Diethylene glycol monobutyl ether (DGBE): two- and thirteen-week oral toxicity studies in Fischer 344 rats.

Standard toxicologic endpoints, supplemented by additional examinations, were studied for groups of 10 Fischer 344 rats/sex given drinking water formulated to supply 0, 50, 250, or 1000 mg diethylene glycol monobutyl ether (DGBE)/kg/day for 13 weeks. These dose levels were based upon initial investigations using drinking water formulated to supply 0, 1000, 1500 or 2000 mg DGBE/kg/day for two weeks. All rats survived the respective treatment intervals with no adverse treatment-related in-life effects, including no alterations in a functional observational battery. In both studies, rats given > or = 1000 mg/kg/day consumed less water and feed and weighed slightly less than controls. For rats given > or = 1000 mg DGBE/kg/day, the liver and red blood cells (RBC) were the primary target organs although the effects were slight. In the 13-week study, rats given 1000 mg/kg/day had statistically significant increased relative liver weight (7-10%) and hepatic cytochrome P450s (24-39%) and UGT (approximately 16%) levels along with slight, statistically significant, decreases in serum total protein, cholesterol and aspartate aminotransferase. Histopathologically, very slight hepatocyte hypertrophy and increased individual hepatocyte degeneration were found in females only. At 1000 mg/kg/day, the RBC count, hemoglobin (Hgb) and hematocrit (Hct) were minimally, but statistically significantly, decreased (5.1-8.7%) but RBC morphology, RBC indices, reticuloctye count and bone marrow and spleen histopathology were unaffected. Absolute and relative kidney weights statistically significantly increased (6-13%) with an equivocal increase in minor histopathologic changes typical of early spontaneous nephropathy. There were no adverse effects on urinalysis, clinical chemistry, sperm parameters or testis histopathology. At 250 mg/kg/day, there were equivocal decreases (approximately 2-3%) in RBC count, Hgb and Hct that were statistically significant for the RBC count and Hgb, but these changes were within the historical control range. This dose level was considered the no adverse effect level (NOAEL).

Effect of strain and diet upon constitutive and chemically induced activities of several xenobiotic-metabolizing enzymes in rats.

The response of animals in toxicity studies reflects a complex interaction of a number of variables, some intrinsic to a particular study design and others resulting from the treatment itself. The influences of strain and diet upon constitutive and benzo(a)pyrene (B(a)P) induced activities of several hepatic Phase I and II enzymes were studied in a multifactoral design. Male and female CDF and Crl:CD rats were fed a standard rodent diet ad libitum, a 75% of ad libitum restricted feeding regimen or a phytoestrogen-free diet for approximately 3 weeks. During the last five days of the study, rats were administered either corn oil (vehicle) or 15 mg/kg/day B(a)P via oral gavage. The constitutive activities of hepatic CYP1A1, CYP1A2, CYP2B1/2, and mixed isoforms of UDP-glucuronosyl transferase, sulfotransferase, and glutathione-S-transferase varied significantly by feeding regimen and strain. Responses to B(a)P administration were also observed to be influenced by diet and strain in a manner similar to that observed for constitutive activities. These findings point out the potentially significant interactions of relatively commonly encountered variables that may affect results of hazard testing, especially when employing near metabolically saturating dosages of test chemicals.