U.S. Food and Drug Administration

1. U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

2. CVM’s Procedure for Setting Tolerances Lynn G. Friedlander, Ph. D. Division of Human Food Safety Residue Chemistry Team

3. Tolerance Setting • Chemical residues • Other approaches

4. Tolerance Setting Residue: Any compound present in the edible tissues of the target animal which results from the use of the sponsored compound, including the sponsored compound, its metabolites, and any other substances formed in or on food because of the sponsored compound’s use. 21 CFR 500.82 (b)

5. Tolerance Setting • Office of New Animal Drug Evaluation • Division of Human Food Safety • Toxicity data from the model species • Microbial safety data • Residue data from the target food-producing species • Analytical methodology • Good Laboratory Practices (GLP)

6. Tolerance Setting-Toxicology • Basic Toxicology Package • Additional/special toxicology studies • Calculate the No Observable Effect Level (NOEL) • Determine the appropriate safety factor • Calculate the Allowable Daily Intake (ADI)

7. Tolerance Setting-Toxicology ADI = No Observable Effect Level Safety Factor

8. Tolerance Setting-ToxicologyCalculating the Safe Concentration Safe Concentration = ADI x 60 kg consumption factor

9. Tolerance Setting-Toxicology The safe concentration is the amount of residue that can be eaten in any edible tissue each day for an entire lifetime without exposing the consumer to residues in excess of the ADI.

10. Tolerance Setting-Residue Chemistry • Risk = Hazard X Exposure • Mitigates the hazard identified in the toxicology safety studies by controlling exposure to the hazard through the assigning of tolerances and withdrawal periods or milk discard periods, where needed.

11. Tolerance Setting-Residue Chemistry • Basic Studies • Comparative Metabolism-Toxicology Species • Total Residue and Metabolism-Target Species • Analytical Method • Residue Depletion/Withdrawal-Target Species

12. Tolerance Setting-Residue Chemistry • Comparative Metabolism Study • Did the toxicology testing evaluate the right compound(s)? • Qualitative comparison of the metabolic profiles in the toxicological and food-producing species • Ensures that the toxicological species has been exposed to the same residues to which humans will be exposed when they consume products derived from treated food-producing animals • If profiles are not comparable, more toxicology testing may be indicated.

13. Tolerance Setting-Residue Chemistry • Total Residue and Metabolism Study • Radiolabeled drug • 1-1.5X the proposed dose • Proposed route of administration • Intended duration of treatment/steady state • Intended species; males and females

14. Tolerance Setting-Residue Chemistry • Total Residue and Metabolism Study • Determines the MARKER RESIDUE • the residue that monitors the depletion of total residues in a tissue • Determines the TARGET TISSUE • generally, the edible tissue from which residues deplete most slowly • often, liver or kidney • rarely, muscle or fat

15. Tolerance Setting-Residue Chemistry • Total Residue and Metabolism Study • Provides a METABOLISM PROFILEin the food-producing animal • for comparison with the metabolism profile of the toxicological species • Establishes the MARKER:TOTAL ratio • to calculate the tolerance

16. Tolerance Setting-Residue Chemistry • Analytical Methodology • Determinative • measures concentrations of drug residues in tissue • Confirmatory • verifies the identity of the drug residue • Screening • assesses impact the new drug on pre-existing residue tests • not required

17. 1000.0 Total Residue 100.0 Safe Concentration 10.0 Drug Concentration 1.0 Marker Residue 0.1 0.01 1 2 3 4 5 Time (days)

18. Tolerance Setting-Residue Chemistry • Determine the time at which the concentration of total radiolabeled residues in the target tissue is less than the target tissue safe concentration • Determine the concentration of the marker residue in the target tissue at that time using the proposed analytical methodology

19. Tolerance Setting-Residue Chemistry • The concentration of the marker residue in the target tissue at the time the total radiolabeled residue in the target tissue has depleted to less than the target tissue safe concentration is the target tissue TOLERANCE

20. Tolerance Setting-Residue Chemistry • Can establish tolerances for more than one tissue, i.e., target tissue and muscle • must have data for the tissue(s) to support the tolerance assignment(s) • often these data are available as part of the total residue and metabolism study

21. 1000.0 Total Residue 100.0 Safe Concentration 10.0 Drug Concentration 1.0 Marker Residue Tolerance 0.1 0.01 1 2 3 4 5 Time (days)

22. Tolerance Setting-Residue Chemistry • Target tissue tolerance is a monitor for the depletion of residues from all the edible tissues • When the concentration of the marker residue in the target tissue is less than the target tissue tolerance, total residues in all of the edible tissues are less than their respective safe concentrations

23. Tolerance Setting-Residue Chemistry • Non-target tissue tolerance monitors depletion of residues only from the specific non-target tissue • For example, if we assign a muscle tolerance and muscle is not the target tissue: • Muscle tolerance monitors the depletion of residues from the muscle • When the concentration of the marker residue in the muscle is less than the muscle tolerance, the total residues in the muscle are less than the muscle safe concentrations • Muscle tolerance does not monitor any other edible tissues

24. Tolerance Setting-Residue Chemistry • Tolerance • links the ADI and safe concentrations of total radiolabeled residues to “cold” residues that result from the use of the proposed market formulation as measured with the regulatory analytical method

25. Tolerance Setting-Residue Chemistry

26. Tolerance Setting-Residue ChemistryApplying the Tolerance • The preslaughter withdrawal period and, if applicable, the milk discard period • on the product labeling • in the relevant section of 21 CFR Part 500 • The established tolerance is codified under 21 CFR 556

27. Tolerance Setting-Residue ChemistryApplying the ToleranceUS Approvals