Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
13 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
10 mg/m³

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose toxicity studies on cyanides of relevance for the human exposure situation have been conducted by the oral and inhalation route. Some of the oral studies were designed to evaluate the impact of cassava diets on animal health and included groups that received cyanide supplemented food diets for comparison of the effects.

When reviewing the existing oral studies on cyanides, the only well controlled repeated-dose studies are the 90 -day drinking-water study in rats and mice by Hebert (1993), the 13 -week study of KCN by Leuschner (1989) and the 90 -day inhalation study in rats by Monsanto (1984). In those three studies, no effect on the thyroid weight or histopathology were observed up to the highest dose tested. In the Monsanto study no effects were observed on thyroid hormones up to the highest dose tested and the NOAEL for thyroid effects seems to be higher than that for general toxicity. Furthermore, as the adminstered dose levels were limited by the acute toxicity of cyanide it can be concluded that thyroid toxicity will not occur in animals at concentrations that are not acutely toxic.

The selection of the thyroid gland as the target organ derives from the general absence of toxicity in the subchronic studies and observations from the only chronic oral study of cyanide (Philbrick et.al., 1979). A LOAEL of 40 mg CN ion/kg/d is established for thyroid effects, as this amount of cyanide obtained from KCN added to the diet of rats for 1 year resulted in increased thyroid gland weight and decreased thyroxine secretion rate (both normalized to body weight). This is supported by mechanistic work which demonstrates that cyanide ion decreases the secretion of T4 hormone with resultant stimulation of T4 production by thyroid stimulating hormone.

 

The repeated-dose studies apparently fall into two distinct categories: those that relate thyroid effects to cyanide exposure and others that do not observe this effect up to generally toxic dose levels. The apparent NOELs for general toxicity related to the mechanism of inhibiting oxygen utilisation, in particular in organs with high oxygen demand, such as brain and testes in the first group of studies are higher than (approximately double) the acute LD/LC50 values reported in rats using the same routes of exposure. This can be explained by the kinetics of the detoxification reactions. It is understood that sustained, lower-level exposures to CN ion are better accommodated by the detoxification mechanisms (conversion to thiocyanate) in animals. Acute exposure to levels that are above the detoxification capacity will result in direct HCN-mediated cell toxicity and death particularly in tissues with a high oxygen demand, such as the brain. Hence, by spreading the applied dose over a longer exposure period a higher total dose per day can be tolerated.

 

Studies of occupationally exposed workers and epidemiology studies of human populations are informative for understanding repeated dose exposure to cyanides. In some of the occupational studies a number of symptoms consistently observed following acute cyanide poisoning were reported by worker with, presumably, repeated exposure to cyanide. However, considering the mode of action of cyanide as a respiratory poison and the likelihood that repeated exposures to acutely toxic levels of cyanide cannot be ruled out, the weight of evidence would point to these symptoms being more consistent with acute cyanide poisoning than repeated (chronic) lower level exposure.

In a number of the occupational studies repeated exposure to cyanide had an effect on the thyroid and thyroid hormones. This is consistent with the primary mode of detoxification of cyanide to thiocyanate in the body and the fact that although less toxic than cyanide, chronic exposure to thiocyanate can exacerbate the effects of low iodine content in the diet and result in goitre and thyroid hormone imbalance. However, based upon the work of Hennartet al.(1982) and Knudsen et al. (2002), there is support for the conclusion that the thyroid is not a repeat STOT for cyanide in populations with adequate dietary iodide.

It should be recognized that normal individuals with sufficient dietary iodide have a capacity to detoxify cyanide and eliminate it in the urine. Under these conditions there are no significant target organs for repeat-dose cyanide toxicity and any toxicity observed is due to acute, single exposure toxicity. This is consistent with the extremely steep dose-response of cyanide poisoning reflecting the finite detoxification capacity of the body.

 


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
valid scientific study

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
valid scientific study

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: epididymides

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

Justification for classification or non-classification

When considering the global mechanism of action of the CN- ion as a respiratory toxin (binding irreversibly to cytochrome c oxidase), it is concluded that there are no specific target organs for toxicity to cyanide. However, in reviewing the data from dietary studies in human populations, there is evidence for the existence of sensitive subgroups of individuals with dietary deficiency of iodide who may be susceptible to cyanide's effects on the thyroid gland (decreasing T4 with resultant increase in serum TSH). Individuals with impaired renal function would be especially vulnerable. Considering the breadth of the population with iodine deficiency, it is not possible to discount the chance that such persons may have contact with cyanides. Hence, out of an abundance of caution, STOT-RE Category 1, H372, for the thyroid gland, is applied to protect and inform this sensitive subgroup of workers.