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        INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

        WORLD HEALTH ORGANIZATION



        SAFETY EVALUATION OF CERTAIN
        FOOD ADDITIVES AND CONTAMINANTS



        WHO FOOD ADDITIVES SERIES 40





        Prepared by:
          The forty-ninth meeting of the Joint FAO/WHO Expert
          Committee on Food Additives (JECFA)



        World Health Organization, Geneva 1998



    ANNEX 1

    Reports and other documents resulting from previous meetings of the
    Joint FAO/WHO Expert Committee on Food Additives

    1. General principles governing the use of food additives (First
    report of the Joint FAO/WHO Expert Committee on Food Additives).
    FAO Nutrition Meetings Report Series, No. 15, 1957; WHO Technical
    Report Series, No. 129, 1957 (out of print).

    2. Procedures for the testing of intentional food additives to
    establish their safety for use (Second report of the Joint FAO/WHO
    Expert Committee on Food Additives). FAO Nutrition Meetings Report
    Series, No. 17, 1958; WHO Technical Report Series, No. 144, 1958
    (out of print).

    3. Specifications for identity and purity of food additives
    (antimicrobial preservatives and antioxidants) (Third report of the
    Joint FAO/WHO Expert Committee on Food Additives). These
    specifications were subsequently revised and published as
    Specifications for identity and purity of food additives, Vol. I.
    Antimicrobial preservatives and antioxidants, Rome, Food and
    Agriculture Organization of the United Nations, 1962 (out of
    print).

    4. Specifications for identity and purity of food additives (food
    colours) (Fourth report of the Joint FAO/WHO Expert Committee on
    Food Additives). These specifications were subsequently revised and
    published as Specifications for identity and purity of food
    additives, Vol. II. Food colours, Rome, Food and Agriculture
    Organization of the United Nations, 1963 (out of print).

    5. Evaluation of the carcinogenic hazards of food additives (Fifth
    report of the Joint FAO/WHO Expert Committee on Food Additives).
    FAO Nutrition Meetings Report Series, No. 29, 1961; WHO Technical
    Report Series, No. 220, 1961 (out of print).

    6. Evaluation of the toxicity of a number of antimicrobials and
    antioxidants (Sixth report of the Joint FAO/WHO Expert Committee on
    Food Additives). FAO Nutrition Meetings Report Series, No. 31,
    1962; WHO Technical Report Series, No. 228, 1962 (out of print).

    7. Specifications for the identity and purity of food additives and
    their toxicological evaluation: emulsifiers, stabilizers, bleaching
    and maturing agents (Seventh report of the Joint FAO/WHO Expert
    Committee on Food Additives). FAO Nutrition Meetings Report Series,
    No. 35, 1964; WHO Technical Report Series, No. 281, 1964 (out of
    print).

    8. Specifications for the identity and purity of food additives and
    their toxicological evaluation: food colours and some
    antimicrobials and antioxidants (Eighth report of the Joint FAO/WHO
    Expert Committee on Food Additives). FAO Nutrition Meetings Report
    Series, No. 38, 1965; WHO Technical Report Series, No. 309, 1965
    (out of print).

    9. Specifications for identity and purity and toxicological
    evaluation of some antimicrobials and antioxidants. FAO Nutrition
    Meetings Report Series, No. 38A, 1965; WHO/Food Add/24.65 (out of
    print).

    10. Specifications for identity and purity and toxicological
    evaluation of food colours. FAO Nutrition Meetings Report Series,
    No. 38B, 1966; WHO/Food Add/66.25  (out of print).

    11. Specifications for the identity and purity of food additives
    and their toxicological evaluation: some antimicrobials,
    antioxidants, emulsifiers, stabilizers, flour-treatment agents,
    acids, and bases (Ninth report of the Joint FAO/WHO Expert
    Committee on Food Additives). FAO Nutrition Meetings Report Series,
    No. 40, 1966; WHO Technical Report Series, No. 339, 1966 (out of
    print).

    12. Toxicological evaluation of some antimicrobials, antioxidants,
    emulsifiers, stabilizers, flour-treatment agents, acids, and bases.
    FAO Nutrition Meetings Report Series, No. 40A, B, C; WHO/Food
    Add/67.29  (out of print).

    13. Specifications for the identity and purity of food additives
    and their toxicological evaluation: some emulsifiers and
    stabilizers and certain other substances (Tenth report of the Joint
    FAO/WHO Expert Committee on Food Additives). FAO Nutrition Meetings
    Report Series, No. 43, 1967; WHO Technical Report Series, No. 373,
    1967  (out of   print).

    14. Specifications for the identity and purity of food additives
    and their toxicological evaluation: some flavouring substances and
    non-nutritive sweetening agents (Eleventh report of the Joint
    FAO/WHO Expert Committee on Food Additives). FAO Nutrition Meetings
    Report Series, No. 44, 1968; WHO Technical Report Series, No. 383,
    1968  (out of print).

    15. Toxicological evaluation of some flavouring substances and
    non-nutritive sweetening agents. FAO Nutrition Meetings Report
    Series, No. 44A, 1968; WHO/Food Add/68.33  (out of print).

    16. Specifications and criteria for identity and purity of some
    flavouring substances and non-nutritive sweetening agents. FAO
    Nutrition Meetings Report Series, No. 44B, 1969; WHO/Food Add/69.31
     (out of print).

