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Repeated dose dermal toxicity (OECD 410, GLP): Wistar rats were exposed for 4 weeks to (+/-) alpha-Bisabolol at doses of 50, 200 and 1000 mg/kg bw/day. A NOAEL of 200 mg/kg bw/day has been set (BASF 1996; 33S0144/95020)

Key value for chemical safety assessment

Additional information

In the chosen key study for repeated dose toxicity (acc. to OECD 410 and GLP), (+/-) alpha-Bisabolol was administered to groups of 5 male and 5 female Wistar rats by dermal route (6 hours/day; 7 days/week, semiocclusive dressing) for 4 weeks at doses of 0 (vehicle control), 50, 200 and 1000 mg/kg body weight/day (BASF 1996; 33S0144/95020). The vehicle used was olive oil DAB 10. Transient effects of (+/-) alpha-Bisabolol on the treated skin (moderate erythema, diffuse scale formation) were seen in some high dose females. Body weight change and food efficiency were impaired transiently in high dose males and females. Although the effects were observed only transiently, a substance-relationship cannot be excluded with certainty. Transient effects of (+/-) alpha-Bisabolol on the treated skin and slight impairment of body weight change and food efficiency were seen at the highest dose level, only. Thus, the no observed adverse effect level under the conditions of this study was therefore 200 mg/kg body weight/day.

 

In a supporting study, reported from literature with limited documentation (-) alpha-Bisabolol, i.e. a main component (stereoisomer) of the registered substance racemic alpha-Bisabolol, was studied in Sprague-Dawley rats of both sexes. The investigations were divided into a  orientation 6-week study and a main 4-week study (Habersang et al. 1979).
In the orientation study, the test substance (purity 85%) was administered to two groups of 20 rats (10/sex) by gavage at a dose level of 1  mL/kg bw/d (approx. 930 mg/kg bw/d). The animals were treated daily for 6 weeks. In the main study, three groups of 40 Sprague-Dawley rats (20/sex) were treated with the test substance at dose levels of 2 and 3 mL/kg bw/day (approx. 1860 and 2790 mg/kg bw/day). All  animals of the main study were treated by gavage, 7 days per week for 4  weeks.

In the 6-week preliminary study no adverse effects were observed after oral administration of 1 mL/kg (930 mg/kg bw/d). In the main study reduced body weight gain and motor restlessness was observed in the tested groups, the high dose animals being more affected than the low dose animals. The high dose level was lethal, mortality was 20% in this dose group. Clinical-chemical examination showed increases in SGOT and alkaline phosphatase (slightly increased in males and significantly increased in females). The final examination revealed severe inflammatory effects in the liver, kidney, trachea, thymus, spleen and stomach, according the reduction of body weight, however, these inflammatory reactions were considered to be caused by reduced body weights leading to an impaired immune defense according to the authors. At the low dose level, these changes were only minimal. The NOAEL has been set at 1 ml/ kg bw/d (approx. 930 mg/kg bw/d) based on the absence of adverse substance related effects in the orientating study.

In a further supporting study, reported from literature with limited documentation, the subacute oral toxicity of (-) alpha-Bisabolol was studied in dogs of both sexes. The investigations were divided into a orientating 2-week  study and a main 4-week study (Habersang et al. 1979). In the orientating study, the test substance (purity 85%) was administered to two groups of 2 mixed-bred dogs (1/sex) by gavage at a dose level of 1 mL/kg bw/d (approx. 930 mg/kg bw/d). The animals were treated daily for 2 weeks. In the main study, three groups of 6 mixed-bred dogs (3/sex and dose) were treated with the test substance at levels of 2 and 3 mL/kg bw/d (approx. 1860 and 2790 mg/kg bw/d, respectively). After 2 weeks of treatment, the high dose was increased to 4 mL/kg bw/d (approx. 3720 mg/kg bw/d). All animals of the main study were treated by gavage, 7 days per week for 4 weeks. A control group was included in the orientating and the main study.

In the 2-week orientating study, no adverse effects were observed after oral administration of 1 mL/kg (930 mg/kg bw/d). In the low dose group of the main study, adverse effects were limited to inappetence and reduced food intake (all treated dogs); vomiting was noted in 2/4  animals. In the high dose group, the same signs were observed in a more pronounced manner. The intensity of vomiting and reduced food consumption increased after increasing the dose to 4 ml/kg bw/d (3720 mg/kg bw/d). Body weights were decreased. Creatinine and SGPT activity were significantly elevated during the fourth weeks of treatment, and there was a trend to increased liver function. The remaining clinical chemical parameters as well as hematological, urine, and electrocardiogram parameters were unaffected. At necropsy, a significant increase of the liver-to-body weight was observed, probably due to emaciation. No other substance-related alterations were observed at the final examinations. The NOAEL has been set at 1 ml/ kg bw/d (approx. 930 mg/kg bw/d) based on the absence of adverse substance related effects in the orientating study.

 



Justification for classification or non-classification

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