A Two-Generation Reproductive Toxicity Study of Benzophenone in Rats

Abstract

The reproductive toxicity of benzophenone (BZP) was evaluated in a two generation test in which male and female Sprague-Dawley (SD) rats, parental (F0) and first generation (F1), were exposed to BZP by feeding diet containing BZP at concentrations of 0 (control), 100, 450 or 2000 ppm. With regard to the effects of BZP on the F0 and F1 parental animals, inhibition of body weight gain and food consumption, significantly elevated renal weights, dilatation of the renal proximal tubules, and regeneration of the proximal tubular epithelium were recognized at doses of 450 ppm and 2000 ppm, along with an increase in hepatic weight and centrilobular hepatocytic hypertrophy, considered as vital adaptive changes, at the doses of 100 ppm or more. Obvious effects on the endocrine system and reproductive toxicological effects were not found even at the dose of 2000 ppm in the F0 or F1 parent. There were no test substance related changes in the estrous cycle, reproductive capability, delivery and lactation, sperm parameters, serum hormone levels, or necropsy findings. As for effects on the offspring, inhibition of body weight gain was observed in both the F1 and F2 males and females of the 2000 ppm group. No effects of BZP treatment were recognized in the number of male and female F1 or F2 pups delivered, viability, anogenital distance (AGD), physical development, the results of reflex and response tests, or on the observation results of external abnormalities. From the present study of BZP administered to rats over two successive generations, the no observed effect level (NOEL) on the parental animals is concluded to be less than 100 ppm. Concerning the effects on the endocrine system and the reproductive toxicity in the parental animals, the NOEL is 2000 ppm. In terms of the effects on the offspring, the NOEL is considered to be 450 ppm.

Toxicological evaluation of benzophenone

“…The reproductive toxicity of benzophenone was examined in a two-generation study in rats (Hoshino et al, 2005). Male and female Sprague-Dawley (SD) rats, parental (F0) and first generation (F1), were exposed to benzophenone by feeding diet with concentrations of 0 (control), 100, 450 or 2000 ppm (corresponding approximately to doses of 6-9, 29-40 and 130-179 mg/kg body weight/day, respectively) .…”

“…The Panel considered neoplastic and non-neoplastic end-points in rats and in mice, obtained from chronic carcinogenicity (NTP, 2006) and reproductive toxicity studies (Hoshino et al, 2005).…”

“…Liver and kidney were identified as the primary target organs of benzophenone toxicity in rats and mice. The Panel considered neoplastic and non-neoplastic end-points in rats and in mice, obtained from chronic carcinogenicity (NTP, 2006) and reproductive toxicity assessments (Hoshino et al, 2005).…”

“…Benzophenone caused liver hypertrophy in the rat at the lowest dose level (~6 mg/kg/day) in a two-generation study (Hoshino et al, 2005), described as a slight hypertrophy of centrilobular hepatocytes without any increase in liver weight. However, in a chronic carcinogenicity study in rats benzophenone did not cause liver tumours, even at exposure levels yielding severe liver damage.…”

“…Consequences of the new TDI for benzophenone on the risk assessment of 4-methylbenzophenone For the purpose of providing an urgent advice to the risk managers, the EFSA in its statement considered the liver hypertrophy seen in the two-generation study (Hoshino et al, 2005) with benzophenone as adverse effects. Thus, EFSA derived a LOAEL of 6 mg benzophenone/kg b.w.…”