EVALUATION OF TOXICOLOGICAL DATA All toxicology studies were performed using TKA 40116. Toxicity Summary of the toxicity of TKA 40116 Test Species Outcome Reference acute oral toxicity rat LD50 > 2 000 mg/kg (McRae & Mason, 1995) acute dermal toxicity rat LD50 > 2 000 mg/kg (Arcelin, 1997) skin irritation rabbit slight to moderate irritant (Parcell, 1995b) eye irritation rabbit slight irritant (Parcell, 1995a) skin sensitisation guinea pig non-sensitiser (Allan, 1995) Oral Toxicity (McRae & Mason, 1995) Species/strain: rat/Sprague-Dawley Number/sex of animals: 5/sex Observation period: 14 days Method of administration: gavage Clinical observations: piloerection in all rats within seven minutes of dosing and over five days Mortality: none Morphological findings: none Test method: EEC Method B.1 (European Economic Community, 1992) LD50: > 2 000 mg/kg Result: the notified chemical was of very low acute oral toxicity in rats
Dermal Toxicity (Arcelin, 1997) Species/strain: rat/HanIbm:WIST(SPF) Number/sex of animals: 5/sex Observation period: 14 days Method of administration: under semi-occlusive dressing for 24 hours Clinical observations: no clinical signs or local effects on the skin Mortality: none Morphological findings: none Test method: OECD guideline TG 402 (Organisation for Economic Co-operation and Development, 1995- 1996) LD50: > 2 000 mg/kg Result: the notified chemical was of low acute dermal toxicity in rats Inhalation Toxicity not available Skin Irritation (Parcell, 1995b) Species/strain: rabbit/New Zealand White Number/sex of animals: 3/unspecified Observation period: 4 days Method of administration: 0.5 mL of the notified chemical under semi- occlusive dressing for 4 hours
Draize scores (Draize, 1959): Time after Animal # treatment (days) Erythema 1 1 2 3 Oedema a see Attachment 1 for Draize scales Test method: EEC method B.4 (European Economic Community, 1992) Result: the notified chemical was a slight to moderate skin irritant in rabbits Eye Irritation (Parcell, Species/strain: rabbit/New Zealand Number/sex of animals: 3/unspecified Observation period: 7 days Method of administration: 0.1 mL into the lower everted lid of one eye of each animal Test method: EEC method B.5 (European Economic Community, 1992)
Result: no mutagenic activity of the notified chemical was observed in bacteria at doses up to 5 000 g/plate in the presence or absence of metabolic activation provided by rat liver S9 fraction; positive controls demonstrated the sensitivity of the assay and negative controls were within normal limits; no cytotoxicity was evident at the top dose Chromosomal Aberration Assay in Chinese Hamster V79 Cells (Czich, 1997) Cell line: Chinese Hamster V79 concentrations ( g/mL) without S9 mix: 18 hours 10 – 300 (plus 1 000 in one replicate) 28 hours 50 – 300 (plus 1 000 in one replicate) with S9 mix: 18 hours 10 – 1 000 28 hours 50 – 1 000 Treatment details: S9 mix was prepared from Wistar rats treated with phenobarbital and -naphthoflavone; treatment with S9 was for 4 hours, followed by 18 or 28 hours in the test article, with colcemid added 2.5 hours prior to harvest Test method: OECD guideline TG 473 (Organisation for Economic Co-operation and Development, 1995- 1996) Result: no increase in chromosomal aberrations was induced by the notified chemical; negative controls were within historical limits and positive controls demonstrated the sensitivity of the