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Toxicological investigation of di(2-ethylhexyl)phthalate in rats. The determination of a no-observed-effect-level

Synopsis

Two animal experiments are described in which male rats have been exposed to di(2-ethylhexyl)phthalate (DEHP) for 2 and 4 weeks. Besides morphometric analysis using both light and electron microscopy, a number of enzyme parameters in liver homogenates have been determined which have a relation with the proliferation of peroxisomes in hepatocytes, such as palmitoyl coenzyme-A oxidase (PCO), enoyl coenzyme-A hydratase (ECH), carnitine acetyl transferase (CAT), catalase (cat) and lauric acid hydroxylase (LAH). Glutamate dehydrogenase (GIDH) was measured as a control enzyme for mitochondria. For all enzymes, except GIDH, a dose-response relationship was observed. There were not many differences between the results of the parameters examined in the 2 and 4 weeks exposed animals. In the 2 weeks exposure experiment, the enzyme parameters appeared to be slightly more sensitive. Therefore the parameters from this experiment were taken for determination of the doses-without-effect (DWE). Also the morphometric analysis has been performed on the 2 weeks-experiment. Although CAT turned out the most sensitive parameter, this enzyme activity was not considered in the establishment of an overall no-observed-effect-level since it is not specific for peroxisome proliferation. The second most sensitive parameters were the morphometric analysis and the induction of LAH and ECH activity (DWE = 5 mg/kg b.w./day) followed by PCO (DWE = 18 mg/kg b.w./day). Catalase activity was not a very sensitive parameter (52 mg/kg b.w./day). An overall no-observed-effect-level for DEHP was established as 5 mg/kg b.w./day, based on the parameters mentioned for peroxisome proliferation.
 

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