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EC number: 931-384-6 | CAS number: -
Repeat dose study by gavage in accordance with OECD Test Guideline 407 is available for this substance. The no observable adverse effect level (NOAEL) for this study is 150 mg/kg/day.
The reported animal housing temperature range for this study (17.8–22.2ºC) is slightly lower than that recommended by OECD (19–25 ºC), but this is not expected to have had any impact on the study.
Bile acids were not measured as part of clinical chemistry and Prostate glands and seminal vesicles with coagulating glands were not weighed at necropsy. These measures were not requirements of the 1995 OECD TG 407, which was current at the time of the study, but are included in the 2008 revised guideline.
Oral administration of the test substance to CD rats produced treatment-related microscopic changes in the adrenal glands of the male and female rats and kidneys of the male rats of the 150 and 500 mg/kg/day groups. Microscopic changes also were noted in the stomach of the male and female rats of the 500-mg/kg/day group and these changes were possibly treatment related. The dosing problems encountered in the 500 mg/kg/day animals probably were related to the changes in the stomach.
The Functional Observational Battery data revealed a statistically significant decrease in landing foot splay in the 150 and 500 mg/kg/day females and a statistically significant decrease in rectal temperature in the 500 mg/kg/day females. However, there were no microscopic changes in the brain, spinal cord, skeletal muscle, peripheral nerves, spinal nerve roots/ganglia and trigeminal ganglion that were considered treatment-related.
Oral administration of the test substance to CD rats did not cause any biologically significant changes in the clinical pathology data or general clinical observations. There was an increase in the adrenal weight parameters in the 500 mg/kg/day females that appears to correlate with the microscopic findings of the adrenals.
The test material was investigated for subacute oral toxicity and neurotoxicity/neuropathology in a GLP study conducted in accordance with OECD Test Guideline 407 (1995). Four groups of 10 male and 10 female CD Sprague-Dawley rats were administered the test material (in Primol 542 carrier) by daily gavage at doses of 0, 50, 150 and 500 mg/kg/day for 28 days. The dose volume used was 5 mL/kg body weight. In addition to the observation and measurement of standard parameters, a complete functional observational battery (FOB) was conducted on all animals prior to dosing and during Week 4 of dosing. Additionally, once during Weeks 1, 2 and 3, all animals were observed in a standard arena. Motor activity was assessed using a photobeam activity system at the same intervals as the FOB. Neuropathology was additionally examined in five animals per sex form the control and high-dose groups.
One mid-dose and five high-dose animals died during the study. Four of the high-dose deaths were attributed to dosing trauma. The incidence of clinical in-life observations was minimal and did not appear treatment-related.
Statistically significant increases in body weight, weight gain and/or food consumption were seen in high-dose females and, in Week 3 only, mid-dose females
No treatment-related gross pathology was observed, but microscopic changes were seen variously in the mid- and high-dose groups in the adrenals, kidneys, and stomach/forestomach. The gastric effects in the high-dose were likely to have caused the resistance of these animals to dosing, which led to the dosing trauma. The effects on the adrenals were accompanied by an increased organ weight.
The FOB identified decreased landing foot splay in the mid- and high-dose females, and also decreased rectal temperature in the high-dose females. Microscopic examination of the nervous system revealed no treatment-related changes.
Therefore, the no observable adverse effect level (NOAEL) for this study is 150 mg/kg/day, and the no observable effect level (NOEL) is 50 mg/kg/day. Principal treatment-related effects occurring at higher doses include effects on the adrenals, kidneys, stomach, as well as rectal temperature and landing foot splay.
Oral administration of the test substance to rats by gavage in accordance with OECD Test Guideline 407 (1995) produces treatment related microscopic changes in the adrenal glands of the male and female rats and kidneys of the male rats of the 150 and 500 mg/kg/day groups. The adrenal gland changes are accompanied by an increase in adrenal weight only at the high doses level. The male kidney effects are accompanied by an increase in hyaline droplets which is consistent with male rat species specific effect resulting from the excessive accumulation of α2-microglobulin in renal proximal tubular epithelial cells. Microscopic changes also are present in the stomach of the male and female rats of the 500 mg/kg/day group and these changes were possibly treatment related. Landing foot splay was statistically significantly decreased in mid- and high-dose females, and rectal temperature was also statistically significantly decreased in the high-dose females. However, because landing foot splay was not increased and there were no statistically significant differences in mean motor activity data or other functional observational battery parameters, this is not considered to be evidence of serious adverse effects. Therefore, the no observable adverse effect level (NOAEL) for this study is 150 mg/kg/day, and the no observable effect level (NOEL) is 50 mg/kg/day.
In accordance to Directive 67/548/EEC and EU CLP (Regulation (EC) No. 1272/2008), classification of this substance is not required for prolonged exposure.
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