Hydrogen Cyanide: Toxicity and Management

This assignment delves into the multifaceted aspects of hydrogen cyanide (HCN), a highly toxic chemical compound. It examines the various routes of HCN exposure, its acute and chronic health effects, including the impact on cellular respiration and neurological function. The document also discusses the principles of managing HCN poisoning, emphasizing the crucial role of antidotes like hydroxocobalamin and supportive care measures. Furthermore, it touches upon legal frameworks surrounding HCN use and occupational safety protocols designed to minimize exposure risks.

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Table of Contents
Introduction and sources of exposure......................................................................................................................2
Effects of hydrogen cyanide on human health........................................................................................................2
Legislations, Standards, Codes of Practice.............................................................................................................3
Occupational Exposure limits for hydrogen cyanide..............................................................................................5
Toxicokinetics and toxicodynamics........................................................................................................................6
Conclusion...............................................................................................................................................................8
References...............................................................................................................................................................9

Introduction and sources of exposure
Hydrogen cyanide is a compound that is highly flammable and poisonous; it is found in liquid form
and is a precursor of many other compounds. It is spontaneously absorbed and transferred after inhalation, to
different parts of the body. It has fatal implications in the human body; it can drastically affect the working of
the body by exposure to any part irrespective of its location. Hydrogen cyanide is highly toxic in many ways.
It has several neurological effects that can lead to permanent impairment of organs and even death. The
different sources of exposure are stated below:
 Inhalation- HCN is readily absorbed by the lungs. Cyanide containing dust particles produce toxicity
upon inhalation. HCN creates localized damage that manifests in the form of pulmonary congestion,
dryness and burning sensation in throat, by acting as a lung irritant. Lethal doses are around 0.3mg/l
HCN. 0.2mg/l (181 ppm) is considered as a lethal dose after 10 minutes of exposure. Owing to the
presence of larger ratio of lung surface area to body weight, children are found to receive larger doses
of the gas.
 Oral route- Solutions containing HCN are absorbed form the alimentary canal and are corrosive and
fatal in nature. Severe intoxication is produced at higher doses. Lower doses exhibit symptoms at a
slower rate. The stomach gets inflamed and ulcer is formed.
 Dermal route- It is also absorbed through uninjured skin 1. This causes systemic toxicity within the
body. The absorption rate increases with increase in pH, due to unionized HCN. Breathing
abnormalities like plasma extravasations, Cheyne Stokes respiration, and peripheral vasoconstriction
occur. The person can even reach a state of coma.
Effects of hydrogen cyanide on human health
Toxicity of hydrogen cyanide is higher than any other compound. The symptoms associated with its
exposure to the body occur rapidly after contact or inhalation. It adversely affects the mechanism of
respiration by blocking the oxidative respiration, and leads to hypoxia. Immediate symptoms on acute
exposure affect the tissues in the central nervous system (CNS). Tachycardia and tachypnoea also occur due
1 Ballantyne BR. The forensic diagnosis of acute cyanide poisoning. Forensic toxicology (B. Ballantyne, ed.). 2013 Oct 22:99-113.

