Carcinogenic potential of phthalic acid esters and related compounds: structure-activity relationships

Chronic toxicity and carcinogenicity studies of several phthalic acid esters (PAEs) and compounds containing a 2-ethylhexyl moiety were conducted in Fischer 344 rats and B6C3F1 (hybrid) mice. The compounds studied were phthalic anhydride, di(2-ethylhexyl) phthalate, butyl benzyl phthalate, diallyl phthalate, di(2-ethylhexyl) adipate, tris(2-ethylhexyl) phosphate, and 2-ethylhexyl sulfate (sodium salt). Estimated maximum tolerable doses and fractionally lower doses of each compound were administered to groups of 50 male and 50 female rats and mice for 2 years, followed by sacrifice, necropsy, and histopathological examination of major organs and tissues. The low toxic potencies of most of the compounds allowed for relatively high doses to be given during the chronic studies. In general, the toxic manifestations of the PAEs were closely correlated with their ester substituents. Although many of the PAEs possessed some carcinogenic activity, target sites for such effects were dissimilar, suggesting the absence of a common mode of action. In contrast, all of the 2-ethylhexyl-containing compounds studied possessed some hepatocarcinogenic activity, indicating that this moiety may have a propensity for causing hepatocarcinogenesis in mice, particularly those of the female sex. The 2-ethylhexyl compound that caused the greatest hepatocarcinogenic response in mice, di(2-ethylhexyl) phthalate, was also hepatocarcinogenic in rats. Similarly, those with a relatively greater effect in female mice were also active in male mice. Thus, sex and species differences in 2-ethylhexyl-induced hepatocarcinogenesis in rodents are probably quantitative rather than qualitative in nature.