Download Use of Threshold of Concern in determining data requirements for

Use of Threshold of Concern in
determining data requirements
for the evaluation of tobacco
ingredients
Richard A. Ford. Ph.D.
International Aroma Chemical
Consultants
Tobacco Additives
• Approximately 500 substances are used
• Approximately 70% are chemically defined
substances
• Remainder are complex mixtures (natural
extracts, etc.)
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
Chemical structures vary widely
O
HO
to
O
O
Acetic acid
Decahydro-3a,6,6,9a-tetramethylnaphtho[2,1-b]furan-2(1H)-one
(Sclareolide)
Amount of available toxicological
data vary widely
• Propylene glycol – complete HEDSET
including chronic inhalation studies
• Amyl octanoate – no toxicological data
Variation in use levels is very
large
<0.0001% to > 10%
Variation in exposure may be
even larger due to
differences in volatility, etc.
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
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?
Structure and use levels
(exposure) can be used to
systematically determine the
database that would normally be
expected for safety evaluation
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
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
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
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 FoodContact 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
This approach has now adapted
specifically for additives to
tobacco
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
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)
Use of this adaptation could
make a monumental evaluation
project (covering several hundred
materials) more practical and
efficient
Applies to all structurally defined
organic chemical additives and
most natural mixtures
Allows safety evaluation (and
testing) efforts to be expended
where most needed – diverting
resources from those substances
of very low exposures and
innocuous structures
LSRO is urged to ask the Panel to
consider a detailed and in depth
presentation of this practical and
logical approach