Diisotridecyl adipate

Carcinogenicity

Description of key information

Data on carcinogenicity are not available for diisotridecyl adipate. Data on di-2-ethylhexyl adipate (DEHA) as supporting substance are used for cross reading.
In a 103-week carcinogenicity study, DEHA was administered to F344 rats and B6C3F1 mice in the diet at levels of 12000 or 25000 ppm, equivalent to a daily intake of 600 or 1250 mg/kg bw/day in rats and 1715 and 3570 mg/kg bw/day in mice. In rats no tumors were found, whereas in mice the hepatocellular tumors were found in groups receiving remarkably high dose levels.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 715 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Reliability 2

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

Based on the available data in both mice and rats it is concluded that DEHA is not considered carcinogenic to man. The same statement is considered for the test substance diisotridecyl adipate.

At very high doses (1715 and 3750 mg/kg) hepatocellular carcinomas were noted at both dose levels in mice only; these carcinomas were related to peroxisomal proliferation; an effect that is threshold-driven and less relevant to man.

Therefore, the animal data are not considered sufficient for a strong presumption that human exposure to DEHA may result in cancer. There is limited evidence in experimental animals for the carcinogenicity of di(2 -ethylhexyl) adipate. The substance is not classifiable as to its carcinogenicity to humans (IARC, 77).

There are no data that are contradictory or provide evidence that diisotridecyl adipate would induce hyperplasia or pre-neoplastic lesions.

According to EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 classification is not warranted.

Additional information

In a 103-week carcinogenicity study, the read-across substance DEHA was administered to F344 rats and B6C3F1 mice in the diet at levels of 12000 or 25000 ppm, equivalent to a daily intake of 600 or 1250 mg/kg of body weight in rats and 1715 or 3570 mg/kg of body weight in mice (conversion based on data from the WHO report (2004)).

No test substance related tumors were found in the rat (no increased tumour incidences). In the (female) mice an increased number of hepatocellular carcinomas was found at both doses. Hepatocellular adenomas and carcinomas occured combined in high-dose mice of both sexes and in low-dose female mice at incidences that were dose-related and significantly higher than those in control mice. The association of liver tumours in male mice with the administration of DEHA was not considered to be conclusive because the increased number of liver tumours in males reflected only an increase in adenomas in the high-dose group and because the time to observation of tumours was not significantly different in dosed and control males (NTP, 1982).

DEHA does not show evidence of genotoxicity and does not form adducts with DNA.. The founded liver tumours in mice are under conditions of the bioassay where DEHA induces peroxisome proliferation and cell replication in liver that are characteristic of a peroxisome proliferation in mice and, to a limited extent, in rats. Marked species differences in hepatic peroxisome proliferation have been reported. While peroxisome proliferation may be readily demonstrated in cultured rat and mouse hepatocytes, such effects are not observed in hepatocytes from non-responsive species including guinea-pigs, primates and humans. Rodent peroxisome proliferators exercise their pleiotropic effects due to activation of PPARalpha. This process

is essential for liver hypertrophy and hyperplasia and eventual hepatocarcinogenesis in response to peroxisome proliferators. The PPARalpha-mediated regulation of gene expression in the human liver is different from the mode of action in mice and rats.

Hepatic peroxisome proliferation has not been evaluated in studies of human subjects or systems treated with di(2 -ethylhexyl) adipate. However, interspecies comparisons with other peroxisome proliferators, along with the role of PPARalpha in this response, indicate that humans can reasonable be predicted to be refractory to induction of peroxisome proliferation and hepatocellular proliferation by di(2 -ethylhexyl) adipate. Overall, these findings suggest that the increased incidence of liver tumours in mice treated with di(2 -ethylhexyl)adipate results from a mechanism that does not operate in humans. However, studies of di(2 -ethylhexyl) adipate or its metabolites regarding peroxisome proliferation in human cells are not available (IARC, Vol.77).

For diisotridecyl adipate, the same is valid. There are no data that are contradictory or provide evidence that diisotridecyl adipate would induce hyperplasia or pre-neoplastic lesions.

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