to systemic toxicity 2. Acute exposure also manifests itself in the form of muscular abnormalities, fixed
unreactive pupils, conjunctivitis and blepharospasm. Skin burns and swelling in eyes also occur. Exposure to
larger doses causes loss of consciousness, depression of cardio respiration, pulmonary oedema and death.
Behavioural abnormalities and intellectual impairment are found to occur. Parkinson’s disease and memory
deficit may also develop. The eyes, skin, gastrointestinal tract and thyroid get affected 3. Enlargement of
thyroid gland occurs due to exposure to minimal HCN doses 4.
Chronic or repeated exposure leads to visual impairment among workers. No in-vivo human data are
available to assess genotoxicity of HCN. However, it has been found that HCN does not cause structural
changes that can lead to DNA damage. Data from in-vitro studies can be used to conclude that it does not
have significant mutagenic effects. Several studies also show that hydrogen cyanide is not a mutagenic
compound. It also has no carcinogenicity and there are no evidences available that imply its association with
occurrence of any type of cancer. The exposure has no effect on the process of reproduction and body
development.
Legislations, Standards, Codes of Practice
Relevant legislation has been imposed to control the amount of HCN in the atmosphere with the aim
of improving human health and protecting the environment form the risks of cyanide exposure. The Hydrogen
Cyanide Fumigation Act (chapter 132) has been formulated with the aim of protecting people from danger
related to fumigation of areas and goods that contain HCN. These regulations control the generation of HCN,
prohibit fumigation processes without supervision, regulate the issue and cancellation of fumigation licences
and holds a person guilty, who contravenes the regulations 5. Furthermore, the Act regulates the disposal of
residues produced from substances used in fumigation. The Singapore Workplace Safety and Health
2 Anseeuw K, Delvau N, Burillo-Putze G, De Iaco F, Geldner G, Holmström P, Lambert Y, Sabbe M. Cyanide poisoning by fire
smoke inhalation: a European expert consensus. European Journal of Emergency Medicine. 2013 Feb 1;20(1):2-9.
3 Grabowska T, Skowronek R, Nowicka J, Sybirska H. Prevalence of hydrogen cyanide and carboxyhaemoglobin in victims of
smoke inhalation during enclosed-space fires: a combined toxicological risk. Clinical toxicology. 2012 Sep 1;50(8):759-63.
4 Sweeney LM, Sommerville DR, Channel SR. Impact of non-constant concentration exposure on lethality of inhaled hydrogen
cyanide. toxicological sciences. 2013 Dec 13;138(1):205-16.

Regulations state that it is the duty a workplace occupier to take practicable measures that ensure no person is
exposed to toxic substances that are specified in the first schedule of the law, at limits that exceed the
specified permissible exposure levels. Part IV of the law also mentions that accumulation of toxic substances
at workplace should be avoided, there should be provisions for adequate ventilation to dilute the gas or fumes,
work should be carried out in an isolated place and toxic dust or fibres should be removed from walls and
floors by washing or using vacuum cleaners. The Australia WHS Regulations state that it the duty of
manufacturers to label the chemicals in accordance to the guidelines. The duty holders should identify
foreseeable hazards that can give rise to risks and should try to eliminate or minimize risks by implementing
control measures in accordance to the hierarchy of risk control. The Singapore Standards SS 586:2008 for
hazardous chemicals and dangerous goods focus on the following:
 Ensuring that every container has one or more warning labels according to the standards that
are approved by the Council.
 A particular vehicle shall be deemed to be used for transporting a hazardous substance from
commencement of loading until the vehicle (tanker) has been cleaned to ensure that the
substances remaining in them are insufficient to cause health hazards.
 Obtaining safety data sheet at places where there is usage, handling and storage of hazardous
substances. The codes of practice state that it is the duty of workplace occupiers to assess the
data sheet information and take precautionary measures for safe usage of the substance.
The codes of practice set out the installation methods of equipment and procedures that are needed to be
followed for efficient use and maintenance of the equipment. The codes recommend necessary precautions for
using the equipment and specify the measures that should be taken to design and construct them.
Occupational Exposure limits for hydrogen cyanide
Threshold limit value of a particular chemical is the level of a particular chemical, to which a worker
can remain exposed for prolonged period of time at a workplace setting, without exhibiting any adverse health
effects, is termed as threshold limit value or TLV. The adverse effects that can generally arise are tissue
5 Statutes.agc.gov.sg. Singapore Statutes Online - 132 - Hydrogen Cyanide (Fumigation) Act [Internet]. Statutes.agc.gov.sg. 2017
[cited 31 October 2017]. Available from: http://statutes.agc.gov.sg/aol/search/display/view.w3p;page=0;query=DocId
%3Afa1a46a0-9c8e-484a-95e4-39eafa0c6e28%20Depth%3A0%20Status%3Ainforce;rec=0

