Use of Threshold of Concern in determining data requirements for the evaluation of tobacco ingredients

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

• lt0.0001 to gt 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

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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