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Toxicological information

Specific investigations: other studies

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Description of key information

NOAEL: 3 mg/kg bw/day (acute oral; rabbit)

Additional information

An acute toxicity study similar to OECD 401 and according to GLP was performed with the test substance in female New Zealand White rabbits (M-416191-01-1, 2011). This study was designed to establish an acute reference dose based on the investigation of total cytochrome P450 levels, the activity of specific Phase I and II metabolic enzymes in liver, changes in thyroid hormones as well as morphological and histopathological alterations in liver and thyroid gland. Two groups, each consisting of 15 females, were gavaged with a dose volume of 4 mL/kg bw at concentrations of 0.21, 0.375 and 0.75 g/L (corresponding to doses of 0.85, 1.5 and 3.0 mg/kg bw) in 0.5% aqueous methylcellulose solution as vehicle. The control group was administered corresponding dose volumes of the vehicle only. After a 24-hour (group 1) or 14-day (group 2) post-exposure period, blood samples were taken and used for thyroid hormone (triiodothyronine and thyroxine) analysis. At each observation period (24 h or 14 days), 10/15 randomly selected animals per group were sacrificed and subjected to necropsy, which included the determination of organ weights of liver and thyroid gland as well as macroscopic and microscopic examination s of these organs. To assess the hepatotoxic potential of the test substance, liver microsomes were prepared from each animal for the determination of total cytochrome P450 content, the activity of the specific cytochrome P450 isoenzymes 1A, 2B and 3A (Phase I metabolic enzymes) and UDP-glucuronosyltransferase (UDPGT), which belongs to the Phase II metabolic enzymes. No treatment-related changes were observed after gross examination and microscopic evaluation of liver and thyroid gland at both time points of sacrifice. Thyroid hormones analysis in plasma did not reveal any dose-related changes in the mean levels of the triiodothyronine (T3) and thyroxine (T4) compared to controls. The total cytochrome P450 content as well as the activity of the analysed Phase I and II metabolic enzymes was not altered compared to controls. Only minor statistically significant changes in the activity of the cytochrome P450 isoenzymes 2B and 3A were noted. However, these changes were inconsistent and not related to treatment, and therefore not considered to be toxicologically relevant. Based on these results, the NOAEL for acute effects on the liver and thyroid in female rabbits and therewith associated alterations in thyroid hormones and liver Phase I and II metabolic enzymes was set at 3 mg/kg bw.