Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
other: review article or handbook
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Experimental data was reviewed by the ECETOC Task Force, author of the 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)”, 2007. The report is a weight of evidence approach to an extensive body of literature, much of which was undertaken prior to development of guidelines. The report was peer reviewed by the scientific non-governmental organization (NGO), which judged the data to be reliable with restrictions.

Data source

Reference
Reference Type:
review article or handbook
Title:
Unnamed
Year:
2007

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Various methods have been employed to study the toxicokinetics of HCN. This data was reviewed by the ECETOC Task Force, author of the JACC Report No. 53 on Cyanides, and judged to be valid.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Radiolabelling:
other: some studies utilized radiolabelling

Results and discussion

Preliminary studies:
The toxicokinetics of cyanide are based on its physico-chemical properties. As HCN is a relatively weak acid, with a pKa value of 9.11 at 30°C, at the physiological pH of about 7, HCN is distributed in the body as such and is not present as CN anion. Hence, the form of cyanide, to which exposure takes place, i.e. a simple salt or the free acid, does not influence the distribution, metabolism or excretion from the body.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Cyanides can be absorbed by inhalation, dermal uptake, intraocular administration and ingestion. Absorption of gaseous HCN is related to the water solubility of HCN and the ease of absorption in the moist respiratory tract. On the basis of experimental observations, the retention of HCN in the nasal passages was reported to be between 13 and 23% (average 19%) and the retention in the lung from mouth breathing between 39 to 77% (average 61%). From this an average retention in the respiratory tract of 50% is estimated. Probably the majority of the HCN retained in the respiratory tract is absorbed into the blood as it is likely to diffuse readily due to its water solubility, low molecular mass (size) and the fact that it is undissociated at cellular pH. All cyanides ingested will be present, at the physiological pH of the stomach, as HCN. The HCN is absorbed in the blood via the stomach wall and in the intestines. Cyanide is able to be absorbed through the skin from aqueous solutions or from gaseous sources. The permeation of cyanide from aqueous solutions of NaCN through human skin in vitro was strongly influenced by the pH of the solution. HCN appeared to permeate 30 times faster than CN ion. At a pH of 9.11 (= pKa) about 50% is present as undissociated HCN. The ratio of HCN and CN ion at a certain pH follows from the Henderson-Hasselbach equation. Dermal absorption from airborne HCN must take into account (i) the stagnant concentration at the skin surface (default 3 cm simulating clothing), (ii) from the stagnant air to water layer on the skin and (iii) from the water layer into the skin. Using an overall permeation coefficient (Kp skin-air-air) for HCN of 6.25 cm/h, it has been calculated that the ratio of absorption by skin compared to lung for HCN is 0.18 or 18%.
Details on distribution in tissues:
HCN is not equally distributed through the body. In Beagle bitches an apparent distribution volume of 0.209 l/kgbw for HCN (from administered KCN) was found. A complete analysis of the body distribution in humans (3 fatally poisoned persons) showed that 50% of the absorbed cyanide was present in the blood, about 25% in the muscles and the remaining 25% in all the organs together. The apparent distribution volume was 0.075 l/kgbw. Measuring total blood levels provides useful information on the total body burden of HCN.
Details on excretion:
Thiocyanate, cobalamin, formates and 2-imino-4-thiazolidine carboxylic acid are excreted via the urine. HCN and CO2 are exhaled.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Thiocyanate is the major metabolite. Cyanocobalamin, formates and 2-imino-4-thiazolidine carboxylic acid are minor metabolites.

Any other information on results incl. tables

The main pathway of transformation of cyanide into thiocyanate is catalysed by the enzyme rhodanese, a mitochondrial enzyme that occurs in many tissues. The other enzyme capable of converting CN ion to thiocyanate is 3-mercaptopyruvate sulphotransferase in liver and erythrocytes. In the rat, the olfactory bulb showed the highest rhodanese activity. Rhodanese activity was also high in the thalamus, septum, hippocampus and dorsal part of the midbrain, but low in the cerebral cortex. The distribution in human brain post mortem was essentially the same as in rat brain. 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. The maximum detoxification rate is approximately 3.0 μg CN ion/kgbw/min (80 minutes 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 3 to 8. However, rhodanese is present in all body tissues in considerable excess and is not rate-limiting, unlike thiosulphate, which may be only available in the body in small amounts depending on the nutritional status. No major polymorphisms have been identified to date. Protein deficient populations are more susceptible to cyanide intoxication as thioamino acid levels are reduced.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Regardless of whether the exposure is to gaseous HCN or via a soluble cyanide salt, it is HCN which is absorbed into the blood after oral, dermal or inhalation exposure. Its absorption is rapid. HCN is distributed preferentially from the blood to muscles, and then to all other organs with an apparent distribution volume was 0.075 l/kgbw. There is a first-pass effect in the liver, from orally absorbed cyanide. Cyanide is metabolized via enzymatic (rhodanese) trans-sulphuration into thiocyanate, primarily in the liver and muscles. The overall maximum detoxification capacity in humans is limited to about 0.008 mg CN ion/kgbw/min, while detoxification rates for other species ranged between 0.01 and 0.03 mg CN ion/kgbw/min.