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Description of key information

The repeated dose toxicity of cyanide salts is based on effects observed from related compounds, hydrogen cyanide and acetone cyanohydrins.  All category members behave similarly in generating HCN at the physiological pH of 7, and are not present as either the salt or the free CN‾ ion.  As there is a significant body of data on human exposure to cyanides, this data is utilized over animal data for derivation of the DNELs  The level of blood thiocyanate which is without adverse effect on the thyroid gland or other organs is established, and chronic exposure resulting in this value is calculated as an acceptable limit (see ECETOC, 2007 approach in the JACC Report No. 53).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
1.35 mg/kg bw/day
Study duration:
subchronic

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
9.4 mg/m³
Study duration:
subchronic

Additional information

Potassium cyanide and sodium cyanide can be considered as a chemical category, along with hydrogen cyanide (HCN) and acetone cyanohydrin (ACH, also known as 2-hydroxy-2-methylpropanenitrile), based on structural similarity, similar physico-chemical properties and common breakdown/metabolic products in physical and biological systems. Particular attention is paid to the dissociation constant of HCN. In the vast majority of environmental and physiologic conditions, the cyanide salts will dissolve in water to form hydrogen cyanide. The physico-chemical hazards and toxicity result from the activity of this common proximal toxicant, HCN.

Both are alkali salts of the anion, cyanide, CN-, which is the solitary functional group which defines the chemical and toxicologic activity of these substances. KCN and NaCN are soluble in water, resulting in the immediate formation of HCN. Likewise, ACH, upon contact with water, liberates CN- to form HCN. The presence of the acetone moiety does not affect the activity and toxicity of HCN. 

 

Hydrogen cyanide has a measured pKa value (dissociation constant) of 9.36 at 20°C (Izatt, et al, 1962), indicating that, in all but the most alkali of water, the salts of cyanide will be hydrated, as HCN. This has been verified experimentally; the HCN fraction is 92% at pH 8.5 and over 99% when the pH falls below 7 (Leducet al,1982). At the pH of approximately 7, cyanide salts are distributed in an organism as HCN and are not present as either the salt or the free CNion. Hence, the form of cyanide to which exposure takes place does not influence the distribution, metabolism or excretion from the body.  

 

Support for this category approach is provided in examination of acute toxicity by oral, dermal, ocular and intraperitoneal administration of various forms of cyanide. The data expressed as mg/kg body weight are generally consistent across the different species of cyanide. However, when the data are expressed as mmol CN anion/kg body weight, the consistent numbers demonstrate a common basis of action for the cyanide ion, regardless of the alkali salt. In risk assessment, dose descriptors and DNELs are calculated based on the critical concentration of CN-, then are converted on a molar basis to therespective salts. 

 

A review of experimental data on cyanides was undertaken by an ECETOC Task Force, and published as the 2007 ECETOC Joint Assessment of Commodity Chemicals ( 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)”.  The report is a weight of evidence approach to an extensive body of literature by this scientific non-governmental organization (NGO).  This body of work supports the hypothesis of a chemical category comprised of potassium cyanide, sodium cyanide, hydrogen cyanide and acetone cyanohydrin.  Dose descriptors are calculated as mg CN-anion, underscoring the common mechanism of these category members.

Limit values can be obtained from both animal data and human data, and final calculations indicate that both provide similar limit values. The leading health effect of repeat dose exposure to cyanides is development of goitre. This chronic toxicity of HCN was reviewed by ECETOC in the JACC report on Cyanides (No. 53, 2007) which concluded that an acceptable chronic level of exposure to CN- in humans could be established using levels of cyanide and its metabolite, thiocyanate (SCN).

The ECETOC review recognised that due to background variations in co-exposure to cyanogenic sources (e.g., environmental (combustion), dietary (cyanogenic foods) and habitual (i.e. smoking)) and levels of dietary iodine, it is not possible to distinguish precisely the effects of exogenous CN- on thyroid hormone levels, the critical effect. For this reason, ECETOC selected the threshold for clinical diagnosis between adaptive and goitrogenic changes as a NOAEL rather than a NOEL.

 

The ECETOC Task Force further proposed that a level of 15 μg SCN-/ml can be used as a starting point to derive a safe concentration of cyanide for humans, using the following equation. 

 

 [CN-] mg/m3= [SCN-] mg/l × 0.25 l/kg bw × 70 kg bw × 26

                                            10 m3 × 0.8 × 3.9 × 58

 

Where

15 = [SCN-] mg/l

0.25 l/kg bw = distribution volume of SCN

70 kg = body weight

26 = molecular weight CN

10 m3= respiratory volume during an 8-hour day

 0.8 = conversion of cyanide to thiocyanate: ~ 80%

3.9 = elimination of thiocyanate, half-life = 2.7 d, residence time (t0.5/ln 2) = 3.9 d

58 = molecular weight SCN-

 

The derived safe inhalation concentration of cyanide anion for humans exposed for 8 hours at the workplace of 3.75 mg/m3can be used as a derived dose descriptor for the calculation of a DNEL for the worker.

