OCULAR TOXICITY STUDIES ::
These studies should be carried out in two species one of which should be the albino rabbit which has asufficiently large conjunctival sac Direct delivery of drug onto the cornea in case of animals having small conjunctival sacs should be ensured Liquids ointments gels or soft contact lenses (Saturated with drug ) should be used Initial single dose application should be done to decide the exposure concentrations for repeated -dose studies and if needed one should include a recovery group Duration of the final study depends on the proposed length of human exposure Subject to a maximum of 90 days At least two different concentrations exceeding the human dose should be used for demonstrating the margin of safety in acute studies one eye is used as control administration and the other kept as control A separate control group should be included in repeated -dose studies
Slit-lamp examination should be done to detect the changes in cornea iris and aqueous humor Fluorescent dyes (sodium fluorescein 0.25 to 1.0% ) should be used to detect the defects in surface epithelium of cornea and conjunctiva changes in intra-ocular tension should be monitored by a tonometer Histological examination of eyes is done at the end of the study after fixation in Davidson s or Zenker s fluid
Inhalation toxicity studies ::
The studies are to be undertaken in one rodent and one non -rodent species using the formulation Acute subacute and chronic toxicity studies should be performed according to the intended duration of human exposure Standard systemic toxicity study designs as described above are normally be used Gases and vapors should be given in whole body exposure chambers aerosols are to be given through the nasal route Exposure time and concentrations of test substance (limit dose of 5 mg/l) is adjusted to ensure exposure at levels comparable to multiples of intended human exposure Three dose groups and a control (plus vehicle control if needed ) are required Duration of exposure may vary Subject to a -maximum of 6 hours per day and five days a week Food and water are withdrawn during the period of exposure to test substance
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