    17. Specifications for the identity and purity of food additives
    and their toxicological evaluation: some antibiotics (Twelfth
    report of the Joint FAO/WHO Expert Committee on Food Additives).
    FAO Nutrition Meetings Report Series, No. 45, 1969; WHO Technical
    Report Series, No. 430, 1969.

    18. Specifications for the identity and purity of some antibiotics.
    FAO Nutrition Meetings Report Series, No. 45A, 1969; WHO/Food
    Add/69.34  (out of print).

    19. Specifications for the identity and purity of food additives
    and their toxicological evaluation: some food colours, emulsifiers,
    stabilizers, anticaking agents, and certain other substances
    (Thirteenth report of the Joint FAO/WHO Expert Committee on Food
    Additives). FAO Nutrition Meetings Report Series, No. 46, 1970; WHO
    Technical Report Series, No. 445, 1970.

    20. Toxicological evaluation of some food colours, emulsifiers,
    stabilizers, anticaking agents, and certain other substances. FAO
    Nutrition Meetings Report Series, No. 46A, 1970; WHO/Food Add/70.36
     (out of print).

    21. Specifications for the identity and purity of some food
    colours, emulsifiers, stabilizers, anticaking agents, and certain
    other food additives. FAO Nutrition Meetings Report Series, No.
    46B, 1970; WHO/Food Add/70.37  (out of print).

    22. Evaluation of food additives: specifications for the identity
    and purity of food additives and their toxicological evaluation:
    some extraction solvents and certain other substances; and a review
    of the technological efficacy of some antimicrobial agents.
    (Fourteenth report of the Joint FAO/WHO Expert Committee on Food
    Additives). FAO Nutrition Meetings Report Series, No. 48, 1971; WHO
    Technical Report Series, No. 462, 1971.

    23. Toxicological evaluation of some extraction solvents and
    certain other substances. FAO Nutrition Meetings Report Series, No.
    48A, 1971; WHO/Food Add/70.39  (out of print).

    24. Specifications for the identity and purity of some extraction
    solvents and certain other substances. FAO Nutrition Meetings
    Report Series, No. 48B, 1971; WHO/Food Add/70.40  (out of print).

    25. A review of the technological efficacy of some antimicrobial
    agents. FAO Nutrition Meetings Report Series, No. 48C, 1971;
    WHO/Food Add/70.41  (out of print).

    26. Evaluation of food additives: some enzymes, modified starches,
    and certain other substances: Toxicological evaluations and
    specifications and a review of the technological efficacy of some
    antioxidants (Fifteenth report of the Joint FAO/WHO Expert
    Committee on Food Additives). FAO Nutrition Meetings Report Series,
    No. 50, 1972; WHO Technical Report Series, No. 488, 1972.

    27. Toxicological evaluation of some enzymes, modified starches,
    and certain other substances. FAO Nutrition Meetings Report Series,
    No. 50A, 1972; WHO Food Additives Series, No. 1, 1972.

    28. Specifications for the identity and purity of some enzymes and
    certain other substances. FAO Nutrition Meetings Report Series, No.
    50B, 1972; WHO Food Additives Series, No. 2, 1972.

    29. A review of the technological efficacy of some antioxidants and
    synergists. FAO Nutrition Meetings Report Series, No. 50C, 1972;
    WHO Food Additives Series, No. 3, 1972.

    30. Evaluation of certain food additives and the contaminants
    mercury, lead, and cadmium (Sixteenth report of the Joint FAO/WHO
    Expert Committee on Food Additives). FAO Nutrition Meetings Report
    Series, No. 51, 1972; WHO Technical Report Series, No. 505, 1972,
    and corrigendum.

    31. Evaluation of mercury, lead, cadmium and the food additives
    amaranth, diethylpyrocarbonate, and octyl gallate. FAO Nutrition
    Meetings Report Series, No. 51A, 1972; WHO Food Additives Series,
    No. 4, 1972.

    32. Toxicological evaluation of certain food additives with a
    review of general principles and of specifications (Seventeenth
    report of the Joint FAO/WHO Expert Committee on Food Additives).
    FAO Nutrition Meetings Report Series, No. 53, 1974; WHO Technical
    Report Series, No. 539, 1974, and corrigendum (out of print).

    33. Toxicological evaluation of some food additives including
    anticaking agents, antimicrobials, antioxidants, emulsifiers, and
    thickening agents. FAO Nutrition Meetings Report Series, No. 53A,
    1974; WHO Food Additives Series, No. 5, 1974.

    34. Specifications for identity and purity of thickening agents,
    anticaking agents, antimicrobials, antioxidants and emulsifiers.
    FAO Food and Nutrition Paper, No. 4, 1978.

    35. Evaluation of certain food additives (Eighteenth report of the
    Joint FAO/WHO Expert Committee on Food Additives). FAO Nutrition
    Meetings Report Series, No. 54, 1974; WHO Technical Report Series,
    No. 557, 1974, and corrigendum.

    36. Toxicological evaluation of some food colours, enzymes, flavour
    enhancers, thickening agents, and certain other food additives. FAO
    Nutrition Meetings Report Series, No. 54A, 1975; WHO Food Additives
    Series, No. 6, 1975.

    37. Specifications for the identity and purity of some food colours
    enhancers, thickening agents, and certain food flavour additives.
    FAO Nutrition Meetings Report Series, No. 54B, 1975; WHO Food
    Additives Series, No. 7, 1975.

