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Description of key information

Toxicity after repeated dose administration of the test substance was not assessed. Information on subchronic toxicity are derived from a strucutral analogue. In the course of a GLP conform subacute toxicity study, the test substance was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 0, 50, 200 and 1000 mg/kg body weight/day for a period of 28 days according to the OECD guideline 407 (RCC Ltd, 2002). Administration of the test item did not induce mortalities, signs of treatment related toxicity or any other changes. A transient decrease in locomotor activity at high dose animals is regarded as an unspecific high dose effect. Thus the NOEL is considered to be 200 mg/kg bw /day and the NOAEL 1000 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat

Additional information

Toxicity after repeated dose administration of the test item (intermediate) was not determined. There are reliable studies of an analogue substance (final product) available to assess the potential for subacute oral toxicity. The compounds share high similaritiy in structure, are of low water solubility and have a log Pow > 8. The toxicity profile of the analogue as well as of the test item is determined by the main component; the side products are structural analogues of the main product without influence on substance toxicity. Derived from repeated dose studies with the analogue substance and other analogues of the same compound class and with regard to the molecular weight of the test item (494 g/mol) and the low solubility, it is expected that the test item is of low bioavailability. Possibly metabolism of the test item will take place at phenolic OH-groups by UDP-glucoronsyltransferases and sulfotransferases which is comparable to the metabolic processes at the analogue. It is, therefore acceptable to derive information on repeated dose toxicity from experimental data of this read across substance. A detailed risk assessment and read across justification was send to the german chemical agency BAuA in 2007 with the purpose of a national substance notification (VIIA). The read across justification was accepted by the national agency.

In this GLP conform subacute toxicity study, the analogue was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 0, 50, 200 and 1000 mg/kg body weight/day for a period of 28 days according to the OECD guideline 407 (RCC Ltd, 2002). The groups comprised 5 animals per sex which were sacrificed after 28 days of treatment. Additional 5 rats per sex and group were used at 0 and 1000 mg/kg. These animals were treated for 28 days and then allowed a 14-day treatment-free recovery period after which they were sacrificed. Clinical signs, outside cage observation, food consumption and body weights were recorded periodically during pretest, the treatment and recovery periods. Functional observational battery, locomotor activity and grip strength were performed during week 4. At the end of the dosing and the treatment-free recovery period, blood samples were withdrawn for hematology and plasma chemistry analyses. Urine samples were collected for urinalyses. All animals were killed, necropsied and examined post mortem. Histological examinations were performed on organs and tissues from all control and high dose animals, and all gross lesions from all animals.

All animals survived until scheduled necropsy. No test item-related clinical signs, no changes in hematology, urinalysis, food consumption or body weight and no effects on organ weight or any micro/macroscopic changes were noted during daily or weekly observations. Slight reductions in locomotor activity were noted in the first 15 min/1h in both sexes treated with 1000 mg/kg/day. These differences were transient and a dose-effect relationship was not obvious. A confirmatory experiment was not conducted. The change in locomotor activity of the high dose group is, therefore regarded as an unspecific high dose effect rather than a treatment related symptom.

Based on the results of this study, 200 mg/kg body weight/day of the test substance was established as the no-observed-effect-level (NOEL) and 1000 mg/kg/day was considered to be the no-observed-adverse-effect-level (NOAEL).

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. As a result the substance is notconsidered to be classified for repeated dose toxicity under Directive 67/548/EEC, as amended for the 30th time in Directive 2008/58/EC.

 

 

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

The available experimental test data are reliable and suitable for classification purposes under Regulation 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 second time in Directive (EC 286/2011).