., l985; Levine et
             a1., l978; Clark et a1., l983;  Birky et a1., l979; Anderson
             & Harland, l982).
             Table 2: Hydrogen cyanide generated by pyrolysis
             Material                            µg/g HCN
             Paper                               llOO
             Cotton                               l3O
             Wool                                65OO
             Nylon                                78O
             Polyurethane foam                   l2OO
             (Montgomery et a1., l975)
             Ingestion of large amounts of cyanogenic glycoside:  bitter
             almonds, stones of cherries, peaches, apricots, apple seeds,
             cabbage and others.  Cassava flour produces long-term effects
             if not well manufactured (see Section 9.2). In the kernels
             themselves, amygdalin (cyanogenic glucoside) seems to be
             completely harmless as long as it is relatively dry. 
             However, the seeds contain an enzyme that is capable of
             catalyzing the following hydrolytic reaction when the seeds
             are crushed and moistened:
             C2OH27NOll + 2H2O ---->  2C6H12O6 +   C6H5CHO    +   HCN
             Amygdalin                  Glucose   Benzaldehyde   Cyanide

             The reaction is slow in acid but rapid in alkaline
             Natural oil of bitter almonds contains 4% HCN.  American
             white lima beans contain lO mg of HCN/lOO g of bean.  The
             dried root of cassava (tapioca) may contain 245 mg of HCN/lOO
             g root.  The cyanide content in lOO g cultivated apricot
             seeds is 8.9 mg and that in wild apricot seeds 2l7 mg.
             Tobacco smoke:  the concentration of hydrogen cyanide has
             been estimated from 100 to 1600 ppm (Osborne et al., 1956).
             Cyanide is also formed during nitroprusside therapy,
             especially when prolonged treatment is necessary because
             tachyphylaxis occasionally necessitates the use of higher
             doses than the recommended maximum of lO mg/kg/min (Atkins,
             l977; Smith & Kruszyna, l974; Anonymous, l978; Macrae and
             Owen, l974; Piper, l975).  Thiocyanates were used some years
             ago as antihypertensive agents and they saw wide use being
             very effective.  However, a variety of subacute toxic
             effects, including fatigue, gastrointestinal tract
             disturbances, anorexia and CNS effects, led to their
             disfavour.  In the stomach, cyanogens present in food and
             drugs may liberate cyanide.
             Laetrile, amygdalin derived from apricot kernels, has been
             used as an anticancer agent, but is now obsolete because a
             therapeutic effect could not be demonstrated in either
             retrospective or prospective studies; laetrile has caused
             fatal cyanide poisoning (Braico et a1., 1979).
             Ingestion of large doses of Laetrile (amygdaline or vitamin B
             l7) as anti-cancer drug.
             Contamination of food, beverages or medicines either
             intentional or accidenta1.

        4.3  Occupationally exposed populations

             Occupations in which contact with cyanide is possible
             are detailed below (Bryson, 1987):
             Acid dippers
             Acrylate makers
             Acrylonitrile makers
             Adipic acid makers
             Adiponitrile makers
             Aircraft workers
             Almond flavour makers
             Ammonium salt makers
             Art printing workers
             Blast furnace workers
             Bone distillers

             Bronzers, gun barrel
             Cadmium platers
             Case hardeners
             Cellulose product treaters
             Cement makers
             Coal tar distillery workers
             Coke oven operators
             Cyanide workers
             Disinfectant makers
             Fertilizer makers
             Fire fighters
             Fulminate mixers
             Fumigant makers
             Fumigators of fruit trees, apiaries, railways, cars,
             warehouses, stored food
             Gas purifiers
             Gas workers
             Gold extractors
             Gold refiners
             Heat treaters
             Hexamethylenediamine insecticide & Hydrogen cyanide workers
             Insecticide and HCN workers
             Laboratory technicians
             Metal cleaners
             Metal polishers
             Methacrylate makers
             Mirror silverers
             Nylon makers
             Organic chemical synthesizers
             Oxalic acid makers
             Phosphoric acid makers
             Photo engravers
             Pigment makers
             Plastic workers
             Polish makers
             Rayon makers
             Rubber makers
             Steel carburizers
             Steel galvanizers
             Steel hardeners
             Tannery workers

             Tree sprayer
             Zinc platers
             Non-industrial: Fire and automobile devices with
             malfunctioning catalytic converters (Voorhoeve et a1., l975)
             generate cyanide. (Table 2).


        5.1  Oral

             Cyanide can be found in various foodstuffs, kernels,
             beer and tobacco.  Cassava is an important foodstuff in
             tropical countries, and may be toxic in acute or chronic use. 
             Cyanide concentration is highest in the outer part of
             tapioca/cassava roots, and in the shoots of certain tapioca
             Suicidal ingestion of cyanide salts commonly occurs in
             personnel with occupational access to cyanide (see Section
             4.3).  Ingestion of cyanide on a full stomach may delay

        5.2  Inhalation

             Poisoning from gaseous hydrogen cyanide gas is more
             frequently accidental than suicida1.  Thus accidental cyanide
             poisoning may occur among fumigators and chemists who use
             hydrogen cyanide during the course of their work.  The
             distinctive almond odour of cyanide is not a useful warning
             sign, since as many as 2O to 4O% of the population cannot
             detect the odour.
             A toxic concentration of hydrogen cyanide (in combination
             with carbon monoxide) can develop from fires.  Natural
             materials such as wool, silk, horsehair and tobacco, as well
             as modern synthetic polyurethane, polyacrylonitriles and
             other synthetic materials release cyanide following

        5.3  Dermal

             Skin ulceration from splash contact with cyanides is a
             hazard in electroplating and gold extraction.  These effects
             are probably due to the alkalinity of aqueous solutions or
             molten materia1.
             Skin absorption of cyanide from aqueous solutions and of
             atmospheric hydrogen cyanide can be harmfu1.

        5.4  Eye

             Cyanides are readily absorbed via the eye and across the
             nasal mucosa (Ballantyne, l983).

        5.5  Parenteral

             Sodium nitroprusside is used in cardiovascular
             emergencies, but has caused cyanide poisoning in few
             Animal studies have shown that there is no significant
             difference in acute lethal toxicity of hydrogen cyanide and
             sodium cyanide but that potassium cyanide is less toxic
             (Ballantyne, 1984).

        5.6  Others

             Cyanide from microorganisms.
              Chromobacterium violaceum and some  Pseudomonas organisms
             produce cyanide.  In urinary and lung infections a common
             pathogenic micro-organism is  Pseudomonas pyocyaneus that
             may be a source of cyanide exposure for man.

    6.  KINETICS

        6.1  Absorption by route of exposure

             Hydrogen cyanide has a low molecular weight, poor
             ionization and thus diffuses easily through cell membranes. 
             It is readily absorbed across biological membranes such as
             the lungs.  Sodium cyanide is absorbed more slowly in the
             intestines due to its higher molecular weight and ionization. 
             The skin presents a greater barrier to absorption, but
             cyanide penetrates abraded skin more readily than intact

        6.2  Distribution by route of exposure

             Inhaled and percutaneously absorbed hydrogen cyanide
             passes immediately into the systemic circulation.  In
             contrast a very high proportion of a dose of sodium cyanide
             ingested will pass through the liver and is detoxified by
             first-pass effect.  The majority of cyanide in blood is
             sequestered in the erythrocytes and a relatively small
             proportion is transported via the plasma to target

        6.3  Biological half-life by route of exposure

             The half-life for hydrogen cyanide elimination is
             approximately one hour (Ansell & Lewis, l97O; Clark et a1.,
             The mean elimination half-life of thiocyanate has been
             estimated at 2.7 days in healthy subjects.  Elimination
             constants were inversely proportional to the creatine
             clearances (Schulz et a1., 1979).

