Oxalonitrile

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Justification for type of information:

Ethanedinitrile, hydrogen cyanide (HCN), potassium cyanide and sodium cyanide can be considered as a chemical category, along with and acetone cyanohydrin (ACH, also known as 2-hydroxy-2-methylpropanenitrile), based on structural similarity, common breakdown/metabolic products in physical and biological systems, and similar physico-chemical properties. Particular attention is paid to the dissociation constant of HCN. Ethanedinitrile breaks down in aqueous solution into cyanide ion (CN-) and cyanate ion (OCN-) (Cotton and Wilkinson 1980). Ethanedinitrile due to its low log Kow (0.07) and relatively high solubility in water (2.34 g/L) needs to get dissolved in aqueous solutions in lungs to enter the body. The rate of hydrolysis of ethanedinitrile is very fast (Ajwa 2015). Also, 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 therefore result from the activity of HCN. An ECETOC Task Force, in 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)” supports the development of the chemical category inclusive hydrogen cyanide, sodium and potassium cyanides. Hydrogen cyanide (Index No.006-006-00-X) and salts of hydrogen cyanides (Index No.006-007-00-5) are both listed in Annex VI, Table 3.1 of Regulation (EC) No. 1272/2008, entry 006-007-00-5, and are restricted in comparable ways taking into account physical characteristics. Thus, the assignment of ethanedinitrile to a chemical category does not result in a less protective regulatory status.

Data source

Reference

Reference 1

Reference Type:

review article or handbook

Title:

Unnamed

Year:

2006

Reference 2

Reference Type:

review article or handbook

Title:

Unnamed

Year:

2004

Reference 3

Reference Type:

publication

Title:

Unnamed

Year:

1988

Results and discussion

Clinical signs:

Cyanides
The effects of acute cyanide exposure are dominated by central nervous system and cardiovascular disturbances. Typical signs of acute cyanide poisoning include tachypnoea, headache, vertigo, lack of motor coordination, weak pulse, cardiac arrhythmias, vomiting, stupor, convulsions, and coma (Ballantyne 1983b, Way 1984, Johnson and Mellors 1988). Pathological findings may include tracheal congestion with haemorrhage, cerebral and pulmonary oedema, gastric erosions, and petechiae of the brain meninges and pericardium (Way 1984 as cited in WHO 2004). Sequelae of severe acute cyanide exposure may also include Parkinson-like syndromes and cardiovascular signs of delayed posthypoxic myocardial lesions, as well as neuropsychiatric manifestations similar to those seen with post-hypoxic post-carbon monoxide encephalopathy (Uitti et al. 1985, Carella et al. 1988, Kadushin et al. 1988, ATSDR 1991 - as cited in WHO 2004).

Symptoms of poisoning
1. High exposure (high dose) may lead without any warning to sudden unconsciousness and respiratory arrest resulting in immediate death.

2. With lower, but still lethal exposure (dose), the poisoning symptoms may be delayed for one to several hours. Ingestion is followed by bitter, pungent, burning taste quickly getting stronger, and by contraction and desensitising of oesophagus. Salivation, nausea and vomiting may also occur.

3. Anxiety, confusion, dizziness and often feeling of stiffness of lower jaw.

4. Deep breathing and breathlessness. Breathing is very fast and then slow and irregular. Typically, breathe in is short, while breathe out very long.

5. Bitter almonds odour in breath or vomitus.

6. Early phase of poisoning includes an increasing vasoconstrictor tonus (narrowing of blood vessels), which is a cause of increased blood pressure and slowed heart pulse. Pulse gets faster, weaker and irregular. Accumulation of oxyhaemoglobin in venous blood causes bright pink colouration of skin and may be confused with carbon monoxide poisoning (Gosselin 1984 as cited in ATSDR 2006).

7. Strong convulsions are quickly followed by unconsciousness, sometimes accompanied by involuntary emptying.

8.Convulsions lead to paralysis. Skin is covered with sweat, eyes are bulging, and pupils are dilated and unresponsive. Froth appears at the mouth, sometimes mixed with blood. Skin may have brick-red colour. Cyanosis may not be apparent despite weak, irregular breathing. Unconsciousness may be accompanied by bradycardia, and cyanosis absence may be crucial for determining diagnosis.

9. Death caused by respiratory failure – if heart is still beating – may be reversed if immediate resuscitation and medical help are applied (Gosselin 1984 as cited in ATSDR 2006).

Serious HCN poisoning begins with quick onset of toxic effects including fainting, seizure, respiratory coma and cardiovascular failure, which may cause death within several minutes.

Applicant's summary and conclusion

Conclusions:

No clinical cases and poisoning incidents are available for ethanedinitrile.

1) Hydrogen cyanide vapours are absorbed through skin and mucous membranes surface. They are hazardous and toxic when inhaled but also when the skin is exposed.