    38. Evaluation of certain food additives: some food colours,
    thickening agents, smoke condensates, and certain other substances.
    (Nineteenth report of the Joint FAO/WHO Expert Committee on Food
    Additives). FAO Nutrition Meetings Report Series, No. 55, 1975; WHO
    Technical Report Series, No. 576, 1975.

    39. Toxicological evaluation of some food colours, thickening
    agents, and certain other substances. FAO Nutrition Meetings Report
    Series, No. 55A, 1975; WHO Food Additives Series, No. 8, 1975.

    40. Specifications for the identity and purity of certain food
    additives. FAO Nutrition Meetings Report Series, No. 55B, 1976; WHO
    Food Additives Series, No. 9, 1976.

    41. Evaluation of certain food additives (Twentieth report of the
    Joint FAO/WHO Expert Committee on Food Additives). FAO Food and
    Nutrition Meetings Series, No. 1, 1976; WHO Technical Report
    Series, No. 599, 1976.

    42. Toxicological evaluation of certain food additives. WHO Food
    Additives Series, No. 10, 1976.

    43. Specifications for the identity and purity of some food
    additives. FAO Food and Nutrition Series, No. 1B, 1977; WHO Food
    Additives Series, No. 11, 1977.

    44. Evaluation of certain food additives (Twenty-first report of
    the Joint FAO/WHO Expert Committee on Food Additives). WHO
    Technical Report Series, No. 617, 1978.

    45. Summary of toxicological data of certain food additives. WHO
    Food Additives Series, No. 12, 1977.

    46. Specifications for identity and purity of some food additives,
    including antioxidants, food colours, thickeners, and others. FAO
    Nutrition Meetings Report Series, No. 57, 1977.

    47. Evaluation of certain food additives and contaminants
    (Twenty-second report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 631, 1978.

    48. Summary of toxicological data of certain food additives and
    contaminants. WHO Food Additives Series, No. 13, 1978.

    49.  Specifications for the identity and purity of certain food
    additives. FAO Food and Nutrition Paper, No. 7, 1978.

    50. Evaluation of certain food additives (Twenty-third report of
    the Joint FAO/WHO Expert Committee on Food Additives). WHO
    Technical Report Series, No. 648, 1980, and corrigenda.

    51. Toxicological evaluation of certain food additives. WHO Food
    Additives Series, No. 14, 1980.

    52. Specifications for identity and purity of food colours,
    flavouring agents, and other food additives. FAO Food and Nutrition
    Paper, No. 12, 1979.

    53. Evaluation of certain food additives (Twenty-fourth report of
    the Joint FAO/WHO Expert Committee on Food Additives). WHO
    Technical Report Series, No. 653, 1980.

    54. Toxicological evaluation of certain food additives. WHO Food
    Additives Series, No. 15, 1980.

    55. Specifications for identity and purity of food additives
    (sweetening agents, emulsifying agents, and other food additives).
    FAO Food and Nutrition Paper, No. 17, 1980.

    56. Evaluation of certain food additives (Twenty-fifth report of
    the Joint FAO/WHO Expert Committee on Food Additives). WHO
    Technical Report Series, No. 669, 1981.

    57. Toxicological evaluation of certain food additives. WHO Food
    Additives Series, No. 16, 1981.

    58. Specifications for identity and purity of food additives
    (carrier solvents, emulsifiers and stabilizers, enzyme
    preparations, flavouring agents, food colours, sweetening agents,
    and other food additives). FAO Food and Nutrition Paper, No. 19,
    1981.

    59. Evaluation of certain food additives and contaminants
    (Twenty-sixth report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 683, 1982.

    60. Toxicological evaluation of certain food additives. WHO Food
    Additives Series, No. 17, 1982.

    61. Specifications for the identity and purity of certain food
    additives. FAO Food and Nutrition Paper, No. 25, 1982.

    62. Evaluation of certain food additives and contaminants
    (Twenty-seventh report of the Joint FAO/WHO Expert Committee on
    Food Additives). WHO Technical Report Series, No. 696, 1983, and
    corrigenda. 

    63. Toxicological evaluation of certain food additives and
    contaminants. WHO Food Additives Series, No. 18, 1983.

    64. Specifications for the identity and purity of certain food
    additives. FAO Food and Nutrition Paper, No. 28, 1983.

    65. Guide to specifications--General notices, general methods,
    identification tests, test solutions, and other reference
    materials. FAO Food and Nutrition Paper, No. 5, Rev. 1, 1983.

    66. Evaluation of certain food additives and contaminants
    (Twenty-eighth report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 710, 1984, and
    corrigendum.

    67. Toxicological evaluation of certain food additives and
    contaminants. WHO Food Additives Series, No. 19, 1984.

    68. Specifications for the identity and purity of food colours. FAO
    Food and Nutrition Paper, No. 31/1, 1984.

    69. Specifications for the identity and purity of food additives.
    FAO Food and nutrition Paper, No. 31/2, 1984.

    70. Evaluation of certain food additives and contaminants
    (Twenty-ninth report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 733, 1986, and
    corrigendum.

    71. Specifications for the identity and purity of certain food
    additives. FAO Food and nutrition Paper, No. 34, 1986.

    72. Toxicological evaluation of certain food additives and
    contaminants. WHO Food Additives Series, No. 20. Cambridge
    University Press, 1987.

    73. Evaluation of certain food additives and contaminants
    (Thirtieth report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 751, 1987.

