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Toxicological information

Carcinogenicity

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Description of key information

Phthalate esters have been shown to induce rodent liver tumours through mechanisms that are not relevant for human risk assessment.  

Key value for chemical safety assessment

Additional information

Phthalate esters have been the subject of a great deal of research with regard to their carcinogenic potential, with results from rodent chronic feeding studies consistently demonstrating an increased incidence of liver tumours despite an absence of genotoxicity. While no bioassay data are available for diisobutyl phthalate, information for the homologue diethylhexyl phthalate (DEHP) is considered relevant to an understanding of the carcinogenic potential of DIBP and is discussed briefly below.

The carcinogenicity of DEHP following oral exposure has been investigated in four long term animal studies in rats and mice (Moore 1996, 1997; NTP, 1982). The EU risk assessment for DEHP (EU, 2008) concluded that these studies were of good quality and adequate for an evaluation of the carcinogenicity of DEHP in experimental animals. Overall, the results provide evidence of hepatocarcinogenicity in male and female rats and mice, with statistically significant dose related increases in incidence apparent. In addition, an increase in the incidence of mononuclear cell leukaemia was also observed in rats which was significant only in males from one study (Moore, 1996). The overall LOAEL and the NOAEL for liver tumours and mononuclear cell leukaemia for rats was 147 mg/kg bw/d and 29 mg/kg bw/d, respectively; the LOAEL and the NOAEL for induction of liver tumours in mice was 292 mg/kg bw/d and 98 mg/kg bw/day, respectively (EU, 2008).

DEHP and its major metabolites are regarded as being non-genotoxic (EU, 2008) hence alternate (threshold-based) mechanisms are therefore likely involved.

When reviewing the relevance of DEHP-induced liver tumours in rats and mice to humans, IARC (2000) concluded that these arose through a non-DNA-reactive mechanism involving peroxisome- and hepatocellular proliferation, processes that had not been documented in human hepatocyte cultures exposed to DEHP or in the liver of exposed non-human primates. Overall, IARC concluded that there was inadequate evidence in humans for the carcinogenicity of DEHP. Based on similar mechanistic considerations, the EU (2008) also concluded that these rodent liver tumours were not relevant to human risk assessment.

The increased incidence of mononuclear cell leukaemia observed in F344 rats exposed to DEHP and other phthalates (e.g. diisononyl phthalate, diallyl phthalate, butylbenzyl phthalate) is believed to be a rat-specific effect of limited relevance for humans (Caldwell (1999), cited in EU (2008)).

Overall, the available information (especially results of mutagenicity and repeated dose toxicity testing) indicate that DIBP is a “typical” phthalate diester likely to cause liver tumours in rodents through an interaction with peroxisome proliferator activated receptors. As discussed above, such tumour findings are of limited relevance to human risk assessment and no classification is warranted. Furthermore, little would be gained by performing a cancer bioassay on DIBP itself and it is therefore proposed to waive this requirement.

EU (2003) European Union Risk Assessment Report: dibutyl phthalate, volume 29. Office for Official Publications of the European Communities, Luxembourg.

EU (2008) European Union Risk Assessment Report: bis(2-ethylhexyl) phthalate (DEHP), volume 80. Office for Official Publications of the European Communities, Luxembourg.

IARC (2000) Some Industrial Chemicals, Volume 77, International Agency for Research on Cancer.

http://monographs.iarc.fr/ENG/Monographs/vol77/index.php

Moore MR (1996) Oncogenicity study in rats with di(2-ethylhexyl)phthalate including ancillary hepatocellular proliferation and biochemical analyses. Corning Hazleton Incorporated, study CHV 663-134.

Moore MR (1997) Oncogenicity study in mice with di(2-ethylhexyl)phthalate including ancillary hepatocellular proliferation and biochemical analyses. Corning Hazleton Incorporated, study CHV 663-135.

Justification for classification or non-classification

Phthalate esters produce liver tumours in rats and mice through a non-DNA-reactive mechanism involving peroxisome proliferation and hepatocellular proliferation. The EU and IARC has concluded that these processes are not relevant to human risk assessment, and therefore no classification is necessary.