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

2. Tolerance Setting
Chemical residues
Other approaches

3. 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 (b)

4. 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)

5. 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)

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

7. Tolerance Setting-Toxicology Calculating the Safe Concentration
Safe Concentration = ADI x 60 kg consumption factor

8. 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.

9. 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.

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

11. 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.

12. 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

13. 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

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

15. 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

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

17. 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

18. 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

19. 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

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

21. 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

22. 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

23. Tolerance Setting-Residue Chemistry
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

24. Tolerance Setting-Residue Chemistry

25. Tolerance Setting-Residue Chemistry Applying 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

26. Tolerance Setting-Residue Chemistry Applying the Tolerance US Approvals