Subchronic toxicity of Di(2-ethylhexyl)phthalate in common marmosets: lack of hepatic peroxisome proliferation, testicular atrophy, or pancreatic acinar cell hyperplasia.
To evaluate the toxicological effect, di(2-ethylhexyl)phthalate (DEHP) was administered orally at 100, 500, and 2500 mg/kg to four male and four female marmosets in each group for 13 weeks. Its potentials of hepatic peroxisome proliferation, testicular atrophy, and pancreatic acinar cell hyperplasia were evaluated more closely. Clofibrate, which potently causes peroxisome proliferation in rodents, was administered in like manner at 250 mg/kg as a reference drug. DEHP induced significant suppression of weight gain in males at 2500 mg/kg. However, the increase in liver mass and hypertrophy of hepatocytes were not detected in organ weight measurements or histopathological examination. The number of peroxisomes, volume density, peroxisome morphology, and peroxisomal enzyme activities were not different from those in the control group, though the males treated with 500 and 2500 mg/kg DEHP showed 1.3- and 1.4-fold increases in mean peroxisome volume, respectively. In contrast, clofibrate induced 2.2 (in male)- and 1.9-fold (in female) increases in hepatic cyanide-insensitive acyl CoA oxidation system activity, 1. 2 (in male)- and 1.7-fold (in female) increases in hepatic carnitine-dependent acetyltransferase activity, and 1.8 (in male)- and 3.0-fold (in female) increases of carnitine-dependent palmitoyltransferase activity. Cytochrome P-450 contents tended to increase in all males and females administered 500 and 2500 mg/kg of DEHP and clofibrate associated with the increase in hepatic microsomal protein content, suggesting a relationship with the treatment. The atrophic change in the testis or proliferative change in the pancreatic acinar cells seen in rodents were not seen histopathologically; also, no changes were observed in testes weight, testicular zinc level, blood levels of testosterone and estradiol, pancreas weight, and blood levels of cholecystokinin. Finally, no changes considered to be due to the administration of DEHP were noted in blood chemical examination or pathological examination of other organs.
Kurata
Y
Y
Mitsubishi Chemical Safety Institute Ltd., 14 Sunayama, Hasaki-machi, Kashima-gun, Ibaraki-ken, 314-02, Japan.
Kidachi
F
F
Yokoyama
M
M
Toyota
N
N
Tsuchitani
M
M
Katoh
M
M
D000818:Animals; D002144:Callithrix; D002994:Clofibrate / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D005260:Female; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008830:Microbodies / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010179:Pancreas / Q000033:anatomy & histology / Q000187:drug effects*; D013045:Species Specificity; D013737:Testis / Q000033:anatomy & histology / Q000187:drug effects*; D018675:Toxicity Tests
D003577:Cytochrome P-450 Enzyme System; D004051:Diethylhexyl Phthalate; D002994:Clofibrate