FAO Nutrition Meetings
Resort Series No. 44A
WHO/Food Add./68.33
TOXICOLOGICAL EVALUATION OF SOME
FLAVOURING SUBSTANCES AND
NON-NUTRITIVE SWEETENING AGENTS
Geneva, 21-28 August 1967
The Eleventh Report of the Joint FAO/WHO Expert Committee on Food
Additives is published as FAO Nutrition Meetings Report Series,
1967, No. 44; Wld Hlth Org. techn. Rep. Ser., 1968, 383. This
Report contains general considerations, including the principles
adopted for the evaluation, and a summary of the results of the
evaluations of a number of food additives. Additional information,
such as biological data and a toxicological evaluation, considered at
that meeting, is to be found in this document.
Food and Agriculture Organization of the United Nations
World Health Organization
1967
CONTENTS
INTRODUCTION
BIOLOGICAL DATA
ALLOCATION OF ACCEPTABLE DAILY INTAKES
ACCEPTABLE DAILY INTAKES FOR MAN OF SOME FLAVOURING SUBSTANCES AND
NON-NUTRITIVE SWEETENING AGENTS
MONOGRAPHS
Anethole, trans-
Benzaldehyde
Benzyl Acetate
Carvone, d- and Carvone, 1-
Cinnamaldehyde
Citral
Citronellol
Ethyl Acetate
Ethyl Butyrate
Ethyl Formate
Ethyl Heptanoate
Ethyl Lactate
Ethyl Laurate
Ethyl Methylphenylglycidate
Ethyl Nonanoate
Ethyl Vanillin
Eugenol
Geranyl Acetate
alpha-Ionone
ß-Ionone
Isoamyl Butyrate
Linalol
Linalyl Acetate
Maltol
d,1-Menthol and 1-Menthol
Methyl Anthranilate
Methyl Salicylate
gamma-Nonalactone
Nonanal
Octanal
Piperonal
gamma-Undecalactone
Vanillin
Calcium Cyclamate
Sodim Cyclamate
4-Ethoxyphenylurea (Dulcin)
Saccharin
Calcim Saccharin
Sodium Saccharin
INTRODUCTION
The monographs contained in this document are the result of the
deliberations of the Joint FAO/WHO Expert Committee an Food Additives,
which met in Geneva from 21-28 August 1967. Therefore the monographs
should be consulted together with the report of this meeting.1
General remarks on the biological data and toxicological
evaluation in these monographs as well as reference to the other food
additives considered by the Joint Expert Committee may be found in a
publication entitled "Explanatory Notes on the Activities of the Joint
FAO/WHO Expert Committee on Food Additives".2
Any new information and comments relating to biological data and
their evaluation should be addressed to: Food Additives Unit, World
Health Organization, Avenue Appia, Geneva, Switzerland.
The part of the monographs relating to chemical identity has
mainly been taken from the Food Chemicals Codex.3
Specifications on these food additives have been prepared and
these will be forwarded to the Codes Committee on Food Additives and
to interested organizations, and will also be available on request
from the Food Standards, Additives and Regulations Section, Nutrition
Division, FAO, Rome, Italy.
1 Eleventh Report of the Joint FAO/WHO Expert Committee on Food
Additives. FAO Nutrition Meetings Report Series, 1967, No. 44;
Wld Hlth Org. techn. Rep. Ser., 1967, 383
2 Off-print from Tenth Report of the Joint FAO/WHO Expert Committee
on Food Additives.
3 Food Protection Committee (1966) Food Chemicals Codex, First
Edition, National Academy of Sciences, Publication 1406, Washington
D.C., USA
BIOLOGICAL DATA
Possible substitution of biochemical and metabolic studies for
formal toxicity studies
The Committee emphasized again the statements in the report of
the WHO Scientific Group on Procedures for Investigating Intentional
and Unintentional Food Additives,1 as already implemented in the
Tenth Report, concerning the importance of metabolic and biochemical
studies. For certain substances where there was evidence that the
flavouring material is broken down into normal body constituents or
where the compounds are known to follow a well established metabolic
pathway, the Committee accepted evidence of this kind where formal
toxicity studies were incomplete. The esters constitute a good example
of this kind.
Acute toxicity
The Committee noted that in a number of flavouring substances the data
for acute oral toxicity were such as to suggest that little absorption
occurred by this route. It might have proved valuable to have acute
toxicity data following intraperitoneal administration. Such
information would have given a guide to the toxic potential of the
substance. It was noted, too, that a short description of signs, and
the time and cause of death would have been useful.