    74. Toxicological evaluation of certain food additives and
    contaminants. WHO Food Additives Series, No. 21. Cambridge
    University Press, 1987.

    75. Specifications for the identity and purity of certain food
    additives. FAO Food and Nutrition Paper, No. 37, 1986.

    76. Principles for the safety assessment of food additives and
    contaminants in food. WHO Environmental Health Criteria, No. 70.
    Geneva, World Health Organization, 1987.

    77. Evaluation of certain food additives and contaminants
    (Thirty-first report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 759, 1987, and
    corrigendum.

    78. Toxicological evaluation of certain food additives. WHO Food
    Additives Series, No. 22. Cambridge University Press, 1988.

    79. Specifications for the identity and purity of certain food
    additives. FAO Food and Nutrition Paper, No. 38, 1988.

    80. Evaluation of certain veterinary drug residues in food
    (Thirty-second report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 763, 1988.

    81. Toxicological evaluation of certain veterinary drug residues in
    food. WHO Food Additives Series, No. 23. Cambridge University
    Press, 1988.

    82. Residues of some veterinary drugs in animals and foods. FAO
    Food and Nutrition paper, No. 41, 1988  (out of print).

    83. Evaluation of certain food additives and contaminants
    (Thirty-third report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 776, 1989.

    84. Toxicological evaluation of certain food additives and
    contaminants. WHO Food Additives Series, No. 24. Cambridge
    University Press, 1989.

    85. Evaluation of certain veterinary drug residues in food
    (Thirty-fourth report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 788, 1989.

    86. Toxicological evaluation of certain veterinary drug residues in
    food. WHO Food Additives Series, No. 25, 1990.

    87. Residues of some veterinary drugs in animals and foods. FAO
    Food and Nutrition Paper, No. 41/2, 1990.

    88. Evaluation of certain food additives and contaminants
    (Thirty-fifth report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 789, 1990, and
    corrigenda.

    89. Toxicological evaluation of certain food additives and
    contaminants. WHO Food Additives Series, No. 26, 1990.

    90. Specifications for identity and purity of certain food
    additives. FAO Food and Nutrition Paper, No. 49, 1990.

    91. Evaluation of certain veterinary drug residues in food
    (Thirty-sixth report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 799, 1990.

    92. Toxicological evaluation of certain veterinary drug residues in
    food. WHO Food Additives Series, No. 27, 1991.

    93. Residues of some veterinary drugs in animals and foods. FAO
    Food and Nutrition Paper, No. 41/3, 1991.

    94. Evaluation of certain food additives and contaminants
    (Thirty-seventh report of the Joint FAO/WHO Expert Committee on
    Food Additives). WHO Technical Report Series, No. 806, 1991, and
    corrigenda.

    95. Toxicological evaluation of certain food additives and
    contaminants. WHO Food Additives Series, No. 28, 1991.

    96. Compendium of Food Additive Specifications. Joint FAO/WHO
    Expert Committee on Food Additives (JECFA). Combined specifications
    from 1st through the 37th Meetings, 1956-1990. FAO, 1992 (2
    volumes).

    97. Evaluation of certain veterinary drug residues in food
    (Thirty-eighth report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 815, 1991.

    98. Toxicological evaluation of certain veterinary residues in
    food. WHO Food Additives Series, No. 29, 1991.

    99. Residues of some veterinary drugs in animals and foods. FAO
    Food and Nutrition Paper, No. 41/4, 1991.

    100. Guide to specifications - General notices, general analytical
    techniques, identification tests, test solutions, and other
    reference materials. FAO Food and Nutrition Paper, No. 5, Ref. 2,
    1991.

    101. Evaluation of certain food additives and naturally occurring
    toxicants (Thirty-ninth report of the Joint FAO/WHO Expert
    Committee on Food Additives). WHO Technical Report Series No. 828,
    1992.

    102. Toxicological evaluation of certain food additives and
    naturally occurring toxicants. WHO Food Additive Series, No. 30,
    1993.

    103. Compendium of food additive specifications: Addendum 1. FAO
    Food and Nutrition Paper, No. 52, 1992.

    104. Evaluation of certain veterinary drug residues in food
    (Fortieth report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 832, 1993.

    105. Toxicological evaluation of certain veterinary drug residues
    in food. WHO Food Additives Series, No. 31, 1993.

    106. Residues of some veterinary drugs in animals and foods. FAO
    Food and Nutrition Paper, No. 41/5, 1993.

    107. Evaluation of certain food additives and contaminants
    (Forty-first report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 837, 1993.

    108. Toxicological evaluation of certain food additives and
    contaminants. WHO Food Additives Series, No. 32, 1993.

    109. Compendium of food additive specifications, addendum 2. FAO
    Food and Nutrition Paper, No. 52, Add. 2, 1993. 

    110. Evaluation of certain veterinary drug residues in food
    (Forty-second report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 851, 1995.

    111. Toxicological evaluation of certain veterinary drug residues
    in food. WHO Food Additives Series, No. 33, 1994.

    112. Residues of some veterinary drugs in animals and foods. FAO
    Food and Nutrition Paper, No. 41/6, 1994.

    113. Evaluation of certain veterinary drug residues in food
    (Forty-third report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 855, 1995, and
    corrigendum.

    114. Toxicological evaluation of certain veterinary drug residues
    in food. WHO Food Additives Series, No. 34, 1995.

    115. Residues of some veterinary drugs in animals and foods. FAO
    Food and Nutrition Paper, No. 41/7, 1995.

    116. Evaluation of certain food additives and contaminants
    (Forty-fourth report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 859, 1995.

