Intravenous tolerability of an acid vehicle in Sprague Dawley rats and beagle dogs after daily slow bolus injection and infusion for one hour during 14 days.
To assess the tolerability of an acid vehicle to be used in toxicology studies, a low pH aqueous solution containing 16.4 mg/ml of citric acid, 4.2 mg/ml of disodium phosphate, 25 mg/ml of mannitol, adjusted with phosphoric acid/NaOH 1 M to pH 3 was daily administered intravenously to rats and dogs for 14 consecutive days. The dosing regimen consisted of a slow intravenous bolus injection given over 30 s (0.75 and 0.625 ml/kg, for rats and dogs, respectively) followed by intravenous infusion for one hour (3.75 and 2.75 ml/kg/h, for rats and dogs, respectively). In rats, the dose was administered via the lateral tail vein. In dogs, the intravenous bolus dose was administered via the vena cephalica, vena saphena or vena jugularis, whilst the infusion dose was given into the vena cephalica or vena saphena. In rats, administration of the vehicle was associated with clinical signs (occasional mild vocalization and agitation) which were considered to be due to local irritation during the dosing procedure. Nevertheless, only mild histopathological changes at the injection site were found, while no relevant clinical chemistry changes were found in this species. However, the vehicle caused significant vascular damage with thrombus formation in the dog. It is therefore concluded that this vehicle is suitable for 2-week rat toxicity studies, if carefully applied. The vehicle with its present regimen should not be used in dogs, in view of the prohibitive findings.
Ploemen
Jan-Peter H T M
JP
NV Organon, Toxicology & Drug Disposition, PO Box 20, 5340 BH Oss, The Netherlands.
van Esch
Eric
E
Oshodi
Rotimi
R
de Hoog
Saskia C M
SC
Frieling
Wilbert J A M
WJ
Kaijser
Gerry
G
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D006863:Hydrogen-Ion Concentration; D007262:Infusions, Intravenous / Q000009:adverse effects; D008297:Male; D014677:Pharmaceutical Vehicles / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D014677:Pharmaceutical Vehicles