Short and long-term studies
In some studies the only adverse effect noted was a slight but
statistically insignificant retardation of growth, compared with the
control grasp. There are two possible explanations for this
observation when the food efficiency was unaffected: toxic anorexia or
unpalatability of the diet. Additional information such as food
preference tests, or paired feeding experiments or related
observations which aided the interpretation of this observation would
be useful. When discussing the choice of animal species for short-term
studies the Committee agreed with the statement made in the WHO
Scientific Group Report that the most appropriate, where known, rather
than the most sensitive species should be used.
Additional information
In certain instances additional collateral information was of
value. Included in this category were a knowledge of the distribution
of the flavouring substances in natural food products and knowledge of
their consumption. It was also valuable to have knowledge of the
toxicology of substances of related structure.
1 Wld Hlth Org. techn. Rep. Ser., 1967, 348
ALLOCATION OF ACCEPTABLE DAILY INTAKES
The present Committee decided to use the terms Unconditional,
Conditional, or Temporary ADI, where appropriate, in the
evaluation of flavouring substances and non-nutritive sweetening
agents.
An Unconditional ADI was allocated only for those substances
for which the biological data supplied for consideration contained
either adequate short-term and long-term toxicological investigations,
or a knowledge of the biochemistry and metabolic fate of the compound
or both.
A Conditional ADI was allocated in either of two different
circumstances.
In the first instance a conditional ADI was allocated for
substances for which the Committee considered the data fell short of
the requirements for an unconditional ADI and for which further
specified work was required to be done. In future re-evaluation this
requirement might be a factor taken into consideration when allocating
an ADI if the work requested has not been forthcoming.
In the second instance a conditional ADI was allocated for the
specific purposes arising from special dietary requirements.
A Temporary ADI was allocated for those substances for which
the data supplied were not fully adequate to establish their safety
and for which there was a need to provide this this evidence within a
stated period of time. If within that limited period the further data
requested have not been submitted the Committee will need to consider
whether the previous allocations of a temporary ACI must be withdrawn.
As has been the practice on previous occasions, the ADI's
established for those substances occurring naturally in foods do not
include the contribution from this source.
ACCEPTABLE DAILY INTAKES FOR MAN OF SOME FLAVOURING SUBSTANCES AND NON-NUTRITIVE
SWEETENING AGENTS
Unconditional ADI Conditional ADI Temporary ADI
Substances (mg/kg body-weight) (mg/kg body-weight) (mg/kg body-weight)
trans-Anethole 0-1.25
Benzaldehyde 0-51
Benzyl Acetate 0-51
d-Carvone and
1-Carvone 0-1.25
Cinnamaldehyde 0-1.25
Citral 0-1
Citronellol, 90 per
cent. and 98 per 0-0.25
cent. total alcohols
Ethyl Acetate 0-25
Ethyl Butyrate 0-15
Ethyl Formate 0-5
Ethyl Heptanoate 0-1
Ethyl Lactate 0-1002
Ethyl Laurate 0-1
Ethyl Methylphenylglycidate 0-0.6
Ethyl Nonanoate 0-1
Ethyl Vanillin 0-10
Eugenol 0-5
Geranyl Acetate 0-5
alpha-Ionone 0-0.1
ß-Ionone 0-0.1
Isoamyl Butyrate 0-5
Linalol, 90 per cent.
and 95 per cent. 0-0.25
Linalyl Acetate,
90 per cent. and 0-0.25
96 per cent.
(continued)
Unconditional ADI Conditional ADI Temporary ADI
Substances (mg/kg body-weight) (mg/kg body-weight) (mg/kg body-weight)
Maltol 0-1
d,1-Menthol and
1-Menthol 0-0.2 0.2-2
Methyl Anthranilate 0-1.5
Methyl Salicylate 0-0.5
gamma-Nonalactone 0-1.25
Nonanal 0-0.1
Octanal 0-0.1
Piperonal 0-2.5
gamma-Undecalactone 0-1.25
Vanillin 0-10
Calcium Cyclamate )
Sodium Cyclamate ) 0-50
4-Ethoxyphenylurea3
(Dulcin)
Saccharin )
Calcium Saccharin ) 0-5 5-154
Sodium Saccharin )
1 As total benzoic acid from all food additive sources.
2 As total D(-)-lactic acid from all food additive sources.
3 The Committee recommended that this substance should not be used as
a food additive
4 For dietetic foods only
See Also:
Toxicological Abbreviations