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Administrative data

Description of key information

Oral administration of the test item by gavage to male and female Wistar rats for 3 months caused no signs of systemic toxicity up to the highest dose level tested (1000 mg/kg bw/d). Therefore, under the conditions of the present study the no observed adverse effect level (NOAEL) was 1000 mg/kg bw/d for male and female Wistar rats.

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
1 000 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 the key study the test item was administered by gavage to groups of 10 male and 10 female Wistar rats at dose levels of 0 (test group 0), 100 (test group 1), 300 (test group 2) and 1000 mg/kg bw/d (test group 3) over a period of 3 months (GLP, OECD guideline 408). With regard to clinical examinations, no signs of general systemic toxicity were observed in any of the test groups. Concerning clinical pathology no treatment-related, adverse effects were observed up to a dose of the test substance of 1000 mg/kg bw/d. Regarding pathology, there was a significant increase in kidney weights in females of test group 3 (1000 mg/kg bw/d). A treatment-related effect seems unlikely due to a missing histopathological correlate. It therefore was regarded to be not an adverse finding. All other findings occurred either individually or were biologically equally distributed over control and 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 to male and female Wistar rats for 3 months caused no signs of systemic toxicity up to the highest dose level tested (1000 mg/kg bw/d). Therefore, under the conditions of the present study the no observed adverse effect level (NOAEL) was 1000 mg/kg bw/d for male and female Wistar rats.

In a supporting subacute study performed according to OECD 407, the test material was administered by gavage to three groups, each of five male and five female Sprague-Dawley Crl:CD® (SD) IGS BR strain rats, for twenty-eight consecutive days, at dose levels of 150, 500 and 1000 mg/kg/day. A control group of five males and five females was dosed with vehicle alone (Polyethylene glycol 400). Two recovery groups, each of five males and five females, were treated with the high dose (1000 mg/kg/day) or the vehicle alone for twenty-eight consecutive days and then maintained without treatment for another 14-day period. Increased salivation was detected up to ten minutes after dosing and, on occasion, up to one hour after dosing, in animals of either sex treated with 1000 mg/kg/day from Day 7 onwards. Increased salivation was also detected in animals treated with 500 mg/kg/day but was confined to two animals on Days 26 and 27 only. Such observations are often recorded following the oral administration of an unpleasant tasting and/or locally irritant test material formulation and, in isolation, are considered not to be indicative of systemic toxicity. Microscopic examination of liver sections revealed a higher severity and incidence of glycogen storage type hepatocyte vacuolation for animals of either sex treated with 1000, 500 and 150 mg/kg/day. A clear dose response was not apparent. Glycogen storage is a highly variable condition in the liver of laboratory maintained rats and any relationship to treatment tends to be entirely adaptive in nature. In the absence of any degenerative or inflammatory changes, this condition is almost certainly adaptive. Absolute and relative liver weight was elevated for 1000 mg/kg/day females but values were within normal ranges. This effect was reversible after 14 days without treatment. There were also no blood chemical changes to suggest an adverse liver effect. No adverse effect on physical condition was evident in treated animals with normal bodyweight development and food consumption evident throughout the study. The changes seen in this study were, therefore, considered to be entirely adaptive and did not represent an adverse health effect at any of the dose levels examined.

 

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 (EC) No 1272/2008. 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 eighth time in Regulation (EU) No 2016/218.