Ocular toxicity toxicokinetics

A 52-week study in monkeys was designed to evaluate ocular effects. Despite the absence of adverse toxicological effects at the highest dose tested (20 mg/kg body weight per day), the study was considered inappropriate for the establishment of an ADI in view of the much higher doses used in several other studies and found to be without effects. The available comparative toxicokinetic data for humans and rats indicated that studies of toxicity in rats could be used to derive an ADI. 

Current guidelines for toxicity evaluation of ophthalmic formulations involve both single and multiple applications, dependent on the proposed clinical use [39]. The multiple applications may extend over a 9-month period and incorporate evaluations of ocular irritation and toxicity, systemic toxicity, and determinations of systemic exposure (toxicokinetics). In many cases the systemic exposure from an ocular route is less than by parenteral administration, information that will assist in determining whether additional studies may be needed to establish systemic safety of the ophthalmic preparation. U.S. and international guidance documents are available [71,72], and regulations and tests have been summarized for ophthalmic preparations [39,73,74],... 

Comparative Toxicokinetics. Available data indicate that ammonia has similar targets of toxicity in humans and animals. Ammonia is most hazardous as a site-of-contact toxicant therefore, the respiratory system is most vulnerable after inhalation exposure, the gastrointestinal tract is most vulnerable after oral exposure, and the skin and eyes are most vulnerable after dermal/ocular exposure. Limited human and animal data are available for toxicokinetics however, these data indicate that humans and animals are probably very similar regarding the toxicokinetic disposition of ammonia. Furthermore, it is reasonable to expect, especially given the biochemical importance of ammonia, that humans and animals would handle this compound similarly. 

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