Registration Dossier

Administrative data

Description of key information

In the absence of significant adverse effects, a NOAEL of 1000 mg/kg bw/day has been considered further for hazard assessment.

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:
subacute
Species:
rat
Quality of whole database:
Guideline compliant study

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

A study was conducted to determine the oral repeated dose toxicity of the test substance according to OECD Guideline 422, EU Method B.7, EPA OPPTS 870.3650 and EPA OPPTS 870.3050, in compliance with GLP. Male and female Wistar Han rats were exposed (by gavage) to the test substance at dose levels of 100, 300 and 1000 mg/kg bw/day from 14 days before mating (Day 1) until Day 31 for males or until Day 4 of lactation for females. A control group of 10 male and 10 female rats was given 5 mL/kg bw/day of the vehicle (corn oil) over the same periods. All animals were observed at least twice daily for morbidity and mortality. Clinical signs were recorded daily during the study. To detect any clinical signs or reactions to treatment, the animals were observed before and at least once after dosing. A full clinical examination was performed on each weighing day. A particular attention was paid to hypersalivation. Body weight was measured once per week in males and once per week during pre-mating and mating periods, on Days 0, 6, 9, 12, 15, 18 and 20 of gestation and on days 1 and 4 of lactation in females. Food consumption was evaluated one per week during the pre-mating period in males and weekly during the pre-mating period, on days 0 to 6, 6 to 9, 9 to 12, 12 to 15, 15 to 18, 18 to 20 of gestation and on days 1 to 4 of lactation in females. Functional tests were performed on males (on the last day of treatment (i.e. Day 31)) and females (females with live pups at the time of test (i.e. lactation day 4)). The tests performed included auditory reflex, pupillary reflex, righting reflex, fore- and hind-limb grip strength and locomotor activity in an open field test. Blood sampling were taken at the end of the pre mating period (i.e. Day 14) from the retro-orbital sinus for heamatology, coagulation and serum clinical chemistry analysis. Adult animals were killed by carbon dioxide inhalation followed by exsanguination then necropsied according to the following schedule: after completion of the mating period for males and on Day 4 of lactation for females. All animals were submitted to a macroscopic examination. For half of the animals/group, selected organs were weighed, and organ/tissue samples were fixed and preserved at necropsy. A limited list of organ/tissue samples were fixed and preserved at necropsy for the remaining animals. Selected organs/tissues, from half of the group 1 (0 mg/kg bw/day) and 4 (1000 mg/kg bw/day) animals killed at the end of the treatment period were examined histopathologically. Oral administration of the test substance at tested doses, were associated with a non-adverse minor decrease in mean body weight gain for males and females during lactation at 300 and 1000 mg/kg bw/day, a slight reduction of food consumption for all treated females (from Day 9 and Day 15 of pre-mating) and from Day 1 to Day 4 of lactation at 1000 mg/kg bw/day and a dose-related decrease in bile acids in test substance-treated males at all dose levels and females at 300 and 1000 mg/kg bw/day. For details on effects on reproduction refer to the discussion under section 5.9.3 of the CSR. Under the study conditions, the NOAEL for parental systemic toxicity of the test substance was determined to be 1000 mg/kg bw/day (highest dose tested) (Mounier, 2017). 


Justification for classification or non-classification

Based on the results of the combined repeated dose with reproductive and development screening study, the test substance does not meet the criteria for classification for this endpoint according to CLP (Regulation 1272/2008/EC) criteria.