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    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
    -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
    -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