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 It was current when produced, but is no longer maintained and may be outdated.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. Human Food Safety Evaluation of Food Animal DrugsImport Tolerances Mark M. Robinson, PhD, DVM Director, Division of Human Food Safety Office of New Animal Drug Evaluation FDA Center for Veterinary Medicine

3. FFD&C Act • SEC 512 (a) (6) … In establishing such tolerance, the Secretary shall rely on data sufficient to demonstrate that a proposed tolerance is safe based on similar food safety criteria used by the Secretary to establish tolerances for applications for new animal drugs filed under subsection (b)1.

4. What Is Evaluated? • Sponsor-generated data demonstrating the effects of defined concentrations of an active ingredient, formulation component, metabolite(s), or drug product in relation to specific endpoints of relevance to public health.

5. Why? • SEC 512 (d) (2) In determining whether such drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof, the Secretary shall consider, among other relevant factors, (A) the probable consumption of the drug and of any substance formed in or on food because of the use of such drug, (B) the cumulative effect on man or animal of such drug, ...

6. The Point? • To identify any potential adverse human health effect(s) that may be caused by the consumption of a new animal drug residue in edible tissues from food animals. • To mitigate any potential adverse human health effect that is identified.

7. What is a Residue? • Any compound present in edible tissues of the target animal which results from the use of the sponsored compound, including the sponsored compound, its metabolites, and any other substance formed in or on food because of the sponsored compound’s use. 21 CFR 500.82 (b)

8. Objectives of Evaluation • Determine the concentration of total residues in the edible tissues of a food animal that, when consumed daily by an individual over a lifetime, will cause no harm (i.e., the acceptable daily intake, orADI). • Define the concentration of a marker residue in the edible tissue(s) of a food animal that will be indicative that the edible tissue is “safe” (i.e., the tolerance).

9. Underlying Assumptions • All factors are constant: • Purity • Strength • Identity • Active ingredient(s) • Formulation • Good Agricultural Practices (GAP)

10. Historical Perspective • Originally (at least in the U.S.), animal drugs were approved on the basis of no residueor zero residuetolerances. • Technologically limited; i.e., as analytical resolution improved, the value of “zero” changed.

11. Historical Perspective • Modified to negligible tolerance - • 0.1 ppm for all drug residues except carcinogens. • Minimal hazard assessment for most drug residues.

12. Historical Perspective • CVM moved to a risk-based evaluation: Risk=HazardXExposure

13. Current Approach • Public health risk is regulated by assessing the potentialhazard posed by the drug substance, and controlling the exposure to this potential hazard to meet the mandated risk standard of: “A Reasonable Certainty of No Harm”.

14. How is “Hazard” Assessed? • Through toxicological evaluation. How is “Exposure” Controlled? • Through residue chemistry evaluation related to toxicological findings.

15. HAZARDASSESSMENT

16. Food Safety Toxicology • Genetic toxicity battery • 90-day feeding studies in rodents and other mammals • Multigeneration reproduction study in rats • Developmental (teratology) study in rats • Antimicrobial drug residue studies • Special studies including chronic (“lifetime”) toxicity and/or carcinogenicity studies in rodents

17. Food Safety Toxicology • All testing is conducted through oral exposure in surrogate species to evaluate the potential toxicity of the new animal drug to humans following oral exposure in food.

18. Food Safety Toxicology • The objective is to define the concentration of drug substance that produces no effect in the toxicological assay of greatest relevance to oral human exposure. N(o) O(bserved) E(ffect) L(evel) or NOEL

19. Food Safety Toxicology • EXPERT OPINION • The appropriate NOEL is divided by a “safety factor” to obtain an “acceptable daily intake” (ADI), which is the amount of drug residue per kilogram body weight per day that can be consumed daily over the lifetime of a human without harmful effect.

20. Safety Factors? • SEC 512 (d) (2) In determining whether such drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof, the Secretary shall consider, among other relevant factors, … (C) safety factors which in the opinion of experts, qualified by scientific training and experience to evaluate the safety of such drugs, are appropriate for the use of animal experimentation data, ...

21. Safety Factors • Variability between humans 10X • Interspecies extrapolation 10-100X • Subchronic extrapolation 10X • Total possible 0-10,000X

22. Safe Concentration forTotal Chemical Residues • Consumption Factors • 0.3 kg muscle 0.05 kg fat • 0.1 kg liver (0.1 kg eggs) * • 0.05 kg kidney (1.5 L milk) * NOEL(ug/kg bw/day) = safety factor ADI (ug/kg bw/day) ADI x 60 kg = consumption factor Safe Concentration

23. Underlying Assumptions • All factors are constant: • Purity • Strength • Identity • Active ingredient(s) • Formulation • Good Agricultural Practices (GAP)