        6.4  Metabolism

             The major pathway of detoxification in the body is
             conversion to thiocyanate by means of thiosulfate.  A sulfur-
             transferase is needed to catalyze the transfer of a sulfur
             atom from the donor thiosulfate to cyanide.  The classical
             theory indicating that mitochondrial thiosulfate sulfur-
             transferase (rhodanese) is the most important enzyme in this
             reaction is now doubted because thiosulfate penetrates lipid
             membranes slowly and it would therefore be unable to act as a
             ready source of sulfur.  The modern concept presumes that the
             serum albumin-sulfane complex is the primary cyanide-
             detoxification buffer operative in normal metabolism
             (Sylvester et a1., l983).
             Erythrocytes have a high affinity for cyanide.  Cyanide will
             be sequestered in erythrocytes which will be interpreted as a
             protective role by  erythrocytes in cyanide detoxification
             (Versey & Wilson, 1978).
             Minor pathways
             A combination with cysteine to 2-iminothiazolin-4-carboxylic
             acid, which tautomerizes to 2-imino-4-thiazolidin carboxylic
             acid (Wood & Couley, 1956; Parke, 1974).
             Binding to hyroxocobalamine to form cyanocobalamine (Brink et
             a1., 1950).

        6.5  Elimination by route of exposure

             Cyanide is eliminated as thiocyanate via the urine. 
             Minor routes for elimination are excretion of hydrogen
             cyanide through the lungs, cystine binding and binding to


        7.1  Mode of action

             Cyanide has a special affinity for ferric ions which are
             found in cytochrome oxidase, the terminal oxidative
             respiratory enzyme within the mitochondria.  This enzyme is
             an essential catalyst for tissue utilization of oxygen.
             When cytochrome oxidase is inhibited by cyanide, cellular
             respiration is inhibited and histotoxic anoxia occurs as
             aerobic metabolism becomes inhibited.  In massive cyanide
             poisoning, the mechanism of toxicity is more complex.  For
             example, autonomic shock from the release of biogenic amines
             may play a role in the lethal effect of cyanide by causing
             cardiac failure (Burrows & Way, l976).  Cyanide may produce
             both pulmonary arteriolar and/or coronary vasoconstriction,
             which results directly or indirectly in heart pump failure
             and decrease of cardiac output.  This theory is supported by
             the sharp increase in central venous pressure observed at the
             same time as arterial blood pressure decreases after
             intravenous sodium cyanide administration to dogs (Vick &
             Froelich, l985).  The observation that phenoxybenzamine, an
             alpha-adrenergic blocking drug, partially prevented these
             early changes supports the concept of an early shock-like
             state which is not related to inhibition of the cytochrome
             oxidase system.  Inhalation of amyl nitrite, an effective
             arteriolar vasodilator, was life-saving in these experimental
             circumstances.  This could be due to a reversal of the early
             cyanide-induced vasoconstriction and restoration of normal
             cardiac function (Vick & Froelich, l985).
             As anaerobic metabolism continues, there is a lactic acid
             accumulation.  The biochemical combination of reduced oxygen
             utilization and lactate acidosis produces severe metabolic

        7.2  Toxicity

             7.2.1  Human data


                    Table 3.  Estimated acute lethal inhalation toxicity
                               of hydrogen cyanide vapour (McNamara, l976).
                    Exposure time (min.)    Approximate LC50 (mg/m3)
                           O.5                   4O64
                           l                     34O4
                           3                     l466
                          lO                      6O7
                          30                      688

              Table 4.  Estimated acute fatal oral toxicity
              Material   Estimated fatal dose           Reference
                HCN      5O to lOO mg (total)     Dubois & Geiling, l959
                         O.7 to 3.5 mg/kg         Hallstrom & Moller, l945
                KCN      l5O to 25O mg (total)    Dubois & Geiling, l959.
             Table 5.  Estimated fatal effect of skin exposure to
                        hydrogen cyanide vapour
             HCN ppm          Area of skin          Fatal after x min.
                              exposed (cm2)
              6OOO                lOOO                    -
             lOOOO               l85OO                lO to l9
             55OOO                lOOO                46 to 83
             (Dugard, l987)


                             No data available.

             7.2.2  Relevant animal data

             Table 6.  LD50 in female rabbits and rats
             Route    Product    Species     LD50 (mg/kg)     Reference
             IV       HCN        Rabbit      O.55 to O.65       Ballantyne
             IV       NaCN       Rabbit      1.ll to 1.34            "
             IV       KCN        Rabbit      1.66 to 2.l3            "
             IM       HCN        Rabbit      O.8l - 1.ll        Ballantyne
                                                                et a1. l972
             IM       NaCN       Rabbit      1.5l - 1.84        Ballantyne
             IM       KCN        Rabbit      2.7O - 4.O8        Ballantyne
                                                                et a1. l972
             oral     HCN        Rabbit      2.26 - 2.81        Ballantyne
                      NaCN       Rabbit      4.62 - 5.66             "
                      KCN        Rabbit      5.5O - 6.3l             "

             Table 6 (cont'd)

             Route    Product    Species     LD50 (mg/kg)     Reference

             oral     HCN         Rat        3.76 - 4.95        Ballantyne,
                      NaCN       Rat         5.23 - 7.O8             "
                      KCN        Rat         6.68 - 8.48             "
             ocular   HCN        Rat         0.95 - 1.l3        Ballantyne
                      NaCN       Rat         4.44 - 6.lO             "
                      KCN        Rat         6.5l - 8.96             "
             cutan.   HCN        Rabbit      6.43 - 7.52        Ballantyne,
             abraded  HCN        Rabbit      2.O2 - 2.6l             "

             cutan.   NaCN       Rabbit      13.8 - l5.4             "
             abraded  NaCN       Rabbit      9.2  - l2.7             "
             cutan.   KCN        Rabbit      2O.4 - 24.O             "
             abraded  KCN        Rabbit      l3.3 - l5.l             "
             Key:  IM=intramuscular, IV=intravenous, cutan.=cutaneous.
             Table 8.  LC50 in female rabbits and rats
             Route  Product   Minutes   Species   LD50(mg/m3) Reference
             inha1.   HCN       45      Rabbit    23O4-2532   Ballantyne,
                                 5         "      32l - 458        "
                                35         "      l54 - 276        "
                                1O        Rat    377l - 43l3       "
                                 l         "      664 - l47l       "
                                 5         "      372 - 66l        "
                                3O         "      l59 - l93        "
                                6O         "      l44 - l74        "
             Key: inha1.=inhalation

             7.2.3  Relevant in vitro data

                    No data available.

