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EC number: 217-886-1 | CAS number: 1999-85-5
There is no valid repeat dose study on the registered substance. An apparently well conducted GLP 28-day study oral gavage study in rats, on the analog substance CAS# 27138-01-8 is considered the key study.
The objective of this study was to evaluate the potential toxicity of the test item following daily oral administration to rats for 4 weeks.
Three groups of five male and five female Sprague-Dawley rats received the test item by daily oral administration for 28 days at dose-levels of 100, 300 or 1000 mg/kg/day. The test item was administered as a suspension in the vehicle (corn oil) at a constant dosage-volume of 5 mL/kg/day. A control group of five males and five females received the vehicle alone under the same experimental conditions.
Test item concentrations were checked on formulations used in weeks 1 and 4.
The animals were checked at least twice daily during the dosing period for mortality and morbidity and once daily for clinical signs. In addition, detailed clinical examinations were performed at least once weekly. Body weight was recorded once before the beginning of the treatment period, and then at least once a week during the study as food consumption. Towards the end of the dosing period, a Functional Observation Battery, motor activity measurement, hematology and blood biochemistry were performed on all animals.
On completion of the treatment period, the animals were euthanized and submitted to a full macroscopic post-mortem examination. Designated organs were weighed and selected tissues were preserved. A microscopic examination was performed on selected tissues from control- and high‑dose animals and on kidneys, liver and adrenals from the low- and intermediate-dose animals sacrificed at the end of the treatment period, as well as on all macroscopic lesions.
The test item concentrations in the administered dose formulations analyzed in weeks 1 and 4 were within the acceptance criteria.
There were no unscheduled deaths during the study.
Piloerection and staggering gait were observed at the very beginning of the treatment period in 4/10 animals treated at 1000 mg/kg/day and ptyalism was noted in all animals from this group. These clinical signs were considered to be test item-related but non adverse.
Although the observation was not required in the study, water consumption was noticed to be higher towards the middle of the treatment period in a dose-related manner at 300 and 1000 mg/kg/day.
There were no test item-related effects at Functional Observation Battery and motor activity or onmean body weight and mean body weight changes.There were no toxicologically relevant effects on mean food consumption and mean hematology parameters.
At 1000 mg/kg/day, males had slightly higher mean protein (66 g/L vs. 60, p<0.05) and albumin (40 g/L vs. 36, p<0.01) blood concentrations and a lower bile acid level (23.6 µmol/L vs. 55.1, p<0.01) than controls. The cholesterol level was slightly higher than in controls in both sexes (males: 2.0 mmol/L vs. 1.5, p<0.05; females: 2.1 mmol/L vs. 1.7, p<0.01) and was considered to be of minor toxicological relevance. These blood biochemical findings were considered to be non adverse.
Mean liver (from +28 to +34% from controls, p<0.01), kidney (up to +23% in males with p<0.01, +10% in females with p<0.05 for the mean relative weight) and adrenal (up to +16%) weights were higher in males and/or females given 1000 mg/kg/day. There were no test item-related macroscopic findings. Microscopic findings were seen in liver (non adverse hepatocellular hypertrophy in 5/5 males and 2/5 females at 1000 mg/kg/day), kidney (hyaline droplets in 4/5 and 5/5 males at 300 and 1000 mg/kg/day, respectively, together with an increase in tubular basophilia in 3/5 males at 1000 mg/kg/day considered as adverse, tubular dilation and infiltrate of mononuclear cells), and adrenals (non adverse increased vacuolation in 2/5 males at 1000 mg/kg/day).
The test item was administered daily for 4 weeks by oral route to male and female Sprague-Dawley rats at dose-levels of 100, 300 or 1000 mg/kg/day in corn oil.
Under the experimental conditions of this study, the No Observed Adverse Effect Level (NOAEL) was considered to be at 1000 mg/kg/day in females and at 300 mg/kg/day in male rats as renal hyaline droplets were associated with increased tubular basophilia at 1000 mg/kg/day in males, suggesting previous chronic cell damage and increased cell turnover. There were no other effects that could be considered as adverse at any doses. Renal hyaline droplets were considered to be specific to male rats and therefore not relevant for human.
The analog was administered daily for 4 weeks by oral route to male and female Sprague-Dawley rats at dose-levels of 100, 300 or 1000 mg/kg/day in corn oil.
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Apparently well conducted GLP study.
There were no effects, in the repeat dose study on the analog substance, that could be considered as adverse at any doses. Renal hyaline droplets were considered to be specific to male rats and therefore not relevant for human.
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