| 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. PHYSICO-CHEMICAL PROPERTIES|
| 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. USES/HIGH RISK CIRCUMSTANCES OF POISONING|
| 4.1 Uses|
| 4.1.1 Use|
| 4.2.2 Description|
| 4.2 High risk circumstances of poisoning|
| 4.3 Occupationally exposed populations|
|5. ROUTES OF EXPOSURE|
| 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|
| 188.8.131.52 Adults|
| 184.108.40.206 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. TOXICOLOGICAL/TOXINOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS|
| 8.1 Material sampling plan|
| 8.1.1 Sampling and specimen collection|
| 220.127.116.11 Toxicological analyses|
| 18.104.22.168 Biomedical analyses|
| 22.214.171.124 Arterial blood gas analysis|
| 126.96.36.199 Haematological analyses|
| 188.8.131.52 Other (unspecified) analyses|
| 8.1.2 Storage of laboratory samples and specimens|
| 184.108.40.206 Toxicological analyses|
| 220.127.116.11 Biomedical analyses|
| 18.104.22.168 Arterial blood gas analysis|
| 22.214.171.124 Haematological analyses|
| 126.96.36.199 Other (unspecified) analyses|
| 8.1.3 Transport of laboratory samples and specimens|
| 188.8.131.52 Toxicological analyses|
| 184.108.40.206 Biomedical analyses|
| 220.127.116.11 Arterial blood gas analysis|
| 18.104.22.168 Haematological analyses|
| 22.214.171.124 Other (unspecified) analyses|
| 8.2 Toxicological Analyses and Their Interpretation|
| 8.2.1 Tests on toxic ingredient(s) of material|
| 126.96.36.199 Simple Qualitative Test(s)|
| 188.8.131.52 Advanced Qualitative Confirmation Test(s)|
| 184.108.40.206 Simple Quantitative Method(s)|
| 220.127.116.11 Advanced Quantitative Method(s)|
| 8.2.2 Tests for biological specimens|
| 18.104.22.168 Simple Qualitative Test(s)|
| 22.214.171.124 Advanced Qualitative Confirmation Test(s)|
| 126.96.36.199 Simple Quantitative Method(s)|
| 188.8.131.52 Advanced Quantitative Method(s)|
| 184.108.40.206 Other Dedicated Method(s)|
| 8.2.3 Interpretation of toxicological analyses|
| 8.3 Biomedical investigations and their interpretation|
| 8.3.1 Biochemical analysis|
| 220.127.116.11 Blood, plasma or serum|
| 18.104.22.168 Urine|
| 22.214.171.124 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. CLINICAL EFFECTS|
| 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|
| 126.96.36.199 Central nervous system (CNS)|
| 188.8.131.52 Peripheral nervous system|
| 184.108.40.206 Autonomic nervous system|
| 220.127.116.11 Skeletal and smooth muscle|
| 9.4.4 Gastrointestinal|
| 9.4.5 Hepatic|
| 9.4.6 Urinary|
| 18.104.22.168 Renal|
| 22.214.171.124 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|
| 126.96.36.199 Acid base disturbances|
| 188.8.131.52 Fluid and electrolyte disturbances|
| 184.108.40.206 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. ILLUSTRATIVE CASES|
| 11.1 Case reports from literature|
|12. ADDITIONAL INFORMATION|
| 12.1 Specific preventive measures|
| 12.2 Other|
|14. AUTHOR(S), REVIEWER(S), DATE(S), COMPLETE ADDRESS(ES)|
International Programme on Chemical Safety
Poisons Information Monograph G003
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
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).
2.1 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
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
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
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.
Nausea, dizziness, drowsiness (blood cyanide concentrations
of less than 2 mg/L). Give oxygen and bed rest, reassure the
3. PHYSICO-CHEMICAL PROPERTIES
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
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
Major compounds are: Hydrogen cyanide (HCN), Sodium cyanide
(NaCN), and Potasssium cyanide (KCN).
3.3 Physical properties
Clear liquid (hydrogen cyanide)
See Table 1, Section 3.3.3.
