BAY 77488

Pivotal Study:

2-year dog study (Hoffmann & Gröning, 1977): Beagles (4/sex/dose) received phoxim in the diet at concentrations of 0, 0.3/0.1, 15, or 750 mg/kg feed for 104 weeks (0, 0.0075/0.0025, 0.38, or 19 mg/kg bw/d). Because plasma cholinesterase activity was decreased by 26% in females at week 77, although erythrocyte acetylcholinesterase activity was not affected, their dose was reduced from 0.3 to 0.1 mg/kg feed from week 83 onwards. High dose and mid-dose males showed a poor nutritional state, with dull, ruffled, and ungroomed coats at the high dose. Dose-dependent reduced body-weight gain was noted in all treated animals due to retarded growth in the second half of the study; the effect reached statistical significance only in high dose males. Plasma alanine aminotransferase & alkaline phosphatase was increased & cholesterold reduced in high dose animals. Although not increased at lower doses, the natural decline of ALP was slowed, resulting in significantly higher values than in controls in mid-dose females from week 26 onwards and in males at the two lower doses from week 52 onwards. These effects on alkaline phosphatase activity are considered to be adaptive, and were probably due to enzyme induction. Cholinesterase activity was reduced in both sexes at 15 and 750 mg/kg feed in plasma and in erythrocytes. Brain acetylcholinesterase activity was significantly reduced at the high dose. Hypoplasia in both testes was noted in one dog at the high dose.Significantly increased absolute and relative liver weights were noted in both sexes at the high dose. Dilated hepatocytes with a light, glassy,structureless cytosol was noted in both sexes at the high dose. On the basis of inhibition of brain acetylcholinesterase activity and effects on the liver, the NOEL was15 mg/kg feed, equivalent to 0.38 mg/kg bw/d.

Animal Specie:

Dog

Effect:

Liver effects and inhibition of brain acetylcholinesterase activity

NOEL:

0.38 mg/kg bw/day

Point of departure:

0.38 mg/kg bw/day