             7.2.4  Workplace standards

                    ACGIH (l986)
                    HCN:           lO ppm ceiling (with skin notation)
                                   NaCN and KCN:5 mg CN/m3 as 8 h TWA-TLV;
                                   equivalent to 9.4 mg NaCN/m3 and
                                   l2.5 mg KCN/m3
                    NIOSH (l976)
                    HCN:           5 mg CN/m3 as ceiling value;
                                   equivalent to 5.2 mg HCN/m3
                    NaCN and KCN:  5 mg CN/m3 as ceiling value;
                                   equivalent to 9.4 NaCN/m3 and
                                   l2.5 mg KCN/m3.

             7.2.5  Acceptable Daily Intake (ADI) and Other Guideline

                    The Food and Agriculture Organization and World
                    Health Organization have recommended an ADI of O.O5 mg
                    cyanide/kg.  The life-time Acceptable Daily Intake for
                    an adult (Drinking Water standard) is 1.5 mg/day
                    (equivalent to O.O2 mg/kg/day), based on a 7O kg adult
                    (EPA, l986).

        7.3  Carcinogenicity

             There is no evidence of any carcinogenic effect. 
             Indeed, in the past there was a vogue for using cyanide
             (amygdalin, laetrile) as an anticancer agent but this use is
             now obsolete.

        7.4  Teratogenicity

             Animal experiments suggests that cyanide has a
             teratogenic effect during the period of maximum organogenesis
             (Doherty et a1., l982).
             Cyanide given to rats and hamsters by slow subcutaneous
             titration at the period of maximum organogenesis, is markedly
             embryofetotoxic and produces malformations, particularly
             neural tube effects (Singh, l982; Doherty et a1., l982).
             Several cyanogens, e.g. acrylonitrile and proprionitrile,
             given in the dose range 3O to 83 mg/kg by intraperitoneal
             injection on day 8 in the hamster, produced exencephaly,
             encephalocele and rib malformations.  There was protection
             against these teratogenic effects by intraperitoneal sodium
             thiosulfate, indicating that cyanide release was a
             significant factor (Willhite et a1., l98l).  However,

             Johanssen et a1. (l986) could not show proprionitrile to be
             teratogenic to rats given by gavage.  The possibility that
             cyanide may contribute to the development of fetotoxic
             effects in women who smoke has been mentioned (McGarrey &
             Andrews, l972; Andrews, l973).

        7.5  Mutagenicity

             Cyanide is not mutagenic (Ballantyne, 1987).

        7.6  Interactions

             Although carbon monoxide will contribute significantly
             to death in fires, hydrogen cyanide, as a product of
             combustion of synthetic materials, may be a factor in
             morbidity and mortality.  Hyperventilation caused by cyanide
             potentiates carbon monoxide toxicity (Birky et a1., 1979). 
             Cyanide may also incapacitate people, thus prolonging their
             exposure to carbon monoxide (Birky et a1., 1979).


        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

            Toxicological analyses

            Biomedical analyses

            Arterial blood gas analysis

            Haematological analyses

            Other (unspecified) analyses

             8.1.2  Storage of laboratory samples and specimens

            Toxicological analyses

            Biomedical analyses

            Arterial blood gas analysis

            Haematological analyses

            Other (unspecified) analyses

             8.1.3  Transport of laboratory samples and specimens

            Toxicological analyses

            Biomedical analyses

            Arterial blood gas analysis

            Haematological analyses

            Other (unspecified) analyses

        8.2  Toxicological Analyses and Their Interpretation

             8.2.1  Tests on toxic ingredient(s) of material

            Simple Qualitative Test(s)

            Advanced Qualitative Confirmation Test(s)

            Simple Quantitative Method(s)

            Advanced Quantitative Method(s)

             8.2.2  Tests for biological specimens

            Simple Qualitative Test(s)

            Advanced Qualitative Confirmation Test(s)

            Simple Quantitative Method(s)

            Advanced Quantitative Method(s)

            Other Dedicated Method(s)

             8.2.3  Interpretation of toxicological analyses

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

            Blood, plasma or serum

                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"


                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"

            Other fluids

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses

                    "Basic analyses"
                    "Dedicated analyses"
                    "Optional analyses"

             8.3.4 Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their

        8.5  Overall interpretation of all toxicological analyses and
             toxicological investigations

             Sample collection
             In order to evaluate the severity of poisoning, blood and
             plasma samples should be collected before administration of
             antidotes because the results of analysis are otherwise
             Biomedical analysis
             Blood gas analysis determines the presence and severity of
             metabolic acidosis.  It should be noted that after antidotal
             therapy, the results of oxygen saturations are rendered
             unreliable.  Hyperglycemia should not be misinterpreted as
             being a primarily diabetic phenomenon.


        9.1  Acute poisoning

             9.1.1  Ingestion

                    Immediately after swallowing cyanide salts very
                    early symptoms such as irritation of the tongue and
                    mucous membranes may be noted.  A blood-stained
                    aspirate may be found on gastric lavage.  Nausea and
                    vomiting are observed.  These minor symptoms are
                    easily overlooked as they are much less important than
                    disturbances of the central nervous system and heart. 
                    Ingestion of cyanide on a full stomach may delay
                    absorption and the appearance of symptoms.  Dyspnea
                    and convulsions occur early in severe poisoning.

             9.1.2  Inhalation

                    Hydrogen cyanide readily diffuses through the
                    alveolar membrane of the lung due to its low molecular
                    weight and poor ionization.  Death from exposure to
                    hydrogen cyanide usually occurs rapidly.  If the
                    patient survives the exposure time, absorbed cyanide
                    may be detoxified by metabolic processes supported by
                    therapeutic measures.

             9.1.3  Skin exposure

                    The amount and rate of absorption depends upon
                    the concentration and pH of the solution, the surface
                    area of contact and the duration of contact (Dugard,

                    Absorption across abraded skin is enhanced.

             9.1.4  Eye contact

                    The local effects on the eye include an initial
                    moderate to severe conjunctival hyperaemia with mild

             9.1.5  Parenteral exposure

                    Iatrogenic poisoning is possible during
                    nitroprusside therapy, especially during the cure of
                    prolonged treatment where tachyphylaxis requires the
                    use of doses higher than the recommended maximum of lO
                    µg/kg/min (Atkins, l977; Smith & Kruszyna, l974;
                    MacRae & Owen, l974; Piper, l975).
                    A few cases of self-inflected poisoning have also been
                    recorded (Lazarus-Barlow & Norman, l94l).

             9.1.6  Other

                    No data available.

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Chronic low-dose neurotoxic effects
                    (demyelinating nervous conditions) have been suggested
                    by epidemiological studies of populations ingesting
                    naturally occurring plant glycosides.  These
                    glycosides are present in a wide variety of plant
                    species, most notably cassava, a major tropical
                    foodstuff (Conn, l973; Cook & Coursey, l98l; Ministry
                    of Health, Mozambique, l984).  Diseases associated
                    with chronic cyanide ingestion or disordered cyanide
                    detoxification are: Leber's hereditary optic atrophy,
                    spinal-cord subacute degeneration, tropical atoxic
                    neuropathy and goitre (Wilson, l983).  Ingestion of
                    endemic Lathyrus sativus, a pea consumed during famine
                    in India, caused an acute spastic paresis (Selye,
                    l957).  A 46-year-old man who took 500 mg laetrile
                    daily for six months for the treatment of cancer,
                    developed a subacute or chronic neurological syndrome
                    (Smith et a1., l978).