    117. Toxicological evaluation of certain food additives and
    contaminants. WHO Food Additives Series, No. 35, 1996.

    118. Compendium of food additive specifications, addendum 3. FAO
    Food and Nutrition Paper, No. 52, Add. 3, 1995.

    119. Evaluation of certain veterinary drug residues in food
    (Forty-fifth report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 864, 1996.

    120. Toxicological evaluation of certain veterinary drug residues
    in food. WHO Food Additives Series, No. 36, 1996.

    121. Residues of some veterinary drugs in animals and foods. FAO
    Food and Nutrition Paper, No. 41/8, 1996.

    122. Evaluation of certain food additives and contaminants
    (Forty-sixth report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 868, 1997.

    123. Toxicological evaluation of certain food additives and
    contaminants. WHO Food Additives Series, No. 37, 1996.

    124. Compendium of food additives specifications, addendum 4. FAO
    Food and Nutrition Paper, No. 52, Add. 4, 1996.

    125. Evaluation of certain veterinary drug residues in food
    (Forty-seventh report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 876, in press.

    126. Toxicological evaluation of certain veterinary drug residues
    in food. WHO Food Additives Series, No. 38, 1996.

    127. Residues of some veterinary drugs in animals and foods. FAO
    Food and Nutrition Paper, No. 41/9, 1997.

    128. Evaluation of certain veterinary drug residues in food
    (Forty-eighth report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series,  in press.

    129. Toxicological evaluation of certain veterinary drug residues
    in food. WHO Food Additives Series, No. 39, 1997.

    130. Residues of some veterinary drugs in animals and foods. FAO
    Food and Nutrition Paper, No. 41/10, in press.

    131. Evaluation of certain food additives and contaminants
    (Forty-ninth report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series,  in preparation.

    ANNEX 2

    ABBREVIATIONS USED IN THE MONOGRAPHS

    ADH       alcohol dehydrogenase
    ADI       acceptable daily intake
    ALD       aldehyde dehydrogenase
    ALDC       alpha-acetolactate decarboxylase
    ALT       alanine transferase
    AP        alkaline phosphatase
    ASAT      aspartate aminotransferase
    BHA       butylated hydroxyanisole
    BSP       bromosulfophthalein
    BUN       blood urea nitrogen
    bw        body weight
    CHO       Chinese hamster ovary
    DMSO      dimethyl sulfoxide
    fm        femtomole (10-15 mole)
    GC        gas chromatography
    GGT        gamma-glutamyltranspeptidase
    GOT       glutamic-oxaloacetic transaminase
    GPT       glutamic-pyruvic transaminase
    GSH       glutathione-SH
    Hb        haemoglobin
    HDL       high density lipoprotein
    HSH       hydrogenated starch hydrolysates
    Ht        haematocrit
    HPLC      high performance liquid chromatography
    i.p.      intraperitoneal
    JECFA     Joint FAO/WHO Committee on Food Additives
    LD50      median lethal dose
    LDH       lactate dehydrogenase
    MCH       mean corpuscular haemoglobin
    MCHC      mean corpuscular haemoglobin concentration
    MCV       mean corpuscular volume
    MNNG       N-methyl- N'-nitro- N-nitrosoguanidine
    MRL       maximum residue limit
    MS        mass spectrometry
    NOEL      no-observed-effect level
    NR        not reported
    OCT       ornithine carbamoyltransferase
    PCV       packed cell volume
    RBC       red blood cell
    s.c.      subcutaneous
    SCE       sister chromatid exchange
    SD        Sprague-Dawley
    SOD       superoxide dismutase
    TBHQ       tert-butylhydroquinone
    TBQ        tert-butylquinone
    TOS       total organic solids
    UDS       unscheduled DNA synthesis
    VLDL      very low density lipoprotein
    WBC       white blood cell

    ANNEX 3

    49TH JOINT FAO/WHO EXPERT COMMITTEE ON FOOD ADDITIVES

    Rome, 17-26 June 1997

    Members

    Mrs J. Baines, Nutritionist, Australia New Zealand Food Authority
    (ANZFA), Barton, ACT, Australia  (Rapporteur)

    Dr Junshi Chen, Deputy Director, Institute of Nutrition and Food
    Hygiene, Chinese Academy of Preventive Medicine, Beijing, China
     (Vice-chairman)

    Dr S.M. Dagher, Associate Professor, American University of Beirut,
    Beirut, Lebanon

    Dr C.E. Fisher, Head, Risk Assessment and Management Branch,
    Ministry of Agriculture, Fisheries and Food (MAFF), London, England

    Dr W. Grunow, Director, Professor, Head of Food Toxicology
    Division, Federal Institute for Health Protection of Consumers and
    Veterinary Medicine (BgVV), Berlin, Germany

    Dr D.G. Hattan, Director, Division of Health Effects Evaluation,
    Center for Food Safety and Applied Nutrition, Food and Drug
    Administration, Washington, DC, USA  (Rapporteur)

    Professor J.H. Hotchkiss, Professor, Department of Food Science,
    Cornell University, Ithaca, NY, USA

    Dr F.N. Johnson, Project Director, Food Chemicals Codex, National
    Academy of Sciences, Washington, DC, USA

