"Clinical observations: Animals inspected visually at least twice daily for signs of ill health or reaction to treatment Cages inspected daily for evidence of animal ill health.

Detailed observations were recorded daily at the following time in relation to exposure to the test substance: Pre-exposure observation; During exposure ;As each animal returned to its

home cage; As late as possible in the working day

Clinical signs: Body weight: the weight of each animal was recorded twice weekly from Week 1 to Week 4, once weekly in Weeks 5 to 13 and on the day of necropsy.

Food consumption: the weight of food supplied to each cage, that remaining and an estimate of any spilled was recorded for the week before treatment started and for each week throughout the study.Ophthalmic examination: the eyes of all animals were examined by means of a binocular indirect ophthalmoscope as follows:

Pretreatment: All animals (including spares)Week 1 3: All animals of Groups 1 & 4

Haematology, Peripheral blood: Blood samples were collected after overnight withdrawal of food and prior to dosing at the following occasion: Week 13: all animals

Animals were held under light anaesthesia by isoflurane. Blood samples (0.5 ml) were taken from the sublingual vein and collected into tubes containing EDTA anticoagulant and examined for the following using a Bayer Advia 120 analyser: Haematocrit (Hct), Haemoglobin (Hb), Erythrocyte count (RBC), Absolute reticulite count (Retic), Mean cell haemoglobin (MCH), Mean cell haemoglobin concentration (MCHC), Mean cell volume (MCV), Red cell distribution width (RDW), Total leucocyte count (WBC): Neutrophils (N), Lymphocytes (L), Eosinophils (E), Basophils (B), Monocytes (M), Large unstained cells (LUC), Platelet count (Plt)

Additional blood samples (0.5 ml) were taken into tubes containing citrate anticoagulant and examined using an ACL series analyser and appropriate reagent in respect of: Prothrombin time (PT) - using IL PT Fibrinogen reagent; Activated partial thromboplastin time (APTT) - using APTT reagent

Blood chemistry: Bloods samples (0.7 ml) were taken from the sublingual vein and collected into tubes containing lithium heparin as anticoagulant. After separation the plasma was examined

using a Roche P Modular Analyser for Alkaline phosphatase (ALP), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Total bilirubin (Bili), Urea, Creatinine (Creat), Glucose (Glu), Total cholesterol (Chol). Trigylerides, (Trig), Sodium (Na), Potassium (K), Chloride (Cl), Calcium (Ca), Inorganic phosphorous (Phos), Total protein ((Total Prot), Albumin (Alb)

Male and Female Wistar Rats