             9.2.2  Inhalation

                    A neurotoxicological role for cyanide has been
                    suggested in tobacco-associated amblyopia (Grant,
                    l98O).  However, in almost half of the patients there
                    was defective absorption of vitamin B12, suggesting
                    visual failure is a consequence of exposure to tobacco
                    smoke when total body vitamin B12 is depleted
                    (Foulds et a1., 1969).

             9.2.3  Skin exposure

                    No data available.

             9.2.4  Eye contact

                    No data available.

             9.2.5  Parenteral exposure

                    No data available.

             9.2.6  Other

                    No data available.

        9.3  Course, prognosis, cause of death

             Course: Immediately after swallowing cyanide very early
             symptoms such as irritation of the tongue and mucous
             membranes may be experienced.  A blood-stained aspirate may
             be observed if gastric lavage is performed.  Early symptoms
             and signs that occur after inhalation of hydrogen cyanide or
             the swallowing of cyanide salts, include:  anxiety, headache,
             vertigo, hyperpnoea, followed by dyspnoea, cyanosis,
             hypertension, bradycardia, sinus or AV nodal arrhythmias.
             In the secondary stage of poisoning, convulsions occur and
             the skin becomes cold, clammy and moist.  The pulse becomes
             weaker and more rapid.  Opisthotonos and trismus may be
             Late signs of cyanide toxicity include hypotension, complex
             arrhythmias, cardiovascular collapse, pulmonary oedema, coma
             and death.
             The bright red coloration of the skin, or absence of
             cyanosis, often mentioned in textbooks (Gosselin et a1.,
             l984; Hanson, l984) is seldom described in case reports of
             cyanide.  Theoretically this sign could be explained by the
             high concentration of oxyhaemoglobin in the venous blood but,
             especially in massive poisoning, cardiovascular collapse will

             prevent this coloration from occurring.  Sometimes, cyanosis
             can be observed initially, while later the patient may become
             bright pink (Hilmann et a1., l974).
             Prognosis: The prognosis in severe poisoning is poor because
             vital functions are damaged immediately after poisoning.  If
             the vital functions are unimpaired, but the patient is in
             deep coma, the prognosis depends entirely on the degree of
             histotoxic anoxia to which the brain was exposed.  As
             complete recovery is still possible at this stage, intensive
             care is necessary.
             Cause of death: Although the brain is obviously a key organ
             involved in cyanide poisoning, new experiments show evidence
             of cardiovascular failure caused by severe cyanide poisoning
             as being a prime factor in the prognosis (Vick & Froelich,

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Cyanide has at least two cardiac effects:  1.
                    an initial effect on the Beta-adrenergic receptors,
                    either directly or indirectly, and 2. reduction of
                    myocardial contractility through inhibition of
                    cytochrome oxidase (Baskin et a1., l987).
                    Early electrocardiographic changes include atrial
                    fibrillation, ectopic ventricular beats, abnormal QRS
                    complex, sinus bradycardia.
                    Cyanide has a marked effect on the systemic blood
                    pressure (Klimmek et a1., l982) as a result of a
                    direct effect on blood vessels and on the autonomic
                    nerve supply to the cardiovascular system (Vick &
                    Froelich, l985).  Cardiovascular collapse may occur
                    especially in cases of massive poisoning (Heijst et
                    a1., l987).

             9.4.2  Respiratory

                    Hyperpnoea may be observed initially followed
                    by dyspnoea.  Pulmonary oedema may result from a
                    direct effect on the myocardium leading to left
                    ventricular failure and increased pulmonary venous
                    pressure.  The smell of bitter almonds can be
                    perceived in some cases.

             9.4.3  Neurological

            Central nervous system (CNS)

                             The brain is a target organ for
                             cyanide.  Cytotoxic hypoxia, decreased brain
                             adenosine triphospahte (ATP) levels and
                             lactic acidosis lead to disturbances in
                             perception and the loss of

            Peripheral nervous system

                             The effects on the peripheral
                             nervous system occur in chronic cyanide
                             (foodstuffs) poisoning for instance in
                             tropical ataxic neuropathy and the related
                             conditions known as tropical ataxia, tropical
                             amblyopia, West Indian neuropathy, and
                             montecassa.  Lathyrism presenting with
                             spastic paresis, with pain and paraesthesia,
                             tobacco amblyopia with visual failure in
                             elderly men who smoke heavily and subacute
                             combined degeneration of the cord are all
                             thought to be due to cyanide metabolism.

            Autonomic nervous system

                             Acute effects on the cardiovascular
                             system in massive cyanide poisoning are life

            Skeletal and smooth muscle

                             No data available.

             9.4.4  Gastrointestinal

                    Ingested salts produce local irritation, nausea
                    and vomiting.  Salivation and epigastric pain are
                    observed after poisoning with cyanogenic glucosides. 
                    Hematemesis can be observed.

             9.4.5  Hepatic

                    Tender hepatomegaly.

             9.4.6  Urinary


                             No data available.


                             No data available.

             9.4.7  Endocrine and reproductive systems

                    The occurrence of tropical diabetes can be
                    observed in areas where the cassava is consumed.  This
                    "type J" diabetes is preceded by malnutrition and is
                    characterized by early age of onset, large insulin
                    requirements and resistance to ketosis (Hugh-Jones,
                    Long-term cyanide intoxication has been shown to be
                    associated with thyroid gland enlargement or
                    dysfunction, both in case reports and in cohort
                    studies of individuals exposed occupationally (Blanc
                    et a1., l985). The same has been reported in areas of
                    single cassava consumption (Cook & Coursey,

             9.4.8  Dermatological

                    Diaphoresis and flushing may be observed in
                    chronic poisoning.  Cyanosis is seen after vascular
                    collapse.  Skin contact may cause mild burns.

             9.4.9  Eyes, ears, nose, throat: local effects

                    Eyes - conjunctival hyperaemia with mild
                    chemosis, lachrymation, photophobia, tingling
                    It is assumed that chronic cyanide poisoning may cause
                    blindness (Heijst et a1., 1994).

             9.4.10 Haematological

                    No data available.

             9.4.11 Immunological

                    No data available.

             9.4.12 Metabolic

           Acid base disturbances

                             Lactic acidosis:  as oxidative
                             phosphorylation is blocked the rate of
                             glycolysis is increased markedly.  The degree
                             of lactic acidosis correlates with the
                             severity of cyanide poisoning (Trapp, l97O;
                             Naughton, l974).

           Fluid and electrolyte disturbances

                             No data available.


                             Cyanide has a reversible effect on
                             pancreatic ß-cells and thus hyperglycemia can
                             be observed after cyanide poisoning.  It may
                             result in the erroneous diagnosis of diabetic

             9.4.13 Allergic reactions

                    No data available.

             9.4.14 Other clinical effects

                    No data available.

             9.4.15 Special risks: pregnancy, breast-feeding, enzyme

                    Cyanide has all kinds of special risks, as can
                    be seen in the foregoing text.

        9.5  Others

             No data available.