    Dr Y. Kawamura, Section Chief, Division of Food Additives, National
    Institute of Health Sciences, Tokyo, Japan

    Dr A.G.A.C. Knaap, Centre for Substances and Risk Assessment,
    National Institute of Public Health and the Environment, Bilthoven,
    Netherlands

    Dr P. Kuznesof, Acting Deputy Director, Division of Product
    Manufacture and Use, Office of Pre-Market Approval, Center for Food
    Safety and Applied Nutrition, Food and Drug Administration,
    Washington, DC, USA  (Chairman)

    Dr J. C. Larsen, Head of Department, Department of Biochemical and
    Molecular Toxicology, Institute of Toxicology, Danish Veterinary
    and Food Administration, Ministry of Food, Agriculture and
    Fisheries, Sborg, Denmark

    Mrs I. Meyland, Senior Scientific Adviser, Danish Veterinary and
    Food Administration, Ministry of Food, Agriculture and Fisheries,
    Sborg, Denmark  (Rapporteur)

    Mrs J. Mutamba, Deputy Director, Department of Nutrition, Ministry
    of Health, Harare, Zimbabwe

    Dr A. M. Pacin, Researcher, Scientific Research Commission of
    Buenos Aires Province, Lujan, Argentina

    Dr G. Pascal, Chairman of the Scientific Committee for Food of the
    European Union, National Centre for Scientific Research, Ministry
    of Higher Education and Research, Paris, France

    Dr B. Petersen, President, Novigen Sciences Inc., Washington, DC,
    USA

    Mrs M. Riordan, Senior Advisor, Food and Nutrition Section Ministry
    of Health, Wellington, New Zealand

    Dr P.J.P. Verger, Director, Foch Research Centre, University Ren
    Descartes-Paris V, Paris, France

    Dr R. Vilu, Professor of Biochemistry, Department of Biochemistry,
    Tallinn Technical University, Tallinn, Estonia

    Professor R. Walker, Professor of Food Science, School of
    Biological Sciences, University  of Surrey, Guildford, Surrey,
    England  (Vice-chairman)

    Mrs H. Wallin, Senior Research Scientist, VTT Biotechnology and
    Food Research, Espoo, Finland

    Dr D. B. Whitehouse, Bowdon, Cheshire, England

    Dr J. Wilson, Senior Fellow, Center for Risk Management, Resources
    for the Future, Washington, DC, USA

    Secretariat

    Dr P.J. Abbott, Australia New Zealand Food Authority (ANZFA),
    Canberra, ACT, Australia  (WHO Temporary Adviser)

    Dr H. Blumenthal, Silver Spring, MD, USA  WHO (WHO Temporary 
     Adviser)

    Dr X. Bosch, Chief, Department of Epidemiology and Cancer Registry,
    Hospital Duran i Reynals, Barcelona, Spain   (WHO Temporary 
     Adviser)

    Dr R. Clarke, Agroindustries and Post-Harvest Management Service,
    Agricultural Support Systems Division, Food and Agriculture
    Organization of the United Nations, Rome, Italy

    Dr J. Greig, Department of Health, London, England   (WHO Temporary 
     Adviser)

    Dr J. Gry, Institute of Toxicology, Danish Veterinary and Food
    Administration, Ministry of Food, Agriculture and Fisheries,
    Sborg, Denmark  (WHO Temporary Adviser)

    Mr E.F.F. Hecker, Chairman, Codex Committee on Food Additives and
    Contaminants and Senior Coordinator Risk, Substances and Nutrition
    Division, Department of Environment, Quality and Health, Ministry
    of Agriculture, Nature Management & Fisheries The Hague,
    Netherlands   (WHO Temporary Adviser)

    Dr S. Henry, Office of Plant and Dairy Foods and Beverages (HFS-
    308), Center for Food Safety and Applied Nutrition, US Food and
    Drug Administration, Washington, DC, USA   (WHO Temporary Adviser)

    Dr J.L. Herrman, Assessment of Risk and Methodologies,
    International Programme on Chemical Safety , World Health
    Organization, Geneva, Switzerland  (Joint Secretary)

    Dr P.G. Jenkins, Editor, International Programme on Chemical Safety,
    World Health Organization, Geneva, Switzerland  (editor)

    Professor R. Kroes, Director, Research Institute Technology
    (RITOX), Utrech University,  Utrecht, Netherlands   (WHO Temporary 
     Adviser)

    Dr J. Lupton, Professor, Faculty of Nutrition, Texas A&M
    University, College Station, TX, USA   (WHO Temporary Adviser)

    Dr A. Mattia, Division of Product Policy, Office of PreMarket
    Approval (HFS-206), Center for Food Safety and Applied Nutrition,
    US Food and Drug Administration, Washington, DC, USA   (WHO
    Temporary Adviser)

    Dr G. Moy, Division of Food and Nutrition, Food Safety, World
    Health Organization, Geneva, Switzerland

    Dr I.C. Munro, CanTox Inc., Mississauga, Ontario, Canada   (WHO 
     Temporary Adviser)

    Dr A. Nishikawa, Division of Pathology, Biological Safety Research
    Center, National Institute of Health Sciences, Kamiyoga, Setagaya,
    Tokyo, Japan   (WHO Temporary Adviser)

    Dr J. Paakkanen, Nutrition Officer, Food and Nutrition Division,
    Food and Agriculture Organization of the United Nations, Rome,
    Italy  (Joint Secretary)

