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Administrative data

Description of key information

Oral: OECD Guideline 408; 90-day gavage, rats. NOAEL = 50 mg/kg (males), based on hepatocellular single cell necrosis and tubular cell vacuolation in kidneys at >250 mg/kg); 10 mg/kg (females, based on hepatocellular single cell necrosis at>50 mg/kg). Reliability = 1

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subchronic
Species:
rat
System:
other: Effects noted at 50 mg/kg were limited to hepatocellular single cell necrosis in females and a single male rat with a minimal grade observation. The findings do not meet the criteria for classification as neither indicates functional organ impairment.  

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

Groups of 10 male and 10 female rats received daily gavage concentrations of 0, 10, 50, 250, or 1000 mg/kg of the test item for 90 or 91 consecutive days according to OECD Guideline 408. Non-adverse test item-related changes were observed in clinical chemistry parameters at 1000 mg/kg/day dose in female rats. At 1000 mg/kg/day, test item related increased relative (to body and brain) liver weights in both sexes and relative kidney (to body) weights in males and absolute and relative (to body and brain) kidney weights in females were observed. Test item related potentially adverse histopathological findings included minimal to mild hepatocellular single cell necrosis (≥250 mg/kg/day in males and ≥50 mg/kg/day in females) and minimal to mild tubular cell vacuolation in kidneys (≥250 mg/kg/day in males and females).Test item related, non-adverse findings included minimal centrilobular hepatocellular hypertrophy (1000 mg/kg/day in males and females) and minimal to moderate pigmentation in hepatocytes and Kupffer cells (1000 mg/kg/day in males and ≥50 mg/kg/day in females). The No-Observed-Adverse-Effect-Level (NOAEL) of the test substance is 10 mg/kg bw/day in the female (based on hepatocellular single cell necrosis at ≥50 mg/kg/day) and 50 mg/kg bw/day in male rats (based on the hepatocellular single cell necrosis and tubular cell vacuolation in kidneys at ≥250 mg/kg/day).

 

Groups of 12 male and female rats received daily gavage concentrations of 10, 50, 200, or 800 mg/kg of the test substance in a combined repeated dose toxicity study with a reproduction/developmental toxicity screening test according to OECD Guideline 422. Statistically significant, potentially adverse effects observed on this study included reduced body weight, body weight gain, and food efficiency in P1 male animals. Treatment-related findings occurred in the kidneys (vacuolation of tubules in the outer stripe of the medulla in male at ≥50 mg/kg/day and females at ≥200 mg/kg/day). Non-adverse findings in the liver consisted of centrilobular hepatocellular hypertrophy considered an adaptive response to xenobiotic administration (800 mg/kg/day males and females) and minimal centrilobular mononuclear cell infiltrates (800 mg/kg/day males and ≥200 mg/kg/day females). The NOAEL was 10 mg/kg/day for systemic toxicity due to adverse treatment-related histopathologic effects on the kidneys in P1 males at 50 mg/kg/day. These effects, however, were limited to a single male rat with a minimal grade observation.

Justification for classification or non-classification

The effects noted at 50 mg/kg/day in the OECD 408 study were limited to hepatocellular single cell necrosis in female rats. The effects noted at 50 mg/kg/day in the OECD 422 study were limited to a single male rat with a minimal grade observation. Neither of these findings not meet the criteria for classification based on the guidance outlined in ECHA’s Guidance on the Application of the CLP Criteria (2015) section 3.9.2.4. since neither finding indicates functional impairment of an organ.  Therefore, classification is not warranted according to the criteria of EU’s Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.