damage, irritation, and narcosis. Time weighted average (TWA) is considered for 8 hours per workday at a
rate of 5 days per week. The permissible exposure limits (short term) are defined as the maximum
concentration of TWA to which a person can remain exposed for a time period of 15 minutes during a
workday. The legislation states that short term exposure limits should remain within TWA levels. The limits
can exceed TWA only thrice, for a maximum duration of 30 minutes per workday. Moreover, the legislation
limits the exposure rates to 5 times. The regulations 2 and 40 have fixed the short term PEL for HCN at 4.7
ppm and 5 mg/m3. Furthermore, the long term PEL has been fixed at 8 hours per working day, for 40 hours
per week. On the other hand, Occupational Exposure Limit (OEL) is defined as the upper limits of
concentration of a hazardous chemical that is acceptable at workplace. The OEL for HCN at Singapore is 10
ppm and 11 mg/m3.
Thus, it can be stated that the Fumigation Act works effectively towards preventing HCN exposure
and occurrence of related adverse health conditions 6. The OSHA PEL is 10 ppm (11mg/m3) TWA for skin
(general, construction and maritime industry) 7. The NIOSH recommends permissible limits of 4.7 ppm (5
mg/m3) as the ceiling limit. The NIOSH guidelines are therefore followed by Singapore 8. The OSHA
guidelines have been revised recently due to the fact that the old PEL were based on researches that were
carried out in the 1950's and fail to provide adequate protection to the workers. Thus, revisions in PEL have
been made in association with labour and professional organizations. The limits for Australia are TWA 10
ppm (skin). In cases where the short term PEL is not specified for a hazardous chemical, the PEL shall be
considered to be more if the TWA of the substance exceeds 5 times the PEL, when measured during any
6 Reade MC, Davies SR, Morley PT, Dennett J, Jacobs IC. Management of cyanide poisoning. Emergency Medicine Australasia.
2012 Jun 1;24(3):225-38.
7 Occupational Safety and Health Administration. Improve Tracking of Workplace Injuries and Illnesses. Final rule. Federal
register. 2016 May 12;81(92):29623.
8 Centers for Disease Control. The National Institute for Occupational Safety and Health (NIOSH). Hydrogen cyanide: systemic
agent. The Emergency Response Safety and Health Database, CAS#: 74-90-8, RTECS#: MW6825000, UN#: 1051 (Guide 117);
2011. Web site.

working day, over a 15-minute period. The Workplace Exposure Standards Australia has fixed HCN exposure
limits to 10 peaks for TWA (ppm) and 11 peaks for TWA (mg/m3).
Toxicokinetics and toxicodynamics
Inhalation, dermal exposure and oral exposure are the common routes of cyanide poisoning.
Following these routes, there is rapid absorption of cyanide into the alveoli and bronchial mucosa. In
equilibrium, cyanide exists in the form of an anion and undissociated HCN. The ionised form is present at a
physiological pH of 7.4 due to 9.22 pKa value 9. Pulmonary absorption is faster than gastrointestinal
absorption. However, after an oral intake, only few portion of the cyanide reaches the bloodstream owing to
the first-pass liver metabolism process. The lungs, brain, heart, liver and blood show comparatively higher
concentrations of cyanide. A major amount of HCN gets sequestered in the erythrocytes at 199:1 red blood
cell to plasma ratio. The major routes for biotransformation of hydrogen cyanide involve detoxification
process in the liver by mitochondrial sulphur transferase enzymes, rhodanese (thiosulphate cyanide
sulfurtransferase) and β-mercaptopyruvate cyanide sulfurtransferase. These enzymes catalyse the transfer of
sulfane sulphur of thiosulphate to cyanide ions 10.
The amount of thiosulphate acts as the rate-limiting step. Rhodanese is present in highest
concentration in the liver and is responsible for 80% of cyanide detoxification. Availability of sulphur acts as
the major limiting factor of the pathway, and a reduction in the amount of sulphur atoms, slows down the
metabolism process.
Exhalation is one of the major routes of cyanide elimination. The pathways that govern elimination of
cyanide are concerned with cyanide conversion to 2-aminothiazoline-4-carboxylicn acid and
9 Bhandari RK, Oda RP, Petrikovics I, Thompson DE, Brenner M, Mahon SB, Bebarta VS, Rockwood GA, Logue BA. Cyanide
toxicokinetics: the behavior of cyanide, thiocyanate and 2-amino-2-thiazoline-4-carboxylic acid in multiple animal models. Journal
of analytical toxicology. 2014 May 1;38(4):218-25
10 Stamyr K, Mörk AK, Johanson G. Physiologically based pharmacokinetic modeling of hydrogen cyanide levels in human breath.
Archives of toxicology. 2015 Aug 1;89(8):1287-96.

