Division 5.1.1 Absorption, distribution, metabolism and excretion after exposure by oral route

Limited data restricted to one in vivo test species (normally rat) may be all that is required as regards absorption, distribution, metabolism and excretion after exposure by oral route. These data can provide information useful in the design and interpretation of subsequent toxicity tests. However, it shall be remembered that information on interspecies differences is crucial in extrapolation of animal data to humans and information on metabolism following administration via other routes may be useful in human risk assessments.

It is not possible to specify detailed data requirements in all areas, since the exact requirements will depend upon the results obtained for each particular test substance.

The studies shall provide sufficient information about the kinetics of the active substance and its metabolites in relevant species after being exposed to the following:

1. (a)

   a single oral dose (low and high dose levels);

2. (b)

   an intravenous dose preferably or, if available, a single oral dose with assessment of biliary excretion (low dose level); and

3. (c)

   a repeated dose.

A key parameter is systemic bioavailability (F), obtained by comparison of the area under the curve (AUC) after oral and intravenous dosing.

When intravenous dosing is not feasible a justification shall be provided.

The design of the kinetic studies required shall include:

1. (a)

   an evaluation of the rate and extent of oral absorption including maximum plasma concentration (C_max), AUC, T_max and other appropriate parameters, such as bioavailability;

2. (b)

   the potential for bioaccumulation;

3. (c)

   plasma half-lives;

4. (d)

   the distribution in major organs and tissues;

5. (e)

   information on the distribution in blood cells;

6. (f)

   the chemical structure and the quantification of metabolites in biological fluids and tissues;

7. (g)

   the different metabolic pathways;

8. (h)

   the route and time course of excretion of active substance and metabolites;

9. (i)

   investigations whether and to what extent enterohepatic circulation takes place.

Comparative in vitro metabolism studies shall be performed on animal species to be used in pivotal studies and on human material (microsomes or intact cell systems) in order to determine the relevance of the toxicological animal data and to guide in the interpretation of findings and in further definition of the testing strategy.

An explanation shall be given or further tests shall be carried out where a metabolite is detected in vitro in human material and not in the tested animal species.