Benzophenone was unpalatable at 20,000 ppm. All 20,000 ppm rats had significant body weight loss and were terminated for humane reasons before the end of studies. All male mice and four female mice in the 20,000 ppm group died. There was no exposure-related mortality in the remaining groups. Significantly decreased body weights relative to the controls were observed in all exposed groups of female rats and all exposed groups of male rats except the 1,250 ppm group. Lower body weights were apparent in 10,000 ppm male mice and in 5,000 ppm or greater female mice.
In rats, the liver and kidney were identified as target organs of benzophenone toxicity. Treatment-related increases in liver weights were attributed to hypertrophy and/or cytoplasmic vacuolization of hepatocytes. Increased kidney weights were associated with a spectrum of renal changes in exposed males and females. Unique lesions observed in animals that died early as well as in survivors were well demarcated, wedge-shaped areas of prominent tubule dilatation. The lesion occurred in 2,500 ppm or greater males and in 10,000 and 20,000 ppm females. Foci of tubule regeneration were increased relative to the controls in exposed males and females.
In exposed mice, significant microscopic findings were limited to centrilobular hypertrophy in the liver that corresponded to increased liver weights. The severity of hepatocyte hypertrophy was exposure-concentration dependent, with marked severity in all 20,000 ppm animals.
Clinical chemistry analyses confirmed liver toxicity. In rats, increases in serum bile salt concentrations indicated cholestatic liver disease. On day 22, a 15-fold increase was evident in the 20,000 ppm groups, and at week 14, a twofold increase was seen in the 10,000 ppm groups. Increases in alanine aminotransferase and sorbitol dehydrogenase activities were mild in mice; however, more convincing of liver damage were increased alkaline phosphatase activities and serum bile salt concentrations, especially in 20,000 ppm females.
Biochemical data indicated that benzophenone was a relatively potent inducer of the phenobarbital-type (2B) cytochrome P450 enzymes. Overall, induction was greater in rats than in mice. The gross (increased organ weights) and microscopic (hepatocellular hypertrophy) liver changes associated with benzophenone administration in rats and mice accompanied benzophenone-induced increases in pentoxyresorufin dealkylase activity. Benzophenone was not mutagenic in S. typhimurium strain TA98, TA100, TA1535, or TA1537, with or without S9 activation, and it did not induce micronuclei in bone marrow erythrocytes of male mice administered benzophenone by intraperitoneal injection.
In conclusion, the liver is the primary target organ of benzophenone toxicity in rats and mice based on increases in liver weights, hepatocellular hypertrophy, clinical chemistry changes, and induction of liver microsomal cytochrome P450 2B isomer. The kidney was also identified as a target organ of benzophenone toxicity in rats only, based on exposure concentration-related increases in kidney weights and microscopic changes. The no-observed-adverse-effect level for benzophenone was not achieved in these studies.