Accounting for the larger molecular weight of KCN, this value is 9.4 mg/m3 .

Similarly, the value for oral/dermal is also calculated based on the thiocyanate level.

[CN-] mg/kg= [SCN-] mg/l × 0.25 l/kg bw × 26

                                    0.8 × 3.9 × 58

 

Where

15 = [SCN-] mg/l

0.25 l/kg bw = distribution volume of SCN

26 = molecular weight CN

0.8 = conversion of cyanide to thiocyanate: 80%

3.9 = elimination of thiocyanate, half-life = 2.7 d, residence time (t0.5/ln 2) = 3.9 d

58 = molecular weight SCN-

 

This equation results in a value of 0.54 mg/kg bw/d, and is the derived safe dermal concentration of cyanide ion for humans exposed for 8 hours at the workplace. A more detailed discussion is provided in the section of the Chemical Safety Report on DNELs. For KCN, this value is 1.35 mg/kg bw/d.

For animal data, the consensus NOAEL from the ECETOC Task Force for the repeated-dose oral exposure in the rat is 12.5 mg CN-/kg bw/d. The NOAEL for repeated-dose inhalation exposure in the rat is 10.4 mg CN-/m3. For sodium cyanide, this corresponds to 23.4 mg/kg bw/d and 19.6 mg/m3. 

Repeated-dose exposure to cyanides can result in two distinct categories of toxicity: general acute toxic effects (related to the mechanism of inhibiting oxygen utilisation in organs with high oxygen demand), and thyroid effects (via competition with iodine uptake and development of goitre as TSH levels increase).

Thyroid hormone secretion is highly regulated and maintained with significant species differences. Both rats and humans have a non-specific low affinity carrier of thyroid hormone, but humans, dogs and other primates also have T4 binding globulin. Rats lack T4 binding globulin and as a consequence the biological half-life of thyroid hormones in rats is about 10 fold shorter than in humans. This would suggest that the rat is more sensitive than humans to changes in thyroid hormone levels.

Study design must be examined to interpret the effects of cyanide in repeated dose studies.  There are often incorrect assumptions regarding the profile of dose delivery. In many studies, cyanide was administered in the form of a salt, either as a single oral bolus or as a food supplement. In both cases, the cyanide was in free form (not a glycoside) and would have been rapidly absorbed from within the gastro-intestinal tract. The profile of absorbed cyanide would peak shortly after dosing and contrasts with the slower, sustained release and absorption that occurred after dietary ingestion of cassava. It is also known that rats learn to avoid taste-aversive water solutions, which further promotes bolus dosing when thirst forces behavioral changes and forces drinking. The significance of this is that the peak in absorbed cyanide exceeded the limited detoxification (conversion to thiocyanate by rhodanese) capacity of the body, resulting in daily acute poisoning. These effects were likely to be due to inhibition of intracellular oxygen utilisation and cell death, particularly in organs with a high oxygen demand, such as the brain and testes. The dose response for the acute effects would have been effectively superimposed over the dose response for those effects that should be associated with circulating thiocyanate. The design and conduct of repeated-dose studies with cyanides are always extremely challenging due to the need to balance the objective of demonstrating significant chronic toxicity with the steep dose-response curve for acute toxicity.

 

Further confounding occurs in that repeated acute poisoning might have affected normal behaviour (decreased water intake and dehydration), caused stress and led to reduced food intake/weight-gain. This could explain why effects on the thyroid were not observed in other repeated-dose studies unless dietary intake and weight gain were markedly affected, such as in the case of the higher dose groups in the study of Philbrick et al (1979). Dehydration and resultant stress may play a role in onset of reproductive effects seen in the Hebert study (1993). Water intake and urine volume were significantly reduced, urine specific gravity was increased. Minor reproductive effects observed, such as decreased cauda epididymus weight and sperm motility, have been seen in dehydration and hibernation studies of species in the wild. No similar effects were observed in the 13-week study by Leuschner (1979) when effects were compared to an extra control group of rats which received equivalent amounts of water as those whose voluntary water intake was lowest (always the high-dose KCN group). 

 


Repeated dose toxicity: via oral route - systemic effects (target organ) glandular: thyroids

Repeated dose toxicity: inhalation - systemic effects (target organ) glandular: thyroids

Justification for classification or non-classification

Thyroid enlargement has been observed in occupational studies (some of questionable validity) as well as in human epidemiologic studies which followed populations ingesting cyanogenic glycosides in the diet. Animal studies of effects on thyroid are complicated by the presence of thyroid control mechanisms different from humans. Human thyroid effects indicate that classification and labeling of cyanide compounds should identify possible specific target organ toxicity (STOT) for the thyroid after chronic exposure.