cyanocobalamine formation (cyanide combined with hydroxycobalamine) 11. Another route of elimination is
through urine in the form of thiocyanate.
HCN exhibits a high affinity for sulfanes that contain 2 unequally charged, covalently bound sulphur
atoms. A high affinity is also present for metallic compounds containing ferric and cobalt ions 12. Once it
enters the bloodstream, cyanide binds to haemoglobin present in the red blood cells. It gets transferred to the
body tissues and combines with the ferric ions, present in cytochrome oxidase that is located in the
mitochondria, thereby preventing the electron transport system 13. This in turn halts oxidative phosphorylation
and the subsequent ATP synthesis. Calcium homeostasis gets disrupted. The demand for anerobic glycolysis
increases and causes accumulation of lactic acid in the muscles. Furthermore, the voltage sensitive calcium
channels get activated and catalase and superoxide dismutase (antioxidant enzymes) get inhibited. This
facilitates the generation of reactive oxygen species (ROS). This causes interference in oxygen supply and
manifests in the form of histotoxic anoxia 14. Visual disturbances also occur, accompanied by pupil dilation
(mydriasis). HCN poisioning upregulates release of enkephalin. This is generally exhibited by symptoms such
as convulsion, less awareness and loss of consciousness. Anaerobic metabolism induces decrease of
ATP/ADP ratio and alters energy-dependent calcium homeostasis processes15. The thyroid glands are
adversely affected by thiocyanate by competitive inhibition of iodide uptake. This disrupts the homeostatic
feedback mechanism, which regulates thyroid hormone synthesis. Cyanide poisoning creates lesions in
11 Thompson JP, Marrs TC. Hydroxocobalamin in cyanide poisoning. Clinical Toxicology. 2012 Dec 1;50(10):875-85.
12 Isom GE, Borowitz JL. Cyanide‐induced neural dysfunction and neurodegeneration. Toxicology of Cyanides and Cyanogens.
2015:209-23.
13 Srinivasan S, Avadhani NG. Cytochrome c oxidase dysfunction in oxidative stress. Free Radical Biology and Medicine. 2012 Sep
15;53(6):1252-63.
14 Youso SL, Rockwood GA, Logue BA. The analysis of protein-bound thiocyanate in plasma of smokers and non-smokers as a
marker of cyanide exposure. Journal of analytical toxicology. 2012 Apr 2;36(4):265-9.
15 Randviir EP, Banks CE. The latest developments in quantifying cyanide and hydrogen cyanide. TrAC Trends in Analytical
Chemistry. 2015 Jan 31;64:75-85.

several parts of the brain, which include the globus pallidus, cerebellum and substantia nigra, as revealed by
PET and MRI scans. HCN also releases endonuclease that cause DNA fragmentation. HCN, present in
amygdalin, is thought to be an anticancer compound owing to the fact that vitamin B17 and beta-glucosidase
on coming in contact with each other, make HCN and benzaldehyde to combine synergistically and produce a
cell that will kill cancer cells.
Conclusion
Thus, it can be concluded that HCN is a deadly poison, which acts on body cells and inhibits
cytochrome oxidase. It is a colourless poisonous gas that binds irreversibly to the iron atoms present in the
pigment hemoglobin. This decreases the transport of oxygen to the body tissues. The possible routes of
exposure include smoke inhalation, metal polishing industries and exposure to liquid cyanide solutions and
insecticides. The first symptoms of cyanide exposure are headache, rapid heartbeat, and drowsiness. On
prolonged exposure, coma and convulsions are seen among workers. At higher dose, HCN can even lead to
death. Cyanide toxicity does not produce lethal effects on immediate exposure. Furthermore, it is possible
to survive on mild exposure. Cyanide poisoning can be treated by reversing the binding of HCN to
haemoglobin. An administration of 100% oxygen helps to support respiration. Several legislations have been
developed to keep a check on exposure to HCN. These standards and codes of practice focus on labelling and
installation of equipment that contain HCN. Moreover, the standards also focus on maintenance of safety data
sheets to handle and store hazardous chemicals. There are specific permissible exposure limits followed by
different countries to avoid cyanide poisoning. Thus, the probable exposure sources should be identified and
legislations should be properly imposed to prevent cyanide toxicity.

