SUPPLEMENTARY MATERIAL Table S1: Toxicological parameters ...

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bone marrow (sternum), mandibular lymph nodes, mesenteric lymph nodes, spleen, liver and lung were examined in all groups. For all other organs (see list ...
SUPPLEMENTARY MATERIAL Table S1: Toxicological parameters studied in rats and monkeys Analyzed parameters

Frequency assessed

Mortality

Twice daily

Local tolerance

Before and approximately 24 hours after each administration, then once weekly during the recovery time Daily

Clinical observation opthalmology Body weight gain Food consumption Cardiovascular examination Functional operational behavior (FOB) hematology

Serum clinical chemistry

Urine analysis

Organ weights Macroscopic examination at necropsy Histopathology

Performed pretest and during the fourth week Weekly for each animal

Systolic and diastolic arterial blood pressure (indirect method using a thigh- or arm-cuff), electrocardiography (leads I, II, III): heart rate, analysis of rhythm, duration of QRS complex and PR and QT intervals Auditory and pupillary reflex tests, in grip strength (gripping test) and locomotor activity in an open-field.

Hemoglobin, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, packed cell volume, red blood cell count, mean corpuscular volume, reticulocyte count, platelet count, total white blood cell count, differential white blood cell count. Coagulation parameters (platelets, activated partial thromboplastin time, prothrombin time, fibrinogen concentration) Sodium, potassium, chloride, calcium, inorganic phosphorus, glucose, urea, total cholesterol, total bilirubin, total protein, albumin, globulin, creatinine, alkaline phosphatase, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), gamma glutamyl transferase, complement factors Bb and C3a (monkeys only) Volume; specific gravity; appearance; semi-quantitative estimations: pH, protein, glucose, ketones, urobilinogen, bilirubin, blood.

External surface, all orifices, cranial cavity, external surface of the brain and samples of the spinal cord, thoracic and abdominal cavities and organs, cervical tissues and organs, carcass, injection sites. Injection sites, stomach, duodenum, jejunum, ileum, caecum, colon, bone marrow (sternum), mandibular lymph nodes, mesenteric lymph nodes, spleen, liver and lung were examined in all groups. For all other organs (see list below), only the highest dose and control animals were examined. Organs: Adrenal glands, Aorta, Bone (femur) and articulation, Bone (sternum) with bone marrow, Brain, Bronchi, Caecum, Colon, Duodenum, Epididymides, Eyes, Harderian glands, Gall bladder, Heart, Ileum, Injection sites, Jejunum, Kidneys, Liver, Lungs, Lymph nodes (mandibular and mesenteric), Mammary gland, Oesophagus, Optic nerves, Ovaries, Pancreas, Parathyroid glands, Pituitary gland, Prostate, Salivary glands (mandibular, parotid, sublingual), Sciatic nerve (left), Seminal vesicles, Skeletal muscle, Skin, Spinal cord (cervical, thoracic, lumbar), Spleen, Stomach, Testes, Thymus , Thyroid glands, Trachea, Urinary bladder, Uterus (horns + cervix), Vagina

Daily for each monkey or weekly for each cage of rats For monkeys only; on days 0 and 26 (6 hours after the last injection) For rats; days 0 and 26

Performed pretest and on days 27 and 41

Performed pretest and on days 27 and 41

Performed pretest and on days 27 and 41 Days 27 and 41 Days 27 and 41

Days 27 and 41