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Effects on fertility

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Effects on developmental toxicity

Description of key information
In two developmental toxicity studies with (-)alpha-Bisabolol in rats and rabbits, the lowest toxic oral dose for both fetuses and dams was concluded to be between 1.0 and 3.0 mL/kg body weight. Accordingly, the observed NOAEL is set at 1.0 mL/kg bw/d (930 mg/kg bw/d). Adverse effects on prenatal development were only observed in rats and rabbits at doses that are also toxic to the dams and are well above the limit dose of 1000 mg/kg bw/d according to current standard test guidelines. Therefore, these findings are considered to be secondary to maternal stress. Furthermore, no teratogenic potential was observed at all dose groups tested. Therefore, under the given testing conditions, no impairment of the prenatal development by Bisabolol became evident. 
Additional information

No key study is available for racemic (+/-)-alpha-Bisabolol concerning developmental toxicity. However, two developmental toxicity studies in rats and rabbits, reported in literature with limited documentation, are used in a weight of evidence to assess the respective endpoint.

Pregnant rats were dosed orally (gavage) with (-)-alpha-Bisabolol, i.e. a main component (stereoisomer) of the registered substance racemic alpha-Bisabolol, at doses of 0.25, 0.5, 1.0 and 3.0 mL/kg bw/d (equivalent to 230, 460, 930, 2790 mg/kg bw/d) on days 6 -15 of gestation, (Habersang 1979). Control groups received 1% tylosis mucus or 1 % carboxyethyl cellulose gel. Fetuses were removed on day 20 and examined for abnormalities of the thoracic/abdominal organs, followed by staining/examination of the skeletal system and body sections for overall malformation investigations.

No effects on pre-natal development were observed at doses up to 1.0 mL/kg bw/d. At the highest dose, significant reductions in fetal numbers and subsequent increases in resorption rates were observed. No teratogenicity/malformations was found up to the highest dose tested. Maternal toxicity was observed at the highest dose only, i.e reduced food intake, reduction of body weights and clinical signs. The authors concluded that the lowest maternal and developmental toxic doses were between 1.0 and 3.0 mL/kg body weight. Accordingly, the observed NOAEL is set at 1.0 mL/kg bw/d (930 mg/kg bw/d).

Pregnant New Zealand White rabbits were dosed orally (gavage) with 0.3, 1.0 or 3.0 mL/kg bw/d (equivalent to 280, 930, 2790 mg/kg bw/d) of (-)-alpha-Bisabolol on days 6 -18 of gestation. A control group received 3 mL of 1% tylosis mucus. Fetuses were removed on day 30 and examined for abnormalities of the thoracic/abdominal organs, followed by staining/examination of the skeletal system and body sections for overall malformation investigations.

No adverse effects on either prenatal development or on the dams was noted at doses up to 1.0 mL/kg bw/d. In the highest dose group (3 ml/kg bw/d), the number of fetuses and the fetal body weights were decreased and the number of resorptions was increased. No dead or malformed fetuses were observed up to the highest dose group. Concerning maternal toxicity, significant depression of body weight gain and clinical signs were noted in the dams of the highest dose group. The lowest toxic oral dose for both fetuses and dams was concluded to be between 1.0 and 3.0 mL/kg body weight.Accordingly, the observed NOAEL is set at 1.0 mL/kg bw/d (930 mg/kg bw/d).

 

Overall, adverse effects on prenatal development were only observed in rats and rabbits at doses that are also toxic to the dams and are well above the limit dose of 1000 mg/kg bw/d according to current standard test guidelines. Therefore, these findings are considered to be secondary to maternal stress. Furthermore, no teratogenic potential was observed at all dose groups tested. Therefore, under the given testing conditions, no impairment of the prenatal development by (-)-alpha-Bisabolol became evident and racemic alpha-Bisabolol is considered to be no developmental toxicant. 

Justification for classification or non-classification

The present data on reproductive toxicity do not fulfill the criteria laid down in 67/548/EEC and regulation (EU) 1272/2008, and therefore, a non-classification is warranted.

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