Oral administration of the notified chemical to rats by gavage for a period of 28 days consecutively, resulted in treatment-related but non-adverse changes in either sex at the high dose and in males treated with the mid dose or low doses. There was no effect of treatment in females treated with mid or low doses. A clear No Observed Effect Level (NOEL) for treatment-related histopathological changes was not established in respect of renal changes in mid or low dose treated males but the NOEL in females was considered to be 150 mg/kg/day. Treatment-related changes seen in male rats treated with mid or low doses were consistent with well-documented condition known as hydrocarbon nephropathy. This only occurs in male rats and is not indicative of a hazard to human health. Furthermore, the effects seen in animals treated with the high dose were confined to minimal clinical observations and adaptive, reversible liver and thyroid changes. Therefore the No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg/day. SafePharm Laboratories Limited (2004g) 7.7. Genotoxicity bacteria – Notified chemical OECD TG 471 Bacterial Reverse Mutation Test. EC Directive 2000/32/EC B.13/14 Mutagenicity Reverse Mutation Test – Bacteria. Species/Strain S. typhimurium: TA1535, TA1537, TA98, E. Coli:WP2 uvrA Metabolic Activation System S9 mix from liver homogenate of Arochlor 1254 induced rats Concentration Range in a) With metabolic activation: 50 to 5000 µg/plate. Main Test b) Without metabolic activation: 50 to 5000 µg/plate. Vehicle Dimethyl sulfoxide Remarks - Method A preliminary assay was carried out to determine the toxicity of the test substance. The concentrations tested were 0, 0.15, 0.5, 1.5, 5, 15, 50, 150, 500, 1500 and 5000 g/plate. The main test was conducted at concentrations ranging from 50 to 5000 g/plate. There was no visible decrease in the bacterial lawn both in the presence and absence of S9 activation.Test conducted in accordance with GLP standards. Metabolic Test Substance Concentration (µg/plate) Resulting in: Activation Cytotoxicity in Cytotoxicity in Precipitation Genotoxic Effect Preliminary Test Main Test Absent Test 1 None None None None Present Test 1 None None None None
Oral administration of the notified chemical to rats by gavage for a period of 28 days consecutively, resulted in treatment-related but non-adverse changes in either sex at the high dose and in males treated with the mid dose or low doses. There was no effect of treatment in females treated with mid or low doses. A clear No Observed Effect Level (NOEL) for treatment-related histopathological changes was not established in respect of renal changes in mid or low dose treated males but the NOEL in females was considered to be 150 mg/kg/day. Treatment-related changes seen in male rats treated with mid or low doses were consistent with well-documented condition known as hydrocarbon nephropathy. This only occurs in male rats and is not indicative of a hazard to human health. Furthermore, the effects seen in animals treated with the high dose were confined to minimal clinical observations and adaptive, reversible liver and thyroid changes. Therefore the No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg/day. SafePharm Laboratories Limited (2004g) 7.7. Genotoxicity – bacteria Notified chemical OECD TG 471 Bacterial Reverse Mutation Test. EC Directive 2000/32/EC B.13/14 Mutagenicity – Reverse Mutation Test Bacteria. Species/Strain S. typhimurium: TA1535, TA1537, TA98, E. Coli:WP2 uvrA Metabolic Activation System S9 mix from liver homogenate of Arochlor 1254 induced rats Concentration Range in Main Test a) With metabolic activation: 50 to 5000 µg/plate. b) Without metabolic activation: 50 to 5000 µg/plate. Vehicle Dimethyl sulfoxide Remarks - Method A preliminary assay was carried out to determine the toxicity of the test substance. The concentrations tested were 0, 0.15, 0.5, 1.5, 5, 15, 50, 150, 500, 1500 and 5000 g/plate. The main test was conducted at concentrations ranging from 50 to 5000 g/plate. There was no visible decrease in the bacterial lawn both in the presence and absence of S9 activation.Test conducted in accordance with GLP standards. Metabolic Activation Test Substance Concentration (µg/plate) Resulting in: Cytotoxicity in Preliminary Test Cytotoxicity in Main Test Precipitation Genotoxic Effect Absent Test 1 None None None None Present Test 1 None None None None
STD1156FR.docx