2-ethylhexan-1-ol

Carcinogenicity

Description of key information

2 -EH was not carcinogenic in two valid long term rodent studies using F344 Fischer rats and B6C3F1 mice of either sex.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

750 mg/kg bw/day

Study duration:

chronic

Species:

other: rats and mice

Quality of whole database:

The key studies are GLP compliant and of high reliability (Klimisch score 1).

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

2 -EH was not carcinogenic in two valid oral long term rodent studies using rats and mice of either sex. No classification according to Regulation (EC) no 1272/2008 is therefore required.

Additional information

The carcinogenic potential of 2 -EH was examined in two rodent long term studies under GLP and in accordance with OECD TG 451, using male and female Fischer F344 rats (dose levels 0, 50, 150, and 500 mg/kg bw/day) and B6C3F1 mice (dose levels 0, 50, 200, and 750 mg/kg bw/day). The studies are reported in the publication of Astill et al. (1996, rat and mouse).

For rats there are two volumes containing the original two study report of BASF (Küttler, 1992; Hellwig et al., 1992). For mice the results are summarized in another BASF report (Hellwig et al., 1991).

2 -EH was neither carcinogenic in male or female rats in the 2 -year study, nor in male mice exposed for 18 months. A weak, or equivocal, carcinogenic potential was seen in female mice since the incidence of hepatic carcinoma was significantly increased in high dose females compared to the vehicle control group (p<0.05). However no hepatic adenomas were observed in the top dose group.

In the study with Fischer 344 rats, in both sexes the sum of primary tumours, the sum of benign tumours and the sum of malignant tumours was lower in the top dose group than in either the vehicle control or the water control groups. The NOAEL (carcinogenicity) was therefore 500 mg/kg bw/day in male and female rats. A dose related increase in mortality was observed in female rats, with 52% mortality in those given 500 mg/kg bw/day 2-EH. Dose related reductions in weight gain were observed (for males: -5% at 50 mg/kg bw/day, -11% at 150 mg/kg bw/day, -23% at 500 mg/kg bw/day; for females: -9% at 150 mg/kg bw/day, -21% at 500 mg/kg bw/day). Increased focal lesions and lung discoloration was observed in rats at 500 mg/kg bw/day. The 50 mg/kg bw/day dose produced a 6% increase in relative female stomach weight. Significant increases in stomach, kidney and brain relative weights were observed in male rats at 150 mg/kg bw/day 2-EH, with testis relative weight increased at 500 mg/kg bw/day. Female rats had significantly increased relative weights of stomach, liver, kidney and brain at the 150 and 500 mg/kg bw/day doses. The effects seen on relative organ weights at 150 mg/kg bw/day were not accounted for as adverse as these presumably were due to the reduced body weights observed at the same dose levels. The NOAEL for systemic toxicity therefore was 150 mg/kg bw/day in this study based on the increased mortality and other effects in the high dose group (Astill et al., 1996).

In the study with mice, at the top dose of 750 mg/kg bw/d 2-EH caused a reduction of body weight gain in both sexes at early stages of the study (approx. from study week 6 onwards), a reduced terminal body weight, and an increased mortality of up to 30% in week 78. Relative organ weight changes were mostly limited to the top dose groups as evidenced by statistically significantly increased relative weights of the stomach, liver, brain and testes in males, and of the stomach, liver, kidneys, and brain in females.  

No neoplastic lesions were seen in males. In top dose females, the incidence of hepatocellular lesions (basophilic foci and carcinoma) was significantly increased, but this was attributed to the toxicity (fatty infiltration of the liver was also observed) that was associated with the high dose (750 mg/kg bw/d).

This was supported by the observation that the incidence of liver carcinoma was high (50%) in decedents. The NOAEL (carcinogenicity) was therefore 750 mg/kg bw/day in male and female mice. The NOAEL for systemic toxicity was 200 mg/kg bw/day in this study. Overall it is concluded, that 2-ethylhexanol was not oncogenic in B6C3F1 mice in a valid GLP carcinogenicity study (Astill et al., 1996). 

The authors of the carcinogenicity study provided data, which indicate that the increased incidences of hepatic carcinoma in female mice that were seen associated with DEHP, DEHA, or other compounds, which may liberate 2-EH during their metabolism, is unlikely to be caused by 2-EH (e.g. different tumour pattern; Astill et al., 1996).

Taken from various studies (see IUCLID section 7.5 or 7.9.3) it is known that 2-EH is a peroxisome proliferator in rodents. However, peroxisomal proliferation is not a plausible explanation for the increased incidence of liver tumours in female mice. In rats, doses which induced peroxisomal proliferation in a 90-day toxicity study (500 mg/kg bw/day) did not cause liver tumours in the 2-year carcinogenicity study of the same species.

It is moreover unknown, whether at the doses tested in the carcinogenicity study in mice peroxisomal proliferation occurred, as no increase of hepatic CN-insensitive palmitoyl coenzyme A activity was observed in a 90-day toxicity study in mice tested up to 500 mg/kg bw/day.

Justification for selection of carcinogenicity via oral route endpoint:
weight-of-evidence: two reliable studies available showing negative results for carcinogenicity after 2-EH administration to either rats or mice. Furthermore, a carcinogenicity study is not required, as the substance is not mutagenic and there are no relevant hyperplasias of pre-neoplastic lesions observed in any available repeated dose toxicity study.

Justification for selection of carcinogenicity via inhalation route endpoint:
Carcinogenicity study neither available nor required (see justifaction for endpoint selection oral route for further details).

Justification for selection of carcinogenicity via dermal route endpoint:
Carcinogenicity study neither available nor required (see justifaction for endpoint selection oral route for further details).

Carcinogenicity: via oral route (target organ): digestive: liver