A toxicological review of lactose to support clinical administration by inhalation.

Although lactose is widely used in the pharmaceutical industry as an excipient in preparations given by several routes of administration, including by inhalation, there is no comprehensive review of its toxicological properties. This document seeks to review the available oral preclinical and clinical safety data from the literature, together with that generated by Fisons in animals using the inhalation route. In animal toxicity studies, lactose has been administered primarily by the inhalation and dietary routes to the rat, dog and/or primate. Adverse findings, such as abdominal distension and diarrhoea, have been demonstrated in rodent feeding studies. However, these changes are considered to be due to non-specific effects associated with high dietary doses of lactose, with a subsequent production of a dietary imbalance which results in physiological disturbances and an overload in the metabolic processes particularly involving calcium. These changes at high dietary intakes of lactose are considered to be of little relevance for man under the normal conditions of use of the material as an excipient in pharmaceutical formulations. No adverse local effects to the lung have been demonstrated in the animal studies using the inhalation route. Although the inhalation dose of lactose in the animal studies, of which most is subsequently swallowed, is markedly higher than the clinical dose, it is considerably less than consumed in animal studies using the dietary route. Consequently, it is not surprising that lactose is well tolerated by the inhalation route. In a small number of susceptible humans, intolerance to lactose is generally observed with oral intake of lactose, usually as a constituent of milk and is associated with lactase deficiency. Swallowed lactose at the levels present in inhaled preparations is unlikely to present any significant problems in patients with lactase deficiency. In conclusion, lactose is well recognized as a safe pharmaceutical excipient for use in oral or inhalation formulations and is not likely to constitute any significant toxicological hazard to man.