Division 3.2.1.2 Residue studies

Consideration shall be given to the amount and the nature of non-extractable residues in edible tissues or products.

Residue studies are required for all substances for which metabolic studies are needed.

If the substance is a natural constituent of body fluids or tissues or is naturally present in significant amounts in food or feedingstuffs, the requirement for residue studies is limited to the comparison of the tissue/product levels in an untreated group and in the group supplemented with the highest dose claimed.

For major species, studies shall simultaneously evaluate the total residues of toxicological significance and identify the marker residue of the active substance in edible tissue (liver, kidney, muscle, skin, skin + fat) and products (milk, eggs and honey). The marker residue is the residue selected for assay whose concentration has a known relationship to the total residue of toxicological concern in the tissues. Studies shall also show the permanence of the residues in the tissues or products to establish an appropriate withdrawal period.

For the determination of a withdrawal period, the suggested minimum number of animals sampled and/or products at each time point are the following:

• edible tissues:

  • bovines, sheep, pigs and minor species 4;

  • poultry 6;

  • salmonids and other fish 10.

• products:

  • milk 8 samples per time point;

  • eggs 10 eggs per time point;

  • honey 8 samples per time point.

Appropriate sex distribution shall be considered.

The residues shall be measured at zero withdrawal time (steady state) and at least three other time sampling points.

A proposal for a marker residue shall be provided.

Studies on the absorption, distribution and excretion, including the identification of main metabolites must be performed in the laboratory animal species in which the lowest NOAEL was obtained, or by default in the rat (both sexes). Additional studies on particular metabolites may be necessary if these metabolites are produced by target species and are not formed to a significant extent in the laboratory species.