The results of different studies gave no indication for a bioaccumulation potential of benzophenone.
NTP (2006)
Doses of 2.5 to 10 mg/kg bw of benzophenone were administered as single dose by gavage to male and female F344/N rats. Concentrations of benzophenone were determined in plasma at various timepoints up to 24 hours after dosing. For males, bioavailability ranged from 0.824 to 1.27 (average 1.09). Estimates of elimination rate constants and half-lives for males were ca. 0.00270 minE–1 and ca. 255 min, with slight decreases in elimination rate constants and concomitant increases in half-lives at the two higher doses (ca. 0.00130 minE–1 and ca. 550 min). For female rats, estimates of elimination rate constants and half-lives were similar for the three doses (ca. 0.00150 minE–1 and ca. 485 min). Bioavailability for females ranged from 1.05 to 1.39 (average 1.18). This study shows that after gavage administration of benzophenone to male rats, plasma concentration versus time curves for the three doses were roughly parallel between 200 and 600 minutes. Less well-defined secondary maxima in mean plasma benzophenone concentrations were observed between 5 and 120 minutes after administration of 7.78 mg/kg (nominal dose 10 mg/kg) to male rats and after administration of 1.88 and 7.68 mg/kg (nominal doses 2.5 and 10 mg/kg, respectively) to female rats.
Doses of 15 to 60 mg/kg bw of benzophenone were administered as single dose by gavage to male and female B6C3F1 mice. Concentrations of benzophenone were determined in plasma at various timepoints up to 24 hours after dosing. The AUCs were supralinear with respect to dose: As the dose was increased, the AUC/dose also increased. The nonlinearity in mice may be due to a first-pass effect of liver metabolism restricting the amount of benzophenone that gets into the general circulation. As the dose is increased, the first-pass metabolism becomes saturated. Mice appear to metabolize benzophenone more rapidly than rats; the doses are higher for mice, yet the half-lives and AUCs are smaller. There were no obvious sex-related differences in noncompartmental pharmacokinetic parameter estimates for mice. This study shows that bioavailability of benzophenone in male and female mice is <= 50 %. AUC/Dose, elimination rate constants and half-lives are dose dependent, with similar dependency for males and females. There was a great deal of fluctuation in plasma benzophenone concentrations at later time points, with clear secondary and even tertiary increases in concentration at all doses tested, regardless of the route of administration.
A single i.v. dose of 2.5 mg/kg bw of benzophenone was administered to male and female F344/N rats. Concentrations of benzophenone were determined in plasma at various timepoints up to 24 hours after dosing. In females, the elimination rate constant was slightly higher than after gavage administration, with a concomitant decrease in half-live (0.00280 minE–1 and 247 min). Overall, there were no apparent sex-related differences in noncompartmental pharmacokinetic parameter estimates for rats. This study shows that after i.v. injection of a nominal dose of 2.5 mg benzophenone/kg to male and female rats, benzophenone initially rapidly cleared from the plasma, followed by a slight increase in plasma benzophenone concentration, and a secondary, slower elimination. Secondary maxima in mean plasma benzophenone concentration were observed during the terminal portion of the plasma concentration versus time curve. Based on the ratios of AUC for intravenous injection, average bioavailability was 1.09 and 1.18 for male and female rats, respectively.
A single i.v. dose of 15 mg/kg bw of benzophenone was administered to male and female B6C3F1 mice. Concentrations of benzophenone were determined in plasma at various timepoints up to 24 hours after dosing. Bioavailability of benzophenone in male and female mice was <= 50 %. AUC/Dose, elimination rate constants and half-lives are dose dependent in mice, with similar dependency for males and females. There was a great deal of fluctuation in plasma benzophenone concentrations at later time points, with clear secondary and even tertiary increases in concentration at all doses tested, regardless of the route of administration. The nonlinearity in mice may be due to a first-pass effect of liver metabolism restricting the amount of benzophenone that gets into the general circulation. This study shows that after i.v. injection of a nominal dose of 15 mg/kg to male and female mice, benzophenone was initially rapidly cleared from plasma, followed by a slower elimination phase. As with rats, fluctuations in mean plasma benzophenone concentration were observed in mice and were most likely due to enterohepatic recirculation. The AUCs were supralinear with respect to dose: As the dose was increased, the AUC/dose also increased. In rats, this parameter was more or less constant over the dose range. The nonlinearity in mice may be due to a first-pass effect of liver metabolism restricting the amount of benzophenone that gets into the general circulation. As the dose is increased, the first-pass metabolism becomes saturated. Mice appear to metabolize benzophenone more rapidly than rats; the doses are higher for mice, yet the half-lives and AUCs are smaller. As with rats, there were no obvious sex-related differences in noncompartmental pharmacokinetic parameter estimates for mice.
Nakagawa et al. (2000)
The metabolism and cytotoxicity of benzophenone and estrogenic activity of its metabolites was studied in freshly isolated rat hepatocytes and cultured MCF-7 human breast cancer cells, respectively. The incubation of hepatocytes with benzophenone (0.25 to 1.0 mM) elicited a concentration- and time-dependent cell death, accompanied by loss of intracellular ATP and depletion of adenine nucleotide pools. Benzophenone at a low-toxic level (0.25 mM) in the hepatocyte suspensions was converted to benzhydrol, p-hydroxybenzophenone and its sulfate conjugate, without marked loss of cell viability. In another experiment, MCF-7 cells, oestrogen-responsible breast cancer cells were cultured in estradiol free medium and then exposed to 10 nM to 500 uM benzophenone or its metabolites for 6 days. Although at higher concentrations all the compounds were toxic, except for benzophenone and benzhydrol, 10 to 100 uM p-hydroxybenzophenone significantly increased cell proliferation. These results indicate that benzophenone is enzymatically converted to benzhydrol, p-hydroxybenzophenone and its sulphate conjugate in rat hepatocytes. Even if there is less free p-hydroxybenzophenone than benzhydrol and sulfate conjugate in hepatocyte suspensions, p-hydroxybenzophenone itself acts as a weak xeno-estrogen on MCF-7 cells. This study shows that in rat hepatocytes, benzophenone (at a low toxic level) is enzymatically converted to at least three metabolites: benzhydrol, p-hydroxybenzophenone and its sulfate conjugate. There was a weak estrogenic effect of p-hydroxybenzophenone on MCF-7 cell proliferation. The parent compound and benzhydrol were inactive in this respect.
Nakagawa & Tayama (2002)
At 24 h after the last dose in ovariectomized rats consecutively treated with benzophenone for 3 days, considerable amounts of these compounds existed in the serum in high-dosed rats; the mean concentrations of benzophenone, benzhydrol and p-hydroxybenzophenone were 10.4±1.0, 1.5±0.3, and 0.7±0.2 (mean ± SE) uM/L, respectively, whereas neither the parent compound nor any metabolite was detected in the serum of the low dosed rats. On the other hand, 6 h after a single oral dose of benzophenone (100 or 400 mg/kg) into intact (un-ovariectomized) female rats, each concentration of benzophenone and its metabolites increased in a dose-dependent manner. There was a preference for the occurrence of benzhydrol rather than p-hydroxybenzophenone.
