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Administrative data

Description of key information

Guideline- and GLP-compliant 28- and 90-d studies in rats.  Results published in the peer-reviewed literature.

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:
subchronic
Species:
rat

Additional information

The 28 -day no-observed-effect-level (NOEL) in the Sprague Dawley rat was >= 1,250 mg/kg/d, the highest dose tested, administered by oral gavage in corn oil. The NOEL was based on the absence of toxicity at this dose as measured by: body weight, food consumption, body weight gain, hematology and serum chemistry values, urinalysis, ocular exam, gross necropsy results, organ weight, and light microscopic exam of selected tissues.

The 90 -day no-adverse-effect level (NOAEL) in the Sprague Dawley rat was 1,000 mg/kg/d, the highest dose tested, administered by oral gavage in corn oil. No animals died on test. Clinical signs were non-specific, low in incidence, non-dose-related and not related to test article administration. No test-article-related ocular lesions were detected on ophthalmic exam. Oral dose levels of up to 1000 mg/kg/day for 90 days produced no evidence of systemic toxicity, ocular effects, or treatment-related alterations in urine, serum chemistry and hematology values in rats. No toxic effect was found on body weights, body weight gains or food consumption. The only organ weight affected was liver. Mean liver weights were increased at 1000 mg/kg/day, but not at 320 mg/kg/day, the next lower dose. Low-grade microscopic liver changes accompanied the increase in liver weights in male rats. The liver changes were characterized by minimal to slight hepatocellular vacuolation (high dose males) and minimal to slight centrilobular hepatocytomegaly (high, and possibly mid dose, males), and were considered an adaptive response. No changes were found in the livers of female rats. The liver changes resolved without any delayed or long-term effect after a 28-day recovery period. The no-adverse-effect-level (NOAEL) was 1,000 mg/kg/d, and was confirmed in the UK's review of the study during their assessment of the product.

Justification for classification or non-classification

Non-classification: NOEL in a rat 28 -day study >= 1250 mg/kg/d; NOAEL in a rat 90-day study = 1,000 mg/kg/d.