        9.6  Summary


        10.1 General principles

             Although effective antidotes are available, general
             supportive measures should not be ignored and may be life-
             saving.  According to Jacobs (l984) who has personal
             experience of lO4 industrial poisoning cases, the use of
             specific antidotes is only indicated in cases of severe
             poisoning with signs of deep coma, with wide non-reactive
             pupils and respiratory insufficiency in combination with
             circulatory insufficiency.  In patients with moderately
             severe poisoning who have suffered only a brief period of
             unconsciousness, convulsions, vomiting and cyanosis, therapy
             should consist of intensive care and sodium thiosulfate and
             100% oxygen.  In cases of mild intoxication with dizziness,
             nausea and drowsiness, rest and oxygen are the only measures

        10.2 Life supportive procedures and symptomatic treatment

             Artificial ventilation with lOO% oxygen using mask and
             balloon, for example, the so-called Watersset, preferably
             (but not necessarily) provided with a non-return valve.
             Hypotension, as a direct consequence of cyanide poisoning, or
             as a result of first-aid therapy with amyl nitrite, should be
             treated with plasma expanders and dopamine infusions.
             Metabolic acidosis should be corrected by the intravenous
             administration of bicarbonate.

        10.3 Decontamination

             Contaminated clothing must be removed immediately. 
             Contaminated skin should be thoroughly washed with water and
             contaminated eyes should be cleaned carefully with lots of
             running water for at least 15 minutes.

        10.4 Enhanced elimination

             The detoxification product of cyanide, thiocyanate, is
             excreted in the urine.  Thiocyanate concentrations normally
             range between l to 4 mg/L in the plasma of nonsmokers and
             between 3 to l2 mg/L in smokers.  The plasma half-life of
             thiocyanate in patients with normal renal function is 4 hours
             (Blaschle & Melmon, l98O) but in those with renal
             insufficiency, it is markedly prolonged and these patients
             are therefore at increased risk of toxicity (Schulz et a1.,
             l978).  Thiocyanate concentration exceeding lOO mg/L is an
             indication of toxicity.  Thiocyanate toxicity is
             characterized by weakness, muscle spasm, nausea,
             disorientation, psychosis, hyperreflexia and stupor (Smith,
             l973; Michenfelder & Tinker, l977).
             Lethal poisoning at concentrations greater than l8O mg/L is
             mentioned in the literature (Domalski et a1., l953; Garvin,
             l939; Healy, l93l; Kessler & Hines, l948; Russel & Stahl,
             l942).  Haemodialysis is recommended as an effective means of
             removing thiocyanate (Marbury et a1., l982).  A dialysance
             value of 82.8 mL/min has been recorded (Pahl & Vaziri,

        10.5 Antidote treatment

             10.5.1 Adults

                    The clinical use of most antidotes is based on
                    animal experiments but animal studies have their
                    limitations. In most studies, the protocols were not
                    designed to resemble the usual medical setting. 
                    Antidotes were mostly given prior to, or

                    simultaneously with, cyanide administration and the
                    route of administration was not comparable to that in
                    human situations.  In addition, the toxicity of the
                    antidotes themselves was not considered.
                    Because of the rapidity of action of cyanide, there
                    are very few complete clinical studies of acute
                    poisoning. Most cases published in the literature do
                    not lend themselves to precise conclusions regarding
                    the value of therapeutic results; even diagnosis is
                    open to doubt in many cases.  Given the uncertainties,
                    the role of antidotes is unclear (Graham et a1.,
                    Although theoretically it has always been difficult to
                    believe that oxygen has a favourable effect in cyanide
                    poisoning (because oxygen utilization within the cell
                    is inhibited), it has been regarded as an important
                    first-aid measure.  There is now evidence that oxygen
                    does have some specific antidotal activity.  Oxygen
                    accelerates reactivation of cytochrome oxidase and
                    protects against cytochrome oxidase inhibition by
                    cyanide (Isom & Way, 1982).  Nevertheless, there are
                    other possible modes of action and those which are
                    clinically important have yet to be determined. 
                    Administration of 100% oxygen longer than 4 hours has
                    to be avoided because of the toxicity of oxygen. 
                    After 4 hours the concentration of oxygen in inspired
                    air should not be higher than 40%.  Hyperbaric oxygen
                    is recommended for smoke inhalation victims suffering
                    from combined carbon monoxide and cyanide poisoning. 
                    The role of hyperbaric oxygen in pure cyanide
                    poisoning remains controversia1.
                    Sodium thiosulfate
                    The major route of cyanide detoxification in the body
                    is conversion to thiocyanate by rhodanase, although
                    other sulfur-transferases, such as mercaptopyruvate
                    sulfur-transferase, may also be involved.  This
                    reaction requires a source of sulfane sulfur but
                    endogenous supplies are limited.  However, cyanide
                    poisoning is an intramitochondrial process and an
                    intravenous supply of sulfur cannot penetrate
                    mitochondria sufficiently quickly.  Sodium thiosulfate
                    should be administered with other antidotes in cases
                    of severe poisoning.  Sodium thiosulfate is assumed to
                    be non-toxic in patients with renal insufficiency (see

                    Dose in adults: 50 mL sodium thiosulfate 25% (12.5 g)
                    in 10 minutes.
                    Nitrites generate methaemoglobin which combines with
                    cyanide to form non-toxic cyanmethaemoglobin. 
                    Methaemoglobin does not have higher affinity for
                    cyanide than does cytochrome oxidase, but there is a
                    much larger potential source of methaemoglobin than
                    there is of cytochrome oxidase.  The efficacy of
                    methaemoglobin as protection from cyanide poisoning is
                    therefore primarily the result of a mass action
                    effect.  A drawback of methaemoglobin generation is
                    the resultant impairment of oxygen transport to cells. 
                    Ideally, the total amount of free haemoglobin should
                    be monitored to ensure aerobic metabolism of the
                    cells.  Methaemoglobin measurements, as usually
                    carried out, do not provide an accurate guide to the
                    amount of haemoglobin available for oxygen transport
                    because the cyanmethaemoglobin concentration is not
                    taken into account.  Indeed the results of
                    methaemoglobin estimation may be misleading.  Amyl
                    nitrite by inhalation has been used for a long time as
                    a simple first-aid measure that generates
                    methaemoglobin and which can be employed by lay
                    personne1.  Its use has been abandoned because the
                    methaemoglobin concentration obtained with amylnitrite
                    is no more than 7%, and at least 15% is required to
                    bind one LD50 of cyanide.  However, a recent report
                    suggests that methaemoglobin formation plays only a
                    small role in the therapeutic effect of nitrites and
                    that vasodilatation is the most important action
                    (Holmes & Way, 1982).  Artificial respiration with
                    amyl nitrite ampoules broken into an Ambu bag proved
                    to be life-saving in dogs severely poisoned with
                    cyanide in an experiment.  Amyl nitrite should
                    therefore be reintroduced as a first-aid measure. 
                    Although no human data is available its use may be
                    justified in cases of severe poisoning.  Glucose-6-
                    phosphate dehydrogenase (G6PD) deficient individuals
                    are at great risk from nitrite therapy because of the
                    likelihood of serious haemolysis.  Excess
                    methaemoglobinaemia may be corrected with either
                    methylene blue or toluidine blue.
                    0.2 to 0.4 mL amylnitrite has to be brought in
                    Watersset-balloon previous to artificial ventilation
                    and followed by sodium nitrite.
                    Sodium Nitrite
                    Sodium nitrite has been in clinical use for about 40
                    years as an antidote for acute cyanide poisoning, most
                    often in combination with amyl nitrite and sodium
                    thiosolfate (Chen & Rose, 1952; Hall & Rumack, 1986). 
                    An intravenous injection of 400 mg in humans produced
                    a peak methaemoglobin level of 10.1%, while 600 mg
                    produced a peak methaemoglobin level of 17.5% (Chen &
                    Rose, 1952).  In volunteers a generally accepted
                    therapeutic dose of 4 mg/kg intravenously resulted in
                    a methaemoglobin level of 6% after 40 minutes (Kiese &
                    Weger, 1969).  This may be considered to be too low a
                    concentration of haemoglobin for too long a time in
                    order to be effective as a methaemoglobin-forming
                    cyanide antidote in severe acute cyanide poisoning. 
                    However, survival following acute cyanide poisoning
                    treated with the amyl nitrite/ sodium nitrite/sodium
                    thiosulfate antidote combination has been published by
                    many authors (De Busk & Seidl, 1969; Stewart, 1974;
                    Feigl et a1., 1983; Wood, 1982; Litowitz et a1., 1983;
                    Wesson et a1., 1985; Hall & Rumack, 1986).  The
                    largest case series comprising a total of 49 patients
                    was assembled by Chen & Rose (l952; l956). However
                    hard data to assess the results in these case reports,
                    such as cyanide concentration at the start and during
                    management were not mentioned.
                    Dose in adults: 10 mL sodium nitrite 3% (300 mg). 
                    Hypotension from the vasodilating properties of sodium
                    nitrite may be avoided by diluting sodium nitrite with
                    normal saline and infusing over a 20-minute period
                    with frequent blood pressure monitoring.
                    Dose in children: to begin with, 0.13 mL/kg sodium
                    nitrite 3% (4 mg/kg) and only administer additional
                    sodium nitrite if no  satisfactory clinical response
                    is achieved after the initial dose.
                    1.       As repeated dosing of sodium nitrite is often
                             necessary to maintain a methaemoglobin
                             concentration of 40 to 50% it would be
                             desirable to be able to monitor the amount of
                             free haemoglobin available for oxygen
                             transport.  However, an analytical method for
                             measuring the cyanhaemoglobin concentration,
                             as well as a reliable method for
                             methaemoglobin concentration analyses in
                             these circumstances has yet to be

