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Under physiological conditions, 2-hydroxy-2-methylpropionitrile (named ACH in the quoted ECETOC report) decomposes to yield its molar equivalent in hydrogen cyanide and acetone. The intrinsic toxicological properties of 2-hydroxy-2-methylpropionitrile are determined for the most part by the degradation product hydrogen cyanide.

(Following quotation taken with kind permission from ECETOC JACC report no. 53; Cyanides of Hydrogen, Sodium and Potassium, and Acetone Cyanohydrin (CAS No. 74-90-8, 143-33-9, 151-50-8 and 75-86-5):

“Commercial and technical grade ACH are stabilised by the addition of 0.01% sulphuric or phosphoric acid. Stabilised ACH will exert a significant vapour pressure, primarily due to the presence of more volatile HCN, at room temperature. Under physiological conditions, acid-stabilised ACH will be buffered by the intracellular buffering capacity resulting in its rapid and quantitative decomposition to HCN and acetone. Hence, ACH will exhibit the combined characteristics of HCN and acetone (Frank et al, 2002).”

 “The predominant speciation of all inorganic cyanide in the body is HCN due to the weak acid dissociation constant (pKa = 9.11). This is also the form in which cyanide is absorbed into the blood after oral, dermal or inhalation exposure. It is rapidly absorbed via all exposure routes. The main route of metabolism is enzymatic (rhodanese) trans-sulphuration into thiocyanate. The liver metabolises nearly all cyanide at subtoxic dose levels via the enzyme rhodanese. So there is a first-pass effect via the oral route. However, the overall maximum detoxification capacity in humans derived from the difference in acute toxicity data at different exposure times is limited to about 0.008 mg CN-/kg bw/min. Detoxification rates for other species ranged between 0.01 and 0.03 mg CN-/kg bw/min and were thus a little higher.

The detoxifying enzyme rhodanese is not only found in the liver but also in muscles and other tissues. Rhodanese in muscles contributes considerably to the detoxification of cyanide in the body to thiocyanate. In the absence of sulphur donating agents in the human body, the maximum detoxification rate was claimed to be as low as 0.9 μg CN-/kgbw/min (Schulz et al, 1982). However, a re-analysis of the data suggests a rate of 3.0 μg CN-/kg bw/min (80 min mean infusion duration), based on the dose rate at which no clinical symptoms occurred.

Inter-individual variation in serum rhodanese activity can vary by a factor of 6 (Nawata et al, 1991) or 3 to 8 (Narendranathan et al, 1989). However, rhodanese is present in all body tissues in considerable excess and not rate-limiting (Himwich and Saunders, 1948; Schulz et al, 1982), unlike thiosulphate, which may be only available in the body in small amounts depending on the nutritional status (Schulz et al, 1982). No major polymorphisms have been identified to date. A rare hereditary disease, Leber’s optic atrophy has been linked by some authors to a deficiency in rhodanese activity (Cagianut et al, 1984; Wilson, 1965, 1983; Poole and Kind, 1986), but this was not confirmed by other authors (Pallini et al, 1987; Berninger et al, 1989; Whitehouse et al, 1989). Protein deficient populations are more susceptible to cyanide intoxication as thioamino acid levels are reduced."

Low-dose cyanide metabolim under normal physiological conditions

Cyanide is presend and metabolised under normal physiolgical conditions as referred in the rationale of Acute Exposure Guideline Levels (AEGLs) established by AEGL-Committee (US-NAC, Acetone Cyanohydrin, Interim Acute Exposure Guideline Levels (AEGLs), Interim final draft, 2005; in the following cited as AEGL):

"With regard to the metabolism of cyanide, it is important to distinguish between low-dose cyanide metabolism, which occurs under circumstances in which cyanide is present in physiological concentrations, and high-dose cyanide disposition, in which there are amounts of cyanide far in excess of those present under normal physiological conditions. Low-dose cyanide metabolism involves incorporation via vitamin B12-dependent enzymes of cyanide into the C1-metabolite pool from which it can be eliminated as carbon dioxide. Under physiological conditions, the normal capacity of rhodanese to handle cyanide is not overwhelmed and circulating cyanide remains in metabolic equilibrium with the C1-metabolic pool (DECOS, 1995; ATSDR, 1997)" (quotation from AEGL).

Mode of action

“Cyanide poisoning is caused by complex formation with the iron in cytochrome oxidase which is present in tissues at cellular level. The complex formation inhibits oxygen from receiving electrons from the cytochrome oxidase and a so-called intracellular or cytotoxic anoxia occurs, i.e. oxygen is present but cannot be utilised by the cell.

Because neurons and cardiac myocytes are highly dependent on aerobic metabolism they are extremely sensitive to the deprivation of oxygen. If aerobic metabolism fails due to the inactivated cytochrome oxidase by cyanide, the neuron immediately loses its capacity to conduct nervous pulses properly and the brain fails to function with consequent loss of consciousness. If this stage continues for some minutes, the damage becomes irreversible and the neurons die. For these reasons, prolonged hypoxia, regardless of its cause, often results in injury to the brain. Toxicants that inhibit aerobic cell respiration like HCN and hydrogen sulphide have the same effect (Anthony and Graham, 1991)" (quotation from ECETOC).