2) Clinical picture of acute hydrogen cyanide poisoning: Superacute poisoning is the result of an unexpected high concentration of HCN, with unconsciousness occurring within only 10–20 seconds, followed by death in convulsions within 2–3 minutes. Acute poisoning symptoms include headache, dizziness, vision disorders, pressure in chest, rapid breathing and pulse, followed by asphyxiation and unconsciousness, and clonic and tonic convulsions, and finally respiratory and cardiac arrest. Mild poisoning symptoms include headache, dizziness, hearing problems, sore throat, and visual impairment and breathing problems. The patient is fully conscious and complete recovery is possible.

3) Clinical picture of chronic hydrogen cyanide poisoning: Chronic poisoning may result from repeated effects of small doses of hydrogen cyanide (cyanides) on organism for a longer time mostly due to regular consumption of food containing cyanogenic glycosides, or to repeated occupational exposures. Persons regularly exposed to effects of HCN have an increased red blood cells count, hypothyreosis as well as neurologically detected changes.

4) Acute toxic levels and doses: The dose-effect curve of the acute effects in humans is steep. Whereas slight effects occur at exposure to hydrogen cyanide levels of 20–40 mg/m3, 50–60 mg/m3 can be tolerated without immediate or late effects for 20 min to 1 h, 120–150 mg/m3 is dangerous to life and may lead to death after 0.5–1 h, 150 mg/m3 is likely to be fatal within 30 min, 200 mg/m3 is likely to be fatal after 10 min, and 300 mg/m3 is immediately fatal.

5) Effective and no-effect levels for chronic exposures: Workers exposed to HCN concentrations 17 mg/m3 revealed a high prevalence of neurological, cardiovascular and gastrointestinal symptoms; after exposure to 5–13 mg/m3 for seven years showed in a large extent of subjective symptoms (headache, weakness, ao).

Executive summary:

 

No clinical cases and poisoning incidents are available for ethanedinitrile.   Cyanide poisoning in humans has two signs. Insufficient consumption of molecular oxygen in peripheral tissues is the result of a high concentration of oxyhaemoglobin in venous blood and causes brick-red or pink colouring of the skin. The organism is trying to even the oxygen exchange inhibition which leads to increased requirements of glycolysis which is responsible for metabolic acidosis (Swai 1992). The most specific aspect of acute poisoning by hydrogen cyanide is bright red colour of venous blood (pathological examination), clear evidence of the tissue cells inability to utilise oxygen. After recovery from hydrogen cyanide poisoning so called after effects may occur for long time: physical and mental tiredness, muscular hypotonia, ataxia and a number of nervous and mental disorders (Ballantyne 1988). The signs of cyanide toxicity at concentrations leading to death in humans are well described. Intoxication at ≥2,000 ppm hydrogen cyanide is characterized by a brief sensation of dryness and burning in the throat due to local irritation, a suffusing warmth, and a hunger for air. Hyperpnea, and sometimes a brief outcry, follows the first breath. In <1 minute, apnea, a few gasps, loss of consciousness, and convulsions occur. Cardiovascular failure may also occur, although the heart may continue to beat for 3-4 minutes after the last breath. Reported signs sometimes include a bitter almond-like odour on the breath and (in light-toned individuals) a rose-coloured hue of the skin. The total absorbed dose of hydrogen cyanide in such rapid deaths can be as low as 0.7 mg/kg. Dyspnea has been observed in survivors of inhalation poisoning incidents, and renal dysfunction (anuria followed by polyuria) was observed in one fatal inhalation exposure case. Similar signs of respiratory distress and renal dysfunction (albuminuria) were reported following ingestion of high doses of cyanide salts. Within a few minutes after swallowing the toxicant, the victim collapses, frequently with a scream. Dyspnea, convulsions, and death from asphyxia follow. Based on case report studies, the following acute median lethal exposure levels for humans were estimated: an LC50 of 524 ppm for a 10-minute inhalation exposure to hydrogen cyanide, an LD50 of 1.52 mg/kg for the oral route, and an LD50 of 100 mg/kg for the dermal route, assuming that CN^-is readily released from the compound. Animal studies also report dyspnea, convulsions, and asphyxiation as effects of high-acute exposure to cyanide by any route of exposure. Nonlethal exposures to hydrogen cyanide gas produces upper respiratory irritation, cough, altered sense of smell, nasal congestion, epistaxis, hemoptysis, and dyspnea in exposed workers. Workers acutely exposed toethanedinitrile, which dissociates into hydrogen cyanide and hydrocyanic acid, experienced nasal irritation. Other effects observed at nonlethal exposure levels include hypotension, heart palpitations, precordial pains, nausea and vomiting resulting from central nervous system stimulation or direct contact with cyanide, and albinuria. Animal studies also report bradycardia, arrhythmia, and T-wave abnormalities, vomiting, increased blood urea nitrogen, and histopathology of the renal proximal tubular epithelium and glomeruli. Hepatic effects have not been reported in humans, but have been observed in some animal studies.