Evaluating the potential carcinogenic hazard of diisononyl phthalate in humans via systematic integration of human, animal cancer studies, and mechanistic data

• A systematic evaluation assessed the carcinogenic potential of DINP in humans. • No reliable epidemiological evidence of association between DINP and cancer. • Liver and kidney tumor modes of action (MoAs) are rodent-specific. • Mechanistic data support key events for rodent-specific tumor MoAs. • Overall, evidence supports that DINP is not anticipated to be a human carcinogen. Diisononyl phthalate (DINP) is a high molecular weight phthalate used in commercial products and polyvinyl chloride production. Herein, a systematic evaluation of DINP evidence streams (i.e., human cancer, animal cancer, and mechanistic data) was carried out to inform carcinogenic hazard in humans. Relevant data from peer-reviewed literature and publicly available laboratory reports were extracted and critically appraised. Mechanistic data were organized according to the Key Characteristics of Carcinogens (KCCs) and integrated into key events in rodent cancer modes of action (MoAs). Evidence from epidemiological studies is limited, but does not indicate an association between DINP exposure and cancer, with three studies reporting no association with breast cancer, and one reporting an imprecise increase in prostate cancer risk. Four chronic bioassays demonstrated DINP causes cancer in rodents, with increases in liver tumors in mice and rats, kidney tumors in male F344 rats, and mononuclear cell leukemia (MNCL) in F344 rats. Mechanistic data strongly support that DINP is non-genotoxic (KCC2), and that in rodents DINP induces oxidative stress (KCC5) and alters cell proliferation (KCC10). Multiple evidence stream integration and interpretation support that DINP elicits rodent-specific liver tumors through the peroxisome proliferator-activated receptor alpha, a MoA widely considered to lack human relevance. Likewise, the weak kidney tumor response in male rats was attributed to α2u-globulin nephropathy, a male rat-specific response. MNCL, a common lesion in aging F344 rats, was not considered relevant for predicting human cancer. Together, these data indicate that DINP is unlikely to pose a carcinogenic hazard to humans.