1. Use of Threshold of Concern in determining data requirements for the evaluation of tobacco ingredients Richard A. Ford. Ph.D. International Aroma Chemical Consultants

2. Tobacco Additives Approximately 500 substances are used Approximately 70% are chemically defined substances Remainder are complex mixtures (natural extracts, etc.)

3. LSRO Plan Phase 1 – Feasibility Phase 2 – Criteria –This presentation addresses one important aspect of criteria – determining data requirements for the evaluation of additives Phase 3 - Evaluation

4. Chemical structures vary widely to (Sclareolide)

5. Amount of available toxicological data vary widely Propylene glycol – complete HEDSET including chronic inhalation studies Amyl octanoate – no toxicological data

6. Variation in use levels is very large 10% Variation in exposure may be even larger due to differences in volatility, etc.

7. In fact, most additives are used are very low levels Approximately 48% are are used below 1 ppm Another approximately 22% are used at between 1 and 10 ppm

8. Clearly not practical nor necessary to require the same degree of toxicological data for each additive To obtain the same amount of data on amyl octanoate as for propylene glycol could cost several million dollars and the use of thousands of rats. Is it necessary?

9. Structure and use levels (exposure) can be used to systematically determine the database that would normally be expected for safety evaluation

10. Combining exposure and structure logically Low exposure / innocuous structure – little concern – less need for data High exposure / structural alerts – high concern – significant data needed High exposure / innocuous structure or low exposure / structural alerts – intermediate

11. Such a system has been in use for years for food additives NAS/NRC, 1958, Insignificant levels of chemical additives in food, Food Drug Cosmetic Law J. 13: 477-479 FDA, 1982, Toxicological principles for the safety assessment of direct food additives and color additives used in food. Red Book, U.S. Food and Drug Administration, Bureau of Foods, Washington DC

12. And particularly for flavors Cramer, G.M., Ford, R.A. and Hall, R.L. 1978, Estimation of toxic hazard – a decision tree approach. Food Cosmet. Toxicol. 16(3): 255-276 Munro I.C., Kennepohl E. and Kroes R. (1999) A procedure for the safety evaluation of flavouring substances Food and Chemical Toxicology, 37(2-3), 207-232

13. And has even been used to determine an exposure below which there is no concern regardless of structure Federal Register, 1995, Food Additives; Threshold of Regulation for Substances Used in Food- Contact Articles. Department of Health and Human Services, Food and Drug Administration. 21 CFR Parts 5, 25, 170, 171 and 174. Docket Nos. 77P-0122 and 92N-0181

14. This approach has now adapted specifically for additives to tobacco

15. The adaptation is compatible with the food additives approaches mentioned Assumes thresholds of concern based on structure and structural alerts –4 Structural categories of concern Combined with possible exposure via smoking tobacco –Calculated based on use levels and resulting exposures

16. Additional factors taken into consideration Exposure somewhat more difficult to quantitate Inhalation is the route of exposure Pyrolysis must be considered Additives cannot be assumed to be safe based only on their occurrence as natural components of food (or status as approved food additives)

17. Use of this adaptation could make a monumental evaluation project (covering several hundred materials) more practical and efficient

18. Applies to all structurally defined organic chemical additives and most natural mixtures

19. Allows safety evaluation (and testing) efforts to be expended where most needed – diverting resources from those substances of very low exposures and innocuous structures

20. LSRO is urged to ask the Panel to consider a detailed and in depth presentation of this practical and logical approach