28-day repeated dose oral toxicity of recombinant human holo-lactoferrin in rats

Recombinant human holo-lactoferrin (holo-rhLF) was orally administered, via gavage, to Wistar rats at 1000, 500 and 100mg/kgbw/day for 28 days. The test article, holo-rhLF, was expressed in rice grain, extracted, purified and saturated with iron. During the 28-day period, animals were examined for evidence of toxicity. On day 29, the animals were exsanguinated, examined for gross pathology, and tissues preserved for histopathology. There were no deaths caused by holo-rhLF and in-life physical signs were generally normal. Although statistical differences were noted in some hematology, clinical chemistry and heart/body weight ratios, they were of questionable biological significance. A significantly greater total iron binding capacity (TIBC) was detected in the blood of male animals dosed with holo-rhLF. Serum was analyzed for the presence of IgG and IgE antibodies; demonstrating low levels of IgG antibodies to the human protein, but no increase in IgE antibodies. There was no increase in serum lactoferrin levels. The results of the 28-day oral administration demonstrate a lack of toxicity of holo-rhLF in rats. There were no treatment related, toxicologically relevant changes in clinical signs, growth, food consumption, hematology, clinical chemistry, organ weights or pathology. The no observed adverse effect level (NOAEL) is greater than 1000 mg/kg/day.