    Dr C.J. Portier, Chief, Laboratory of Computal Biology and Risk
    Analysis, Division of Intramural Research, National Institute of
    Environmental Health Sciences, Research Triangle Park, NC, USA  
     (WHO Temporary Adviser)

    Dr A.G. Renwick, Clinical Pharmacology Group, University of
    Southampton, Medical & Biological Sciences Building, Southampton,
    UK   (WHO Temporary Adviser)

    Dr G. Semino, Institute of Pharmacological Sciences, University of
    Milan, Milano, Italy   (WHO Temporary Adviser)

    Professor P. Shubik, Green College, Oxford, UK   (WHO Temporary 
     Adviser)

    Dr G.J.A. Speijers, Head of the Section Public Health of the Centre
    for Substances and Risk Assessment, National Institute of Public
    Health and Environmental Protection, Bilthoven, Netherlands  
     (WHO Temporary Adviser)

    Ms E. Vavasour, Chemical Health Hazard Assessment Division, Bureau
    of Chemical Safety, Food Directorate, Health Protection Branch,
    Health Canada, Ottawa, Ontario, Canada  (WHO Temporary Adviser)

    ANNEX 4

    Acceptable Daily Intakes, other toxicological information, and 
    information on specifications

    1.  Food additives and food ingredients

                                                                        

    Substance                    Specifications1    Acceptable Daily
    Intake                                          (ADI) and other
                                                    toxicological
                                                    recommendations
                                                                        

    Antioxidant

    tert-Butylhydroquinone             R            0-0.7 mg/kg bw
    (TBHQ)

    Emulsifiers

    Microcrystalline cellulose         R            ADI "not specified"2
    Sucrose esters of fatty acids      R            )    0-30 mg/kg bw3
    and sucroglycerides                R            )

    Enzyme preparations

    alpha-Acetolactate decarboxylase   N,T          Temporary ADI "not
                                                    specified"4
    Maltogenic amylase                 N,T          Temporary ADI "not
                                                    specified"4

    Flavouring agent
    rans-Anethole                      R            0-0.6 mg/kg bw5

    Glazing agent

    Hydrogenated poly-1-decene         N            No ADI allocated6

    Sweetening agent

    Maltitol syrup                     R            ADI "not specified"2

    Miscellaneous substance

    Salatrim (short- and long-chain    N            An adequate basis was
    acyl triglyceride molecules)                    not available for
                                                    evaluating its safety
                                                    and nutritional
                                                    effects7
                                                                        

    1  N, new specfications prepared; O, no specifications prepared; R,
    existing specifications revised; S, specifications exist, revision not
    considered or required; T, the existing, new or revised specifications
    are tentative and comments are invited; W, existing specifications
    withdrawn; NR, specifications not reviewed.
    2  Applies to the product conforming to the revised specifications.
    3  Group ADI for sucrose esters of fatty acids and sucroglycerides.
    4  Temporary pending consideration of the "tentative" designation
    for the specifications.  The "tentative" designation for Appendix B to
    Annex 1 (general specifications for enzyme preparations used in food
    processing) of the Compendium of food additive specifications (1992)
    will be reviewed in 1998.
    5  Temporary ADI extended to 1998 to review studies underway that
    were requested by earlier Committees.
    6  Data were insufficient for establishing an ADI.
    7  The Committee recommended that additional appropriately designed
    studies be performed to assess fully both the toxicological and
    nutritional consequences of ingestion of salatrim.

    2.  Substances evaluated using the Procedure for the Safety Evaluation
    of Flavouring Agents

    A.  Flavouring agents evaluated toxicologically

                                                                      

    No.     Flavouring agent         Specifications1    Conclusion based
                                                        on current levels
                                                        of intake
                                                                      
    0021    Allyl 2-furoate                N,T          No safety concern
                                                                      
    Saturated aliphatic acyclic
    linear primary alcohols,
    aldehydes, and acids

    0079    Formic acid                    R            )
    0080    Acetaldehyde                   N            )
    0081    Acetic acid                    R            )No safety concern
    0082    Propyl alcohol                 R            )
    0083    Propionaldehyde                N            )

    0084    Propionic acid                 N            )
    0085    Butyl alcohol                  R            )
    0086    Butyraldehyde                  N            )No safety concern
    0087    Butyric acid                   N            )
    0088    Amyl alcohol                   N            )

    0089    Valeraldehyde                  N            )
    0090    Valeric acid                   N            )
    0091    Hexyl alcohol                  N            )No safety concern
    0092    Hexanal                        N            )
    0093    Hexanoic acid                  N            )

    0094    Heptyl alcohol                 N            )
    0095    Heptanal                       N            )
    0096    Heptanoic acid                 N            )No safety concern
    0097    1-Octanol                      N            )
    0098    Octanal                        R            )

    0099    Octanoic acid                  N            )
    0100    Nonyl alcohol                  N            )
    0101    Nonanal                        R            )No safety concern
    0102    Nonanoic acid                  N            )
    0103    1-Decanol                      N            )

    0104    Decanal                        N            )
    0105    Decanoic acid                  N            )
    0106    Undecyl alcohol                N            )No safety concern
    0107    Undecanal                      N            )
    0108    Undecanoic acid                N            )
                                                                      

                                                                      

    No.     Flavouring agent         Specifications1    Conclusion based
                                                        on current levels
                                                        of intake
                                                                      
