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Exposure of rats during 4 months at 500 mg/kg bw/d induced a slight increase in cytochrome P450 enzymes (especially CYP 2B isoenzymes) as well as a slight induction in peroxisome proliferation. This is in agreement with increased incidence of hepatocyte hypertrophy and relative liver weight to body weight observed at the same dose level.

As part of the 4-month toxicity study of benzyl toluenes administered orally (0, 5, 50, and 500 mg/kg/day) to Sprague-Dawley rats, the following hepatic enzyme activities were assessed at the end of the study in the high-dose group (Verschuere, 1991):

            - Total cytochrome P450's,

           - Cytochrome P450IA (7-ethoxyresorufin O-deethylation activity),

           - Cytochrome P450IIB (d-benzphetamine N-demethylation activity),

           - Cytochrome P450IIIA (erythromycin N-demethylation activity),

           - Cytochrome P450IVA (lauric acid 12-hydroxylation activity).

The hepatic peroxisome proliferation was determined in all groups by measurement of palmitoyl-Co-A-oxidase activity and peroxisome counting using electron microscopy.

 In male rats, the dose-level of 500 mg/kg/d benzyl toluenes induced a statistically significant increase in activity of total cytochrome P450 (x1.5), cytochrome P450IA (x2.1 compared to x38 for the reference compound), cytochrome P450IIB (x1.4 compared to x2.8 for the reference compound), cytochrome P450IIIA (x1.5 compared to x6.6 for reference compound) and cytochrome P450 IVA (x2.4 compared to3.5 for the reference compound). 

Benzyl toluenes did not modify total cytochrome P450, P450IIIA, and P450IVA contents in female rats. Statistically significant increases of cytochromes P450IA (x1.8 compared to x15 for the reference compound) and P450IIB (x2.2 compared to x3.9 for the reference compound) were observed in female rats at the dose-level of 500 mg/kg/d.

Benzyl toluenes induced a slight increase in palmitoyl-CoA activity in male and female rats at the dose-level of 50 and 500 mg/kg/d (in males : x2.1 and x4.2 compared to control, in females : x2.8 and 6.3 compared to control, respectively). Electron microscopic counting revealed a greater number of peroxisomes (x2 compared to control) in male and females rats of the 500 mg/kg/day group.

 At 500 mg/kg/d, the hypertrophy of hepatocytes associated with the increase in relative liver weight in both sexes, observed during the subchronic toxicity study, and the slight increase in enzyme activities suggest that benzyl toluenes is a slight enzyme inducer. 

The no-observable-effect level for enzyme induction with benzyl toluenes administrated to rat during a 120 day period can be estimated between 5 and 50 mg/kg bw.

 

The possible peroxisome proliferation induced by benzyltoluene (Jarylec BT) was determined by palmitoyl-CoA-oxidase activity on rat (Fischer and Sprague-Dawley) hepatocytes in primary culture following 4 days of treatment. BT was dissolved and diluted in dimethylsulfoxide and tested at 5, 10, 25, 50,75 and 100 µg/ml. A slight toxic effect was observed only after 24 hours of treatment at 100 µg/ml. Benzyltoluene induced a concentration-related increase of palmitoyl-CoA-oxidase activity from 25 µg/ml whatever the species used . In conclusion, benzyltoluene proved to be peroxisome proliferators in rat hepatocyte primary cultures, following daily treatment for 4 days at concentrations of 25, 50, 75 and 100 µg/ml/d.

Additional information

The hypertrophy of hepatocytes associated with the increase in relative liver weight in both sexes, observed during the subchronic toxicity study, and the slight increase in enzyme activities suggest that benzyl toluene is a slight enzyme inducer.

In the two available studies (Verschuere, 1991; Fedtke, 1993) and for male rats only, the dose-level of 500 mg/kg/d of benzyl toluene during 120 days or 90 days induced a statistically significant increase in activity of total cytochrome P450. Nevertheless, particular CYP 450 activity were also increased both in male and in female rats.

Benzyl toluene appears also as being a slight hepatic peroxisome proliferator (Verschuere, 1991; Fedtke, 1993; Dechariaux 1991) and to induce GHS-S-Transeferases (Fedtke, 1993).