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Description of key information

A 90d oral gavage study in rats revealed only non adverse clinical pathology changes of minor severity and resulted in a NOAEL of 750 mg/kg (highest dose tested). A 28-Day oral toxicity study in rats with the test substance induced mainly local irritancy/inflammatory changes in the GI tract. Based on the outcome, a NOAEL of 300 mg/kg/day was established.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
750 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In an oral repeated dose toxicity study in compliance with OECD guideline 408 and GLP, Wistar rats were treated with the test article for 13 weeks by daily oral gavage at dose levels of 0, 30, 150 and 750 mg/kg. The increased incidence of rales among animals at 750 mg/kg was considered to be of no toxicological relevance since this clinical sign remained of minimal severity and generally occurred on a few days only for each of the individual animals showing this symptom. No signs of ill-health were recorded among any animal and body weight and food consumption values were considered to have been unaffected by treatment. Clinical pathology changes recorded at 750 mg/kg consisted of a higher alanine aminotransferase activity in females, and lower total protein and albumin level in males. Since these changes occurred in the absence of supportive histopathological (liver) lesions, these were considered not to be adverse in nature. The lower activated partial thromboplastin time of males at 750 mg/kg was considered to be of no toxicological relevance since this change was slight in nature (mean remained within the range considered normal for rats of this age and strain), and an increase would be expected in case of target organ toxicity. No treatment-related changes were noted in any of the other parameters investigated in this study (i.e. functional observations, ophthalmoscopy, macroscopic examination, organ weights and microscopic examination).

From the results presented in this report a No Observed Adverse Effect Level (NOAEL) of 750 mg/kg was established.

In a supporting subacute study the test substance was administered for 4 weeks daily by gavage to male and female Wistar rats at dose levels of 0, 100, 300 and 1000 mg/kg bw/d (test groups 0-3). Drinking water containing 1% carboxymethylcellulose was used as vehicle control and vehicle for the test substance. With regard to clinical examinations, signs of general systemic toxicity were not observed up to a dose level of 1000 mg/kg bw/d. Regarding clinical pathology the reduced prothrombin time (Hepato Quick’s time) as well as the decreased total protein and albumin levels in males of test group 3 (1000 mg/kg bw/d) were most probably due to an altered liver cell metabolism as consequence of the administration of the compound. Regarding pathology, target organs were the glandular stomach and the liver. One male of test group 3 (1000 mg/kg bw/d) showed a small ulceration in the glandular stomach. In addition, a minimal or slight chronic inflammation between muscularis mucosa and tunica mucosa was observed in the 4 other males of test group 3 (1000 mg/kg bw/d). These results were regarded to be treatment-related but reflect primarily a local irritative effect than an effect of systemic toxicity. It is known that the test substance has an irritation potential. The absolute and relative liver weights were significantly increased in females of test group 3 (1000 mg/kg bw/d). Although there were no histopathological correlates, the increased liver weights were regarded treatment-related but assessed to be adaptive and nonadverse. All other findings occurred either singly or were biologically equally distributed over the control group and the treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment. In conclusion, the oral administration of the test item by gavage over a period of 4 weeks revealed only signs of toxicity in male Wistar rats at dose levels of 1000 mg/kg bw/d. Therefore, under the conditions of the present study, the no observed adverse effect level (NOAEL) concerning systemic toxicity was 300 mg/kg bw/d for male Wistar rats and 1000 mg/kg bw/d in female Wistar rats.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008 (CLP). As a result the substance is not considered to be classified for repeated dose toxicity under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation (EC) No 605/2014.

Dangerous Substance Directive (67/548/EEC)

The available study are considered reliable and suitable for classification purposes under 67/548/EEC. As a result the substance is not considered to be classified for repeated dose toxicity under Directive 67/548/EEC, as amended for the 31st time in Directive 2009/2/EG.