    0109    Lauryl alcohol                 N            )
    0110    Lauric aldehyde                N            )
    0111    Lauric acid                    N            )No safety concern
    0112    Myristaldehyde                 N            )
    0113    Myristic acid                  N            )

    0114    1-Hexadecanol                  N            )
    0115    Palmitic acid                  N            )No safety concern
    0116    Stearic acid                   N            )
                                                                      
    Saturated aliphatic acyclic
    branched-chain primary alcohols,
    aldehydes, and acids

    A. Structural class I
    flavouring agents:

    0251    Isobutyl alcohol               NR           )
    0252    Isobutyraldehyde               NR           )
    0253    Isobutyric acid                NR           )No safety concern
    0254    2-Methylbutyraldehyde          NR           )
    0255    2-Methylbutyric acid           NR           )

    0258    3-Methylbutyraldehyde          NR           )
    0259    Isovaleric acid                NR           )
    0260    2-Methylpentanal               NR           )No safety concern
    0261    2-Methylvaleric acid           NR           )
    0262    3-Methylpentanoic acid         NR           )

    0263    3-Methyl-1-pentanol            NR           )
    0264    4-Methylpentanoic acid         NR           )
    0265    2-Methylhexanoic acid          NR           )No safety concern
    0266    5-Methylhexanoic acid          NR           )
    0268    3,5,5-Trimethyl-1-hexanol      NR           )

    0269    3,5,5-Trimethylhexanal         NR
    0270    2-Methyloctanal                NR
    0271    4-Methyloctanoic acid          NR
    0272    3,7-Dimethyl-1-octanol         NR
    0273    2,6-Dimethyloctanal            NR

    0274    4-Methylnonanoic acid          NR           )
    0275    2-Methylundecanal              NR           )No safety concern
                                                                      

                                                                      

    No.     Flavouring agent         Specifications1    Conclusion based
                                                        on current levels
                                                        of intake
                                                                      
    B. Structural class II
    flavouring agents:

    0256    2-Ethylbutyraldehyde           NR           )
    0257    2-Ethylbutyric acid            NR           )No safety concern
    0267    2-Ethyl-1-hexanol              NR           )
                                                                      
    Aliphatic lactones
    A. Structural class I
    flavouring agents:
    0219    4-Hydroxybutyric acid lactone
            (gamma-butyrolactone)          NR           )
    0220    gamma-Valerolactone            NR           )
    0223    gamma-Hexalactone              NR           )No safety concern
    0224    delta-Hexalactone              NR           )
    0225    gamma-Heptalactone             NR           )

    0226    gamma-Octalactone              NR           )
    0228    delta-Octalactone              NR           )
    0229    gamma-Nonalactone              NR           )No safety concern
    0230    Hydroxynonanoic acid
            delta-lactone                  NR           )
    0231    gamma-Decalactone              NR           )

    0232    delta-Decalactone              NR           )
    0241    epsilon-Decalactone            NR           )
    0233    gamma-Undecalactone            NR           )No safety concern
    0234    5-Hydroxyundecanoic acid
            delta-lactone                  NR           )
    0235    gamma-Dodecalactone            NR           )

    0236    delta-Dodecalactone            NR           )
    0242    epsilon-Dodecalactone          NR           )
    0238    delta-Tetradecalactone         NR           )No safety concern
    0239    omega-Pentadecalactone         NR           )
    0221    4-Hydroxy-3-pentenoic
            acid lactone                   NR           )

    0247    5-Hydroxy-7-decenoic acid
            delta-lactone                  NR           )
    0248    5-Hydroxy-8-undecenoic acid
            delta-lactone                  NR           )
    0249    1,4-Dodec-6-enolactone         NR           )No safety concern
    0240    omega-6-Hexadecenlactone       NR           )
    0227    4,4,-Dibutyl-gamma-
            butyrolactone                  NR           )
                                                                      

                                                                      

    No.     Flavouring agent         Specifications1    Conclusion based
                                                        on current levels
                                                        of intake
                                                                      

    0244    3-Heptyldihydro-5-methyl-
            2(3H)-furanone                 NR           )
    ----    4-Hydroxy-3-methyloctanoic
            acid gamma-lactone             NR           )No safety concern
    0237    6-Hydroxy-3,7-dimethyloctanoic
            acid lactone                   NR           )
    0250    gamma-Methyldecalactone        NR           )
                                                                      
    B. Structural class III
    flavouring agents;

    0246    5-Hydroxy-2-decenoic acid
            delta-lactone                  NR           )
    0245    5-Hydroxy-2,4-decadienoic
            acid delta-lactone             NR           )Not evaluated;
    ---     Mixture of 5-hydroxy-2-                     evaluation
            decenoic acid delta-lactone,                deferred pending
            5-hydroxy-2-dodecenoic acid                 consideration of
            delta-lactone, and 5-hydroxy-               other alpha, beta-
            2-tetradecenoic acid                        unsaturated
            delta-lactone                  NR           )compounds
    ---     5-Hydroxy-2-dodecenoic
            acid delta-lactone             NR           )
    0222    5-Ethyl-3-hydroxy-4-methyl-
            2(5H)-furanone                 NR           )No safety concern
    0243    4,5-Dimethyl-3-hydroxy-2,5-
            dihydrofuran-2-one             NR           )
                                                                      
    Esters of aliphatic acyclic primary
    alcohols with branched-chain
    aliphatic acyclic acids
    0185    Methyl isobutyrate             N            )
    0186    