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. USES/HIGH RISK CIRCUMSTANCES OF POISONING
Chemical used in synthesis; not otherwise specified
Other industrial/commercial product
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
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):
Adipic acid makers
Almond flavour makers
Ammonium salt makers
Art printing workers
Blast furnace workers
Bronzers, gun barrel
Cellulose product treaters
Coal tar distillery workers
Coke oven operators
Fumigators of fruit trees, apiaries, railways, cars,
warehouses, stored food
Hexamethylenediamine insecticide & Hydrogen cyanide workers
Insecticide and HCN workers
Organic chemical synthesizers
Oxalic acid makers
Phosphoric acid makers
Non-industrial: Fire and automobile devices with
malfunctioning catalytic converters (Voorhoeve et a1., l975)
generate cyanide. (Table 2).
5. ROUTES OF EXPOSURE
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
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
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
Skin absorption of cyanide from aqueous solutions and of
atmospheric hydrogen cyanide can be harmfu1.
Cyanides are readily absorbed via the eye and across the
nasal mucosa (Ballantyne, l983).
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
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.
6.1 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).
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).
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
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
7.2.1 Human data
Table 3. Estimated acute lethal inhalation toxicity
of hydrogen cyanide vapour (McNamara, l976).
Exposure time (min.) Approximate LC50 (mg/m3)
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.
6OOO lOOO -
lOOOO l85OO lO to l9
55OOO lOOO 46 to 83
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 "
7.2.3 Relevant in vitro data
No data available.
7.2.4 Workplace standards
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
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
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
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).
Cyanide is not mutagenic (Ballantyne, 1987).
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. TOXICOLOGICAL/TOXINOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
220.127.116.11 Toxicological analyses
18.104.22.168 Biomedical analyses
22.214.171.124 Arterial blood gas analysis
126.96.36.199 Haematological analyses
188.8.131.52 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
184.108.40.206 Toxicological analyses
220.127.116.11 Biomedical analyses
18.104.22.168 Arterial blood gas analysis
22.214.171.124 Haematological analyses
126.96.36.199 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
188.8.131.52 Toxicological analyses
184.108.40.206 Biomedical analyses
220.127.116.11 Arterial blood gas analysis
18.104.22.168 Haematological analyses
22.214.171.124 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
126.96.36.199 Simple Qualitative Test(s)
188.8.131.52 Advanced Qualitative Confirmation Test(s)
184.108.40.206 Simple Quantitative Method(s)
220.127.116.11 Advanced Quantitative Method(s)
8.2.2 Tests for biological specimens
18.104.22.168 Simple Qualitative Test(s)
22.214.171.124 Advanced Qualitative Confirmation Test(s)
126.96.36.199 Simple Quantitative Method(s)
188.8.131.52 Advanced Quantitative Method(s)
184.108.40.206 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
220.127.116.11 Blood, plasma or serum
18.104.22.168 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
8.5 Overall interpretation of all toxicological analyses and
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
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. CLINICAL EFFECTS
9.1 Acute poisoning
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.
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
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).
No data available.
9.2 Chronic poisoning
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).
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.
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
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
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
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.
22.214.171.124 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
126.96.36.199 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.
188.8.131.52 Autonomic nervous system
Acute effects on the cardiovascular
system in massive cyanide poisoning are life
184.108.40.206 Skeletal and smooth muscle
No data available.
Ingested salts produce local irritation, nausea
and vomiting. Salivation and epigastric pain are
observed after poisoning with cyanogenic glucosides.
Hematemesis can be observed.
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,
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).
No data available.
No data available.
220.127.116.11 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;
18.104.22.168 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.
No data available.
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.
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
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.
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 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-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.
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
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.
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.
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.
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
Dose in children is unknown.
Hydroxycobalamin (Vitamin B12a)
Dose in children is unknown.
Dose in children is unknown.
10.6 Management discussion: alternatives, controversies and
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. ILLUSTRATIVE CASES
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. ADDITIONAL INFORMATION
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
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.
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:
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
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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14. AUTHOR(S), REVIEWER(S), DATE(S), COMPLETE ADDRESS(ES)
Author: Dr A.N.P. van Heijst
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)