                    2.       In individuals with G6PD deficiency, therapy
                             with methaemoglobin is contra-indicated
                             because of the likelihood of serious
                    3.       Excess methaemoglobinaemia may be corrected
                             with either methylene blue or toluidine
                    4-Dimethylaminophenol (4-DMAP)
                    4-DMAP generates a methaemoglobin concentration of 30
                    to 50% within a few minutes (Kiese & Weger, 1969) and,
                    theoretically, it should therefore be very useful as a
                    first-aid measure.  The difficulties of methaemoglobin
                    formation, as described above for nitrites, are
                    applicable to 4-DMAP to an even greater extent. 
                    Furthermore, it has very poor dose-response curve
                    reproducibility.  Haemolysis is an adverse reaction
                    following use of the drug at the correct dose. 
                    Treatment with 4-DMAP is contra-indicated in patients
                    with G6PD deficiency.  Excess methaemoglobinaemie may
                    be corrected with either methylene or toluidine
                    Dose in adults: 3.25 mg/kg intravenously
                    It has been recommended that administration of 4-DMAP
                    by deep intramuscular injection in case of emergency
                    be used.  A muscular necrosis will develop at the site
                    of injection, and fever after 12 to 24 hours.
                    The warnings mentioned in 10.5.1 and 10.5.2 are even
                    more applicable in this therapy.
                    Hydroxocobalamin (Vitamin B12a)
                    This antidote binds cyanide strongly to form
                    cyanocobalamin (Vitamin B12).  It has the great
                    advantage of not interfering with tissue oxygenation
                    as does nitrite and 4-DMAP therapy.  The disadvantage
                    of hydroxocobalamin as a cyanide antidote is the large
                    dose required to be effective.  Detoxification of 1
                    mmol cyanide (corresponding to 65 mg KCN) needs 1406
                    mg hydroxocobalamin.  In most countries, it is only
                    commercially available in formulations of 1 to 2 mg
                    per ampoule.  In France, a formulation is available
                    which contains 4 g hydroxocobalamin powder that has to
                    be reconstituted with 80 mL of a 10% sodium
                    thiosulfate solution prior to use.  Recorded side
                    effects are anaphylactoid reactions and acne.  Some

                    authors have recorded a reduced antidotal effect as a
                    result of this combination (Friedberg & Shunkla, 1975;
                    Evans, 1964).  Histological changes apparently induced
                    by hydroxocobalamin in the liver, myocardium and
                    kidney have been reported in animal experiments
                    (Hoebel et a1., 1980) but their relevance to man has
                    not yet been established.  Transient pink
                    discolouration of mucous membranes and urine is an
                    unimportant and non-toxic side-effect.
                    Dose in adults: 135 to 300 mg/kg intravenously.
                    Dicobalt edetate
                    This agent has been shown to be effective in the
                    treatment of cyanide poisoning in man, and in the
                    United Kingdom is the current treatment of choice
                    provided that cyanide toxicity is definitely present. 
                    This strict criterion is used because, as a result of
                    the manufacturing process, some free cobalt ions are
                    always present in solutions of dicobalt edetate. 
                    Indeed, this is important for the antidotal efficacy
                    of this agent, because one cobalt ion complexes six
                    cyanide molecules, whereas one dicobalt edetate
                    molecule will only complex up to two cyanide
                    molecules.  However, cobalt ions are toxic and the use
                    of dicobalt edetate, in the absence of cyanide, will
                    lead to serious cobalt toxicity.  There is evidence
                    from animal experiments that glucose protects against
                    cobalt toxicity.
                    Dose in adults: 300 mg (20 mL of a 1.5% solution)
                    intravenously over about 1 minute followed immediately
                    by 50 mL dextrose 50% intravenously.
                    Dangerous adverse effects are observed: anaphylactic
                    shock, ventricular arrhythmias, laryngeal oedema,
                    hypotension.  Other adverse effects: vomiting,
                    urticaria, facial oedema, rashes.

             10.6.2 Children

                    Inhalation of 100% oxygen is indicated but for no
                    longer than 4 hours because of the toxicity of oxygen.
                    After 4 hours the concentration of oxygen in inspired
                    air should not be higher than 40%.  Hyperbaric oxygen
                    is recommended for smoke inhalation victims suffering

                    from combined carbon monoxide and cyanide poisoning. 
                    The role of hyperbaric oxygen in pure cyanide
                    poisoning remains controversia1.
                    Sodium thiosulfate
                    Dose in children: depends on haemoglobin
                    concentration.  At a haemoglobin concentration of 7
                    g/100 mL the dose is 1 mL/kg of a 25% sodium
                    thiosulfate solution intravenously. At a haemoglobin
                    concentration of 14 g/100 mL the dose is 2 mL/kg
                    sodium thiosulfate 25% intravenously.
                    Sodium Nitrite
                    To start with 0.13 mL/kg sodium nitrite 3% (4 mg/kg)
                    intravenously and only administer additionbal sodium
                    nitrite if clinical response is achieved after the
                    initial dose.
                    4-Dimethylaminophenol (4-DMAP)
                    Dose in children is unknown.
                    Hydroxycobalamin (Vitamin B12a)
                    Dose in children is unknown.
                    Dicobalt edetate
                    Dose in children is unknown.

