Objective To assess the severity and reversibility of the chronic toxicity of a novel recombinant human granulocyte colony-stimulating factor (rhG-CSFa) in rats and the dose-effect relationship.  Methods A total of 100 Sprague-Dawley rats (equal numbers of male and female) were randomly divided into five groups (20 rats in each group): four groups were treated with rhG-CSFa at 500

100

10

1 µg/kg

respectively

and one group was treated with vehicle only to serve as the control. The rats were received subcutaneous injections of rhG-CSFa or vehicle daily for 13 weeks. During the course of the chronic toxicity study

the physical status

body weight

and food consumption were monitored. Half of the rats in each group (n=10) were sacrificed after the last rhG-CSFa administration

and the other half were sacrificed at five weeks after the last rhG-CSFa administration. Urinalyses

blood biochemistry

hematological analysis

histopathological examination

and immunological tests were performed for each of the rats.  Results The hematological analyses revealed that the mean white blood cells count

neutrophils count

and neutrophils percentage were increased in male rats at the dose of 10 µg/kg or higher

and these were related with the biological activity of rhG-CSFa. Some small abnormalities were observed in the spleen of a few rats when used highest dose (500 µg/kg

a dosage of 200 folds higher than the normal clinical dosage)

but these abnormalities were recovered within 5-week recovery period. No other rhG-CSFa-related abnormalities were observed in this chronic toxicity study.  Conclusion No significant toxicity and immunogenicity are observed with rhG-CSFa administration to rats in the chronic toxicity studies.