References
1. Ballantyne BR. The forensic diagnosis of acute cyanide poisoning. Forensic toxicology (B. Ballantyne, ed.).
2013 Oct 22:99-113.
2. Anseeuw K, Delvau N, Burillo-Putze G, De Iaco F, Geldner G, Holmström P, Lambert Y, Sabbe M. Cyanide
poisoning by fire smoke inhalation: a European expert consensus. European Journal of Emergency Medicine.
2013 Feb 1;20(1):2-9.
3. Grabowska T, Skowronek R, Nowicka J, Sybirska H. Prevalence of hydrogen cyanide and carboxyhaemoglobin
in victims of smoke inhalation during enclosed-space fires: a combined toxicological risk. Clinical toxicology.
2012 Sep 1;50(8):759-63.
4. Sweeney LM, Sommerville DR, Channel SR. Impact of non-constant concentration exposure on lethality of
inhaled hydrogen cyanide. toxicological sciences. 2013 Dec 13;138(1):205-16.
5. Statutes.agc.gov.sg. Singapore Statutes Online - 132 - Hydrogen Cyanide (Fumigation) Act [Internet].
Statutes.agc.gov.sg. 2017 [cited 31 October 2017]. Available from:
http://statutes.agc.gov.sg/aol/search/display/view.w3p;page=0;query=DocId%3Afa1a46a0-9c8e-484a-95e4-
39eafa0c6e28%20Depth%3A0%20Status%3Ainforce;rec=0
6. Reade MC, Davies SR, Morley PT, Dennett J, Jacobs IC. Management of cyanide poisoning. Emergency
Medicine Australasia. 2012 Jun 1;24(3):225-38.
7. Occupational Safety and Health Administration. Improve Tracking of Workplace Injuries and Illnesses. Final
rule. Federal register. 2016 May 12;81(92):29623.
8. Centers for Disease Control. The National Institute for Occupational Safety and Health (NIOSH). Hydrogen
cyanide: systemic agent. The Emergency Response Safety and Health Database, CAS#: 74-90-8, RTECS#:
MW6825000, UN#: 1051 (Guide 117); 2011. Web site.
9. Bhandari RK, Oda RP, Petrikovics I, Thompson DE, Brenner M, Mahon SB, Bebarta VS, Rockwood GA,
Logue BA. Cyanide toxicokinetics: the behavior of cyanide, thiocyanate and 2-amino-2-thiazoline-4-carboxylic
acid in multiple animal models. Journal of analytical toxicology. 2014 May 1;38(4):218-25
10. Stamyr K, Mörk AK, Johanson G. Physiologically based pharmacokinetic modeling of hydrogen cyanide levels
in human breath. Archives of toxicology. 2015 Aug 1;89(8):1287-96.
11. Thompson JP, Marrs TC. Hydroxocobalamin in cyanide poisoning. Clinical Toxicology. 2012 Dec
1;50(10):875-85.
12. Isom GE, Borowitz JL. Cyanide‐induced neural dysfunction and neurodegeneration. Toxicology of Cyanides
and Cyanogens. 2015:209-23.

13. Srinivasan S, Avadhani NG. Cytochrome c oxidase dysfunction in oxidative stress. Free Radical Biology and
Medicine. 2012 Sep 15;53(6):1252-63.
14. Youso SL, Rockwood GA, Logue BA. The analysis of protein-bound thiocyanate in plasma of smokers and
non-smokers as a marker of cyanide exposure. Journal of analytical toxicology. 2012 Apr 2;36(4):265-9.
15. Randviir EP, Banks CE. The latest developments in quantifying cyanide and hydrogen cyanide. TrAC Trends
in Analytical Chemistry. 2015 Jan 31;64:75-85.