9.2.1. Inhalation Toxicity Test Substance LC50 Toxic Effects Analogue B 1 700 mg/m3/4 hour; Lacrimation, dyspnoea, changes in structure or function of salivary gland. Analogue C 1 640 mg/m3/4 hour; Somnolence, dyspnoea, weight loss or decreased weight gain. Skin Irritation (Pharma Research Toxicology and Pathology 1987) Test substance: Analogue A Species/strain: Rabbit/New Zealand Number of animals: 3 Observation period: 7 days Method of administration: A semi-occlusive application of 0.5 mL undiluted test substance was made on the dorsal skin. After 4 hours, the substance carefully removed with tap water. Test method: OECD TG 404 Draize scores: Time after Animal # treatment (days) Erythema 1 2 3 1 a2 2 3 2 2 2 2 3 0 2 2 Oedema 1 1 0 1 2 1 0 1 3 0 0 0 a see Attachment 1 for Draize scales
Result: Analogue A was severely irritating to the eye of rabbits Eye Irritation Test Substance Eye Irritancy Analogue B Severe Analogue C Severe Analogue D Moderate Analogue F Severe Analogue G Severe 9.2.1. Skin Sensitisation No data on skin sensitisation were submitted. The notifier indicates evidence of skin sensitivity was not reported in a dermal repeat dose study in rabbits or rats using analogues (see below). Repeated Dose Toxicity 28 day Repeated Dermal Dose Toxicity (Hewstone 1994) The following is summarised from the published paper. No results were presented or tabulated. The original data was not provided for assessment. Test Substance Analogue G Species/Sex Phase 1 – Rabbit (male and female); Phase 2 – Rabbits and Rats (young and mature males). Concentration and Dosing Schedule: 1 0, 1, 3, 5, 25% solutions applied topically at 2 mL/kg/day, 5 days/week for 4 Phase 2 25% solution applied topically at 2 mL/kg/day, 5 days/week for 4 followed by a 28 day recovery period.
Attachment 1 The Draize Scale for evaluation of skin reactions is as follows: Erythema Formation Rating Oedema Formation Rating No erythema 0 No oedema 0 Very slight erythema (barely perceptible) 1 Very slight oedema (barely perceptible) 1 Well-defined erythema 2 Slight oedema (edges of area well-defined 2 by definite raising Moderate to severe erythema 3 Moderate oedema (raised approx. 1 mm) 3 Severe erythema (beet redness) 4 Severe oedema (raised more than 1 mm 4 and extending beyond area of exposure) The Draize for evaluation of eye reactions is as follows: of iris slightly obscure Opalescent areas, no details of iris visible, size of pupil barely discernible 3 moderate Greater than 75% 4 Opaque, iris invisible 4 severe Vessels definitely injected above normal More diffuse, deeper crimson red with individual vessels not easily discernible Diffuse beefy red 1 slight mod. severe Any swelling above normal Obvious swelling with partial eversion of lids Swelling with lids half- closed Swelling with lids half- closed to completely closed slight mild mod. 4 severe Any amount different from normal Discharge with moistening of lids and adjacent hairs Discharge with moistening of lids and hairs and considerable area around eye slight mod. severe IRIS Values Rating Normal 0 none Folds above normal, congestion, swelling, circumcorneal injection, iris reacts to light 1 slight No reaction to light, haemorrhage, gross destruction 2 severe FULL PUBLIC REPORT 2 November, 2000 NA/ 2/26