cvm’s procedure for setting tolerances lynn g. friedlander, ph. d. division of human food safety...
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CVM’s Procedure for Setting Tolerances
Lynn G. Friedlander, Ph. D.
Division of Human Food Safety
Residue Chemistry Team
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Tolerance Setting
Chemical residuesOther approaches
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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)
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Tolerance Setting
Office of New Animal Drug EvaluationDivision 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)
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Tolerance Setting-Toxicology
Basic Toxicology PackageAdditional/special toxicology studiesCalculate the No Observable Effect Level
(NOEL)Determine the appropriate safety factorCalculate the Allowable Daily Intake
(ADI)
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Tolerance Setting-Toxicology
ADI = No Observable Effect Level Safety Factor
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Tolerance Setting-ToxicologyCalculating the Safe Concentration
Safe Concentration = ADI x 60 kg consumption factor
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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.
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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.
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Tolerance Setting-Residue Chemistry
Basic Studies Comparative Metabolism-Toxicology Species Total Residue and Metabolism-Target Species Analytical Method Residue Depletion/Withdrawal-Target Species
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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.
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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
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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
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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
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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
16Time (days)
Dru
g C
once
ntr
atio
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0.01
0.1
1000.0
100.0
10.0
1.0
1 2 3 4
Total Residue
Marker Residue
Safe Concentration
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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
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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
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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
20Time (days)
Dru
g C
once
ntr
atio
n
0.01
0.1
1000.0
100.0
10.0
1.0
1 2 3 4
Total Residue
Tolerance
Marker Residue
Safe Concentration
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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
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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
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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
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Tolerance Setting-Residue Chemistry
Toxicology results Withdrawal Time
ToleranceAnalytical
Method
Radiochemistry results Milk Discard Time
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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
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Tolerance Setting-Residue ChemistryApplying the Tolerance
US Approvals
Formulation A Original Safety Data Tolerance for A
Formulation A2
Formulation A3Must link to or confirm the original
safety dataFormulation AN