Substances Generally Recognized as Safe (GRAS) for Use in Feed

1. Substances Generally Recognized as Safe (GRAS)for Use in Feed Mika Alewynse, Ph.D. Division of Animal Feeds Center for Veterinary Medicine AFIA Spring Forum 2009 Destin, Florida

2. What is GRAS? • 1958 Food Additives Amendment to Federal Food, Drug and Cosmetic Act • Defined “food additive” • Required premarket approval of food additives • Established standards for safety and review • Created exemption to food additive definition • GRAS status for a specific use of substance

3. Food Additives • FD&C Act section 201(s) "food additive" means any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristics of any food …, if such substance is not generally recognized, among experts qualified by scientific training and experience to evaluate its safety, ... to be safe under the conditions of its intended use;

4. GRAS Exemption • Any substance intentionally added to an animal feed must be used in accordance with a food additive regulation for that use unless the substance is GRAS among experts qualified by scientific training and experience to evaluate its safety under the conditions of its intended use

5. GRAS Exemption (cont.) • What does this mean in practical terms? • General recognition of safety is for a substance for an intended use • Two points • Substances are not GRAS, it is a particular use of a substance that is GRAS • Feed use of substances varies with the animal species, thus • Feed GRAS determinations must address intended use in the intended animal species

6. Food Additive GRAS Substance Review & approval by FDA Evidence of safety General recognition Widely known Consensus GRAS Criteria: Comparing GRAS Substance to a Food Additive Evidence of safety

7. Food Additive vs. GRAS • Food additives require FDA premarket approval, a petition process • 21 CFR 571.1 • GRAS status is an exemption to food additive definition • FDA involvement is not required • Firms can do their own determination if requirements of GRAS status are met

8. What Uses can be GRAS? • Food additive definition is very broad, but it does NOT include: • Pesticides • Color additives • Approved under another FDA premarket process • Drugs and new animal drugs • Some substances approved under specific laws administered by USDA • These substances cannot be GRAS

9. GRAS Status • There are two parts to establish that a use of a substance is GRAS • Safety • Defined in 21 CFR 570.3(i) • General recognition • Addressed in 21 CFR 570.30 Other terms defined in 21 CFR 570.3

10. Standards • Standard for safety…reasonable certainty of no harm… • Food additives • GRAS substances • Standard for reviewFair evaluation of the data… • Need to address all data and information • Cannot ignore the “inconvenient” or contradictory

11. GRAS Status • Safety – same as food additive Reasonable certainty of no harm • 21 CFR 570.3(i) lists factors to be considered • Consumption • Cumulative effect\exposure • Appropriate safety factors • For livestock species, need to consider possibility of tissue residues

12. GRAS Status (cont.) • General Recognition • Information needed for GRAS determination • Must be generally available • Must be generally accepted by qualified experts • Information needed to establish GRAS status of an intended use of substance cannot be confidential

13. Information • Generally available data and information • Usually means published studies • Can include information in text books • Availability allows review by any experts qualified by scientific experience and training to evaluate the safety of substances added to food • Consensus among experts about these data and information establish GRAS status of intended use of substance

14. Basis for GRAS Determinations Experts may base safety conclusions on: • Experience based on common use in animal food before 1958 • Data and information must be generally available • Need to show common use OR

15. Basis for GRAS (cont.) • Scientific procedures • Most frequently used • Requires same quantity and quality of scientific evidence as required to obtain approval of a food additive regulation • Scientific evidence must be generally available GRAS status is more difficult to establish than a food additive regulation due to general recognition requirement

16. Safety Evaluations • Addressing animal safety is complex • Difficult to do cross-species comparisons of toxicity data • NRC report found insufficient data to support extrapolation across species • Animal safety studies in the individual target species are often necessary • Human food safety may also need to be addressed, dependent on intended use

17. GRAS Notification • Proposed rule published in 1997 • Changing from petition to notification process • Publication date of final rule is unclear • CVM implementing pilot program • Resources are still an issue • Will be announcement in the Federal Register • Anticipated start date • Summer

18. GRAS Notification (cont.) • Pilot program based on 1997 proposal • Voluntary • Firms can conduct a GRAS determination without notifying FDA • Notice informs FDA of notifier’s determination that a use of a substance is GRAS • Notifier’s determination and responsibility • Summary document, not raw data/complete reports • FDA responds by letter • Notifier can withdraw notice at any time, stops FDA review

19. Highlights of Notice • Talk to CVM as putting notice together • Summary of notifier’s determination • GRAS notice should include: • Statement of GRAS determination • Detailed information about identity and intended use of substance • Chemical identification • Method of manufacture, exclude trade secret information • Source of substance • Characteristic properties • Specifications

20. Highlights of Notice (cont.) • Comprehensive discussion of basis for GRAS determination • Consideration of Food and Water Exposure • Safety – reasonable certainty of no harm • Animal and, potentially human food, safety • Favorable and unfavorable data/information • Basis for GRAS status in light of both favorable and unfavorable information - fair evaluation • Other administrative information

21. Types of FDA Response • No questions • Based on the information provided by [notifier], … the agency has no questions at this time regarding [notifier’s] conclusion that [substance] is GRAS under the intended conditions of use. The agency has not, however, made its own determination regarding ... GRAS status. • No basis • FDA has evaluated the information in [the GRAS Notice] ... as well as other available data and information. Your notice does not provide a sufficient basis for a determination that [substance] is GRAS under the conditions of its intended use.

22. GRAS Notification (cont.) • Inventory of GRAS notices and FDA responses on the Internet • Notices available under Freedom of Information Act (FOIA) • May also be posted on Internet • General recognition means information that establishes safety cannot be confidential • CVM’s process will be similar to CFSAN’s on-going pilot program • Information about CFSAN pilot program at http://www.cfsan.fda.gov/~dms/opa-noti.html

23. Questions?