Lack of rapid initiating, promoting or sequential syncarcinogenic effects of di(2-ethylhexyl)phthalate in rat liver carcinogenesis.

The effect of prolonged dietary administration of the peroxisome proliferating plasticizer di(2-ethylhexyl)phthalate (DEHP) was studied on liver carcinogenesis initiated by N-2-fluorenylacetamide (FAA) and compared with that of the neoplasm-promoter phenobarbital (PB). Also, DEHP was studied as an initiator by giving it in place of FAA before PB. Male rats were fed FAA for 7 weeks to induce hepatocellular altered foci, and were subsequently given no chemical, 12,000 p.p.m. DEHP or 500 p.p.m. PB for 24 weeks in the diet. In the rats fed DEHP, substantial hepatomegaly and peroxisome proliferation were induced. No evidence of induction of hepatocellular altered foci or hepatic neoplasms was found either when DEHP was given alone for 24 weeks or for 7 weeks followed by PB. Also, DEHP fed for 24 weeks had no promoting effect on liver altered foci that were induced by FAA and produced little or no enhancement of the occurrence of FAA-induced liver neoplasms. In contrast, PB exerted a marked enhancing effect on foci and substantially increased the incidence and multiplicity of liver neoplasms. Thus, the findings demonstrate that DEHP did not have either a rapid initiating activity, a significant sequential syncarcinogenic activity, or a promoting effect on liver carcinogenesis under conditions in which numerous agents with such activities have been identified.