        10.6 Management discussion: alternatives, controversies and
             research needs

             General agreement exists in the importance of life
             supportive procedures, but although cyanide antidotes were
             discovered 100 years ago (Pedigo, 1888) and have been used in
             medical practice more than 50 years ago (Chen et a1., 1954),
             the ideal cyanide antidote has not yet been discovered.  Most
             of them are extremely toxic if not administered on a correct
             indication, and in an exact dosage.  Because a situation of
             panic often exists in cyanide poisoning, the possibility of
             errors is clearly present.  Enormous controversies exist in
             the world concerning the use of antidotes.  Nitrites are used
             in the United States, cobalt EDTA in the United Kingdom,
             4-DMAP in Germany, and hydroxocobalamin in France.  Research
             for alternative therapies is indicated and international
             collaboration to assess the results of treatment of these
             intoxications is necessary, since so few can be observed by
             an individual clinician.  Individualization of treatment
             based on clinical presentation and judgement is required with
             a stated protocol as a guideline.


        11.1 Case reports from literature

             A 15-kg, 4-year-old boy with Down syndrome and a
             seizure disorder ingested 12 tablets of laetrile (500 mg).
             During the next 1.5 hours, the child slowly became
             unresponsive  and then had multiple episodes of seizure
             activity. He was unresponsive to painful stimuli, areflexic,
             amd hypoventilating on arrival at the referal hospita1. The
             pupils were widely dilated but sluggishly responsive. The
             puls was initially 60 beats per minute and the blood pressure
             could not be obtained. The patient was intubated and
             ventillated with 100% oxygen. Arterial bloodgases were: pH
             6.85, Pco2 15 mm Hg, and Po2 169 mm Hg on 100% O2 by
             endotracheal tube. Peripheral venous Po2 was 50.5 mmHg. The
             patient received amyl nitrite perles by intermittant
             inhalation. The blood pressure was 100/50 mm Hg shortly after
             inhalation of amylnitrite. Administration of 45 mEq of sodium
             bicarbonate during the next 105 min increased the arterial pH
             to only 6.91. The child was maintained on intermittant amyl
             nitrite during the next two hours. Bradycardia and
             hypotension improved during periods of inhalation and
             worsened during periods of noninhalation. Two hours after
             admission (six hours postingestion) antidote kits were
             obtained and doses of 5 mL (0.33 mL of body weight) of 3%
             sodium nitrite and 25 mL (1.65 mL of body weight) of 25%
             sodium thiosulphate were subsequentially administered
             intravenously. Spontaneous respirations, normal pulse and
             blood pressure, and purposeful movements of all extremities
             were seen within 30 minutes of the completion of sodium
             nitrite infusion. There was a gradual improvement in
             sensorium during the succeeding three hours. Arterial pH
             increased rapidly from 6.91 to 7.27. At 15 hours
             postingestion, the child was extubated, alert and awake.
             Vital sign measurements were norma1. Serial whole blood
             cyanides were measured: at 4 hours postingestion the
             concentration was 8.2, at 7 hours 16.3 and at 15 hours 0.84
             mg/L (Hall et a1., 1986).
             In an industrial plant a suspected leak from a valve allowed
             hydrogen cyanide to escape. Nine man developed symptoms
             compatible with cyanide toxicity, of whom three lost
             conciousness. The symptoms experienced included
             lightheadedness (eight men), breathlessness (eight), feeling
             shaky (six), headache (four), and nausea (four). The three
             unconscious men rapidly recovered conciousness after being
             removed from the area where they had been working. The
             cyanide concentrations of the unconscious men on admission to
             the hospital were 3.1, 3.5, and 2.8 mg/L (Peden et a1.,

             A 43-year-old research chemist ingested a capsule of
             potassium cyanide. Ten minutes after the ingestion he was
             still conscious but complained of headache, and was driven to
             the hospital where he arrived 20 minutes after ingestion. On
             admission a coma (grade III) with hypertonus was observed.
             The pH was 6.8, anion gap 41 mEq/L, blood lactate 20 mmol/1.
             Ventilation with 100% oxygen was started after naso-trachea
             intubation. Gastric lavage was performed. During transport to
             the intensive care department a convulsive state was observed
             and a cardiac arrest occured 90 min after the ingestion.
             After 5 min of cardiac massage associated with infusion of
             200 mmol sodium bicarbonate and administration of
             isoprenaline (1 mg), the heart was restarted. Subsequently
             500 ml of colloid solution was given to expand the vascular
             space and a continuous dopamine infusion was given and a
             continuous dopamine infusion (20 gamma/kg/min) was started.
             Despite knowledge of the nature of the poisoning the patient
             received only non-specific supportive therapy. Three hours
             after admission, despite the 100% oxygen ventilation and the
             disappearance of the lactic acidosis the seizures recurred.
             Five hours after admission, i.e. 7 hours after ingestion the
             clinical and biological status of the patient was considered
             satisfactory (Brivet et a1., 1983).
             A 31-year-old male analytical chemist was found unconscious
             in his laboratory at 06.30 hours having telephoned his wife
             at 05.30 threatening to commit suicide. On admission at 07.20
             he was unconscious with central and peripheral cyanosis, a
             respiratory fate of 2/minute, a heart rate of 72/minute, and
             the arterial blood pressure was 140/70 mm Hg. On transfer to
             the Intensive Care Unit at 08.00 he was comatose and cyanosed
             despite breathing 100% oxygen at a rate of 20 breaths/minute.
             Sustained bilateral leg clonus and dilated pupils were
             observed. Acute cyanide poisoning was presumed and later
             confirmed by eliciting a history of the ingestion of 8 mL of
             5% potassium cyanide. Sodium nitrite 300 mg and sodium
             thiosulphate 25 g were given intravenously. Whole blood
             cyanide concentration 10.5 min after ingestion was 2.6 mg/1.
             The metabolic acidosis was corrected by 200 mL of 8.4% sodium
             carbonate. At 09.45 the patient began hyperventilating; this
             was followed by a fit for which 20 mg of diazepam were given
             intravenously. At 10.15 sodium nitrite and thiosulphate
             therapy was repeated and again at 16.30 and at 20.00 because
             cyanosis was present although methaemoglobine was
             undetectable in venous blood samples. At 24 hours following
             admission the conciousness returned accompanied by an
             extensor Babinski response and extensor spasms. Neurological
             assessment has shown the patient to have cerebellar,
             pyramidal and extrapyramidal neuronal damage and to lack
             reasoming ability, although clinically he continued to
             improve (Peters et a1., 1982).

