OECD SIDS 5. TOXICITY
ID: 79-50-5 DATE: 18.01.2006
5 males/group of groups 1 and 4 to examine staging of spermatogenesis. - The preserved organs and tissues of the animals of all dose groups which died spontaneously or were killed in extremis. - All gross lesions of all animals (all dose groups). - The preserved organs and tissues of all non-pregnant females and animals suspected of infertility. All abnormalities were described and included in the report. Analysis of dose preparations Accuracies were out of the 90-110% range on several days of analysis. It was considered not to be caused by inaccurate preparation of formulations but by analytical problems (i.e. sensitivity fluctuation in time of the LCMSMS system used). For formulations in Milli-U water (19 September 2002), accuracies at a target concentration of 8 mg/g ranged from 84 to 112%. Accuracies at a target concentration of 200 mg/g were between 88 and 91%. For formulations in Milli-U water adjusted to pH 4 (19 September 2002, 09 October 2002, 31 October 2002), accuracies at target concentrations of 8 mg/g ranged from 87 to 134%. Accuracies at a target concentration of 40 mg/g were between 88 and 98%. Accuracies at a target concentration of 200 mg/g were between 80 and 103%. The accuracies of group 4 formulations measured on 23 October 2002 were considered not reliable because concentrations were relatively low at t=0 (68-81% of target) but at target level after 8 days of storage. Homogeneity: The relative standard deviation for the measurements (19 September 2002, 09 October 2002, 31 October 2002) ranged from 1.3 –12% indicating that formulations were homogeneous. The higher relative standard deviation at lower concentration was considered due to the analytical method used. Stability: The measurements on 19 September 2002 showed that concentrations in formulations in Milli-U water and in Milli-U water adjusted to pH 4 were stable for 4 hours at room temperature. Formulations in Milli-U water adjusted to pH 4 are stable for 8 days at 37°C (27 September 2002). The results of 17 October 2002 confirmed stability for 8 days at 37°C for Group 2. However for Group 4, stability was not confirmed. Therefore, it was decided to repeat stability testing for Group 4. Results of these analyses (31 October 2002) showed an increase of 33% over 8 days at 37°C. This was due to the low values at t=0. The values at t=8 days were very close to the target (200 mg/g). Based on this it was concluded that the Group 4 formulations were stable over 8 days at 37°C and thus confirmed the results of 27 September 2002. Conclusion: Taking the analytical problems into account, it could be concluded that formulations were prepared accurately and homogeneously. Furthermore, it could be concluded th at formulations in Milli-U water were stable for 4 hours at room temperature and that formulations in Milli-U water adjusted to pH 4 were stable for 4 hours at room temperature and for 8 days at 37°C.
Mortality No unscheduled deaths occurred during the study period.
Clinical signs Females of the highest dose group showed aggressive and restless behaviour during days 5 to 15 of treatment.