Subchronic toxicity study with ethylene-bis-(oxyethylene)-bis-(3-tert-butyl-4-hydroxy-5-methylhydrocinnamate) the cynomolgus monkey: Lack of stimulation of the pituitary-thyroid-liver axis

To evaluate the toxicological profile of the phenolic antioxidant ethylene- bis-(oxyethylene)-bis-(3-tert-butyl-4-hydroxy-5-methylhydrocinnamate) (EOC) in a non-human primate, male cynomolgus monkeys (Macaca fascicularis) were treated for 4 weeks by oral administration of 0, 200, or 1000 mg/kg body w eight/day. Special attention was directed to parameters of the pituitary-th yroid-liver axis. Moderately increased liver weights and minimal to moderat e hepatocellular hypertrophy were observed in treated animals. Otherwise, n o treatment-related changes were detected in hematological, clinical chemis try, or urinalysis parameters or upon histopathological examination. Except for a slight induction of microsomal testosterone 16 beta-hydroxylation, l iver xenobiotic-metabolising enzyme activities and peroxisomal fatty acid b eta-oxidation remained unchanged. Likewise, serum levels of thyroid stimula ting hormone, thyroxine, 3,3',5-triiodothyronine and 3,3',5'-triiodothyroni ne as well as 5'-monodeiodinase type 1 mRNA levels in the liver, heart, cer ebral cortex, and thyroid were found unchanged. The results demonstrate tha t, in the Cynomolgus monkey, EOC is only a very weak inducer of liver xenob iotic-metabolizing enzymes and has no effect on thyroid function. In contra st, upon feeding rats at dose levels up to 1000 ppm (equivalent to between 50 and 100 mg/kg body weight/day), EOC has been identified as a strong phen obarbital- and peroxisome proliferator-type inducer of hepatic xenobiotic-m etabolizing enzymes, interfering with thyroid hormone homeostasis, causing thyroid follicular hypertrophy, and, upon chronic treatment, inducing thyro id gland follicular cell tumors (Thomas et al., 1995. In Toxicology of Indu strial Compounds, pp. 319-339. Taylor and Francis). Thus, the results of th is study with EOC in the cynomolgus monkey show that effects of xenobiotics on the pituitary-thyroid-liver axis as frequently observed in rodents can not necessarily be extrapolated to primates including man.