Document ID: chunk:federal_register_of_legislation:F2013C00288:reg:3:p4
Version: federal_register_of_legislation:F2013C00288
Segment Type: reg
Provision Reference: reg 3 (pt 4/8)
Character Range: 2788270–2791167

by WHO (2000) indicates that PCE is a non-genotoxic animal carcinogen. Review of the possible mechanisms of tumour formation by PCE in animals suggests that the tumours observed may have little relevance for humans. This is subject to some debate, though recent reviews by WHO (2006) and US EPA (2012) have noted that, in the absence of suitable supporting evidence to the contrary, it must be concluded that the cancers produced by PCE in rodents are of potential relevance to humans.

From the weight of evidence, PCE does not appear to have significant genotoxic potential, however some of the possible metabolites are recognised Ames bacterial mutagens (WHO 2000; WHO 2006, RIVM 2001). Review of the available studies by WHO (2006) suggests that non-genotoxic mechanisms have been recognised for the formation of kidney tumours in male rats and liver tumours in mice for some chemicals. The available data on MoA for PCE are limited, and the dose–response data related to these recognised mechanisms are not consistent with the dose–response relationships for cancer induction by PCE. WHO (2006) has derived a threshold inhalation value for PCE that is considered protective of key end points including carcinogenicity. Hence it may be considered appropriate that a threshold dose-response approach be adopted for PCE.

Review of PCE by US EPA (2012) suggests that PCE has been shown to induce some genotoxic effects. There are a number of limitations noted in the assessment presented by US EPA, in particular, the fact that the MoA for PCE that induces carcinogenesis is not yet fully characterised or understood and that the role of genotoxicity in hepatocarcinogenicity is uncertain. Where US EPA lacks certainty, the default position is to be conservative and, as such, it has suggested considering PCE having a mutagenic MoA, where a non-threshold approach is recommended for the assessment of carcinogenicity and mutagenicity. This is not consistent with the approach adopted in this assessment (consistent with NHMRC 1999 guidance). The assessment of PCE should be updated should additional data become available that supports the US EPA review.

The following quantitative values are available for PCE from Level 1 Australian and International sources:
Source                Value                       Basis/Comments
Australian
ADWG (NHMRC 2011)     TDI = 0.014 mg/kg/day       The current ADWG (NHMRC 2011) have derived a guideline of 0.05 mg/L for PCE based on a NOEL of 14 mg/kg/day from a 90-day drinking water study in rats and mice, and an uncertainty factor of 1000. The uncertainty factor includes an additional 10-fold factor to address possible carcinogenicity.
International
WHO (2011)            TDI = 0.014 mg/kg/day       WHO DWG TDI based on the same study and uncertainty factor as noted in the ADWG (NHMRC 2011).
WHO (2006 and 2010)   TC = 0.2 mg/m3              TC