19085-1701857-UL_Prop_65_Test_Results_2019

CA Prop 65 Cumene NSRL February 11, 2019 Page 6 | 12
3 APPROACH TO DOSE-RESPONSE ANALYSIS
The mechanism(s) by which cumene might cause carcinogenic effects are not understood. It is
unlikely that for any chemical a single mechanism or mode of action will fully explain the multiple
biological alterations and toxicity pathways that can cause normal cells to transform and
ultimately form a tumor. However, potential modes of action or molecular alterations have been
identified. Cumene was associated with neoplasms in several tissue types in rats and mice and
the tumor profiles showed some distinct species and gender differences. Renal tumors were
observed in male rats only, while lung tumors were observed in mice but not in rats. Several
potential modes of action or molecular alterations associated with carcinogenesis have been
identified, including genetic and epigenetic effects, metabolic activation to reactive metabolites
and cell proliferation, and 2u-globulin nephropathy. Proposed mechanistic considerations are
not mutually exclusive and more than one mechanism might operate in a particular tissue.
Although the precise mechanism of carcinogenesis for cumene is not known, following US EPA
and OEHHA guidance for carcinogenic risk, a genotoxic mode of action is presumed. There are
insufficient data to support dose adjustments based on pharmacokinetic models. Therefore, the
default approach (i.e., a linearized multistage model and interspecies scaling) has been applied.
The approach used is described in detail in Appendix A.
4 DOSE-RESPONSE ASSESSMENT
Animal cancer potency estimates were derived for cumene by fitting the multistage model to the
dose-response data from the NTP 2009 studies for all tumor types showing significant
treatment-related dose response effects (Tables 1-2). Multiplying the animal cancer potency
estimates derived from the NTP (2009) studies by the applicable interspecies scaling factor (see
Appendix A) gives an estimate of human cancer potency. The results are summarized in Table
3 below. More details on the derivation of the estimates are provided in the Appendix A.