Oxalonitrile

Carcinogenicity

Description of key information

Ethanedinitrile

The inhalation route is only possible route of admission of ethanedinitrile. Due to a toxikokinetics of ethanedinitrile the long-term studies on cyanides with various routes of admition might be also considered for the assessment. There were no histopatological changes connected to carcinogenicity noted in the long-term toxicity study with ethanedinitrile.

Cyanides

Cyanide has not been reported to cause cancer in people or animals. EPA has determined that cyanide is not classifiable as to its human carcinogenicity (ability to cause cancer in humans) (ATSDR 2006).

There is no evidence that cyanide exposure is correlated with carcinogenicity in humans or animals.

Cyanide has only an indirect genotoxic effect in vitro and in vivo in that dying cells release endonucleases into the cytosol, ultimately resulting in DNA fragmentation (ATSDR 2006).

 

There are no reliable data on carcinogenicity in animals. However, because of the steep dose-response relationship, it would, from a practical perspective, be extremely challenging to conduct a long-term study whilst maintaining near toxic levels of CN. In a limited 2-year dietary study in rats there were no indications of carcinogenicity in animals fed with diets fumigated with maximum tolerated doses of HCN (JACC I 2007).

 

 

The only available chronic study of cyanide that analyzed a wide variety of tissues following near lifetime exposure is an oral rat study (Howard and Hanzal 1955); no tumors or lesions were associated with either dose group following dietary administration of cyanide at doses up to 10.8 mg/kg per day for 2 years. This study is limited by small sample sizes (10/group), histopathologic assessment of only a subset of potential target organs of carcinogenicity, and uncertainty regarding dose due to volatility. Overall, the data are inadequate for an assessment of the human carcinogenic potential of cyanide, based on EPA’s Guidelines for Carcinogenic 90 Risk Assessment (U.S. EPA 2010). Therefore, no quantitative cancer assessment was conducted.

The results of NTP combined chronic toxicity – carcinogenicity study of acetonitrile in rats and mice (NTP 1996) offer an adequate substitute.Extensive two-year inhalation chronic toxicity–carcinogenicity studies with acetonitrile in concentrations 168–670 mg/m³(rats) and 84–335 mg/m³(mice) did not identify any significant treatment-related effects on survival, general health, behaviour, body weight or organ weights in either species. Complete necropsy and histological examination gave no evidence of exposure-related non-neoplastic lesions in rats or mice. Non-significantly higher incidence of hepatocellular adenoma and carcinoma in the highest exposure group of male rats was evaluated as equivocal: the incidences remained in the range of historical controls. The relevance of higher incidence of lung tumours in male mice is dubious with respect to increased survival in the highest exposure group of males, and to extremely wide range of historical controls. The incidence of hepatocellular adenoma or carcinoma in male mice was not a monotonous function of exposure concentration.

Conclusions

Extremely narrow interval between the lowest effective doses and lethal doses of cyanides renders a carcinogenity study not feasible. Even if such study would be attempted, the interpretation of the results could not eliminate the possibility that the effects are secondary to acute cell injury or destruction resulting from unavoidable cyanide concentration peaks.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Justification for classification or non-classification

CLP criteria not met