             A 21-year-old man was brought to the hospital because of
             unconsciousness. He was stuporous, cyanotic, and with
             evidence of recent emesis. Gasping respirations (24/min) were
             present, blood pressure was 160/110 mmHg. Puls rate was 68
             beats perminute and irregular. Diffuse bilateral rales and
             rhonchi were noted. The nailbeds were cyanotic. Urine
             reaction for protein was 1+, for glucose 2+, and was negative
             for ketones.  Arterial blood gases while the patient was
             receiving 5 litres of oxygen per minute were pO2 115 mmHg,
             pCO2 12 mm Hg, bicarbonate 5.6 mEq/L, and pH 7.27. 
             Assisted ventilation was instituted and diuresis occured when
             the patient was given 80 mg of furosemide intravenously.
             Treatment consisted of oxygen and intravenous fluids
             including sodium bicarbonate and potassium chloride. Nine
             hours after admission, it was discovered that the patient had
             ingested potassium cyanide, and because at least ten hours
             had elapsed, no treatment with antidotes was undertaken.
             Blood drawn 12 hours after admission showed a cyanide level
             of 2.0 mg/L; at 22 hours, it was 1.6 mg/L, and at 84 hours
             1.2 mg/1. Analyses of two capsules found on his person showed
             that each contained approximately 200 mg potassium cyanide.
             Following recovery the patient stated that he had ingested
             three capsules. Nine days after admission the patient was
             discharged well (Graham et a1., 1977).


        12.1 Specific preventive measures

             Protective measures for occupational exposure
             Accidental exposure to cyanide, as either hydrogen cyanide or
             cyanide salts, will occur primarily in the occupational
             context, and appropriate preventive and protective measures
             need to be taken wherever cyanides are manufactured or used. 
             As hydrogen cyanide may be generated during combustion of
             organic substances, fire-fighters may also be exposed
             The public may be affected in the case of a major industrial
             emergency, or of a transport accident, involving the release
             of cyanides.  It is essential for local authorities in areas
             where cyanides are used to have contingency plans which will
             enable them to respond effectively.  Adequate hospital
             facilities for treatment of casualties must be available.
             Proper maintenance of plant, good operating practice and
             industrial hygiene are essential to the prevention of cyanide
             poisoning.  Areas in the workplace where cyanides are used,
             and containers for storage and transport of cyanide, should
             be clearly marked.  Work schedules should ensure that there
             is a minimum of two persons in zones where cyanide could be
             released accidentally.  There should be showers and first-aid

             kits in these areas.  Personnel without proper training
             should not be allowed in the plant.  Normal industrial and
             laboratory hygiene measures for personnel handling toxic
             materials, such as dirty and clean locker facilities and
             showers, should be provided.  Eating, drinking and smoking
             should not be allowed in the work area where cyanides are
             used, but should be limited to places specially reserved for
             these purposes.
             Each employee working at a plant or laboratory which handles
             cyanides, as well as emergency service personnel, should
             receive instruction on the dangers of cyanides and be trained
             in appropriate first-aid measures.  They should be aware of
             the hazards and informed about the possible routes of
             exposure (inhalation, skin absorption, ingestion).  Training
             should involve recognition of the symptoms and signs of
             cyanide poisoning and how to achieve safe removal of victims
             from the source of intoxication; personnel should also be
             able to guide a rescue or fire-fighting team to a trapped
             intoxicated person.  Rescue personnel should be able to put
             on protective clothing quickly in an emergency.  There should
             be regular instruction sessions covering procedures for
             handling cyanides and for rescue in case of accidents, as
             well as random alarm exercises.  First-aid training should
             include the essential measures to be taken before medical
             help arrives which may need to be undertaken at the same time
             as removal of contaminated clothing and decontamination of
             exposed skin and eyes.  It should be realized that further
             uptake of cyanide into the blood may occur after showering
             because of continued skin absorption.
             Each plant handling cyanide should have its own medical staff
             trained in the emergency treatment of cyanide poisonings. 
             The atmospheric concentrations of hydrogen cyanide should be
             monitored in plants where the gas is used or may be
             generated.  Warning devices are available for this purpose
             and should be installed.  In certain circumstances in which
             cyanide is used it is possible to add a warning gas, e.g.
             cyanogen chloride and chloropicrin have been added to
             hydrogen cyanide used as a fumigant (Cousineau & Legg, 1935; 
             Polson & Tattersall, 1971).
             Filter respirators should be carried at all times by
             employees working in zones where hydrogen cyanide may be
             released.  In high hydrogen cyanide concentrations, skin
             absorption occurs and impermeable butyl rubber protective
             clothing is required.  Oxygen breathing apparatus may be
             In the case of an accident involving hydrogen cyanide there
             should be both an acoustic and visual alarm for the plant,
             which may be activated by workers in zones where the gas is
             used.  Each worker should be aware of the emergency

             procedures to be followed including the protective clothing
             and equipment to be used.  If a large number of victims are
             involved or if there is a danger to the public, local
             authorities need to be warned, so that contingency plans are
             put into effect and hospitals alerted.
             For accidents at plants in remote areas where a qualified
             physician is not readily available and there are no hospital
             intensive care facilities, attending paramedical personnel
             should have the authority and training to perform the special
             resuscitation measures involved in treating cyanide
             poisonings, including rapid endotracheal intubation and
             techniques for obtaining intravenous access.

        12.2 Other

             The toxicity of nitriles is determined by a number of
             factors.  Toxicity may be due to liberated cyanide, to the
             molecule itself or to its metabolites.  This may be exampled
             by the differences observed following acrylonitrile and
             metacrylnitrile inhalation in animals.  Typical signs in
             lethal poisoning by inhalation:
             Acrylonitrile                 Methacrylonitrile
             salivation                    immediate coma
             convulsions                   hypoxic convulsions
             death 4 hours after           death 3O to 6O minutes
             exposure.                     after exposure.
             The influence of oxidation in the metabolism of
             acrylonitrile, leading to cyanide poisoning, is of minor
             importance following inhalation. The greater part of an
             inhaled dose of acrylonitrile is detoxified by binding to
             glutathione and is then eliminated in the urine as N-acetyl-
             S-2-cyanoethylcysteine.  N-acetylcysteine has been proven to
             be effective as an antidote in acrylonitrile poisoning by
             inhalation (Buchter et a1., l984).  However, metabolism of
             orally ingested dose of acrylonitrile occurs in a different
             manner since detoxification by means of binding to
             glutathione is negligible in comparison to cyanide liberation
             by oxidation.  Treatment with cyanide antidotes is therefore

             In poisoning due to methacrynitrile by inhalation, toxicity
             is primarily the result of cyanide formed by metabolism. 
             However, experiments in rats have shown that treatment with
             cyanide antidotes, as well as with N-acetylcysteine can be
             Treatment with a combination of N-acetylcysteine and cyanide
             antidotes is advised in cases of methacrylate poisoning
             (Bolt, l987).
             Nitriles toxicity may also be due to the molecule itself and
             this can result in different forms of organ damage.  In
             animal experiments, peripheral neurotoxic effects,
             nephrotoxicity and gastro-intestinal ulcer formation has been
             observed (Ballantyne, l987).
             Since there are so many factors which affect cyanogenesis in
             nitrile toxicity and because cyanide formation may not in
             itself be the cause of the clinical features exhibited, one
             should be specially cautious of administering cyanide
             antidotes because the toxicity of the antidotes themselves
             may worsen the clinical picture.


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        Author: Dr A.N.P. van Heijst
        Baarnseweg 42a
        3735 MJ Bosch en Duin
        Date:  February l988.
        Peer Review:  Hamilton, Canada, May 1989
        IPCS Review:  Geneva, Switzerland, September 1991
        Editor:  Dr M. Ruse (August, 1997)

    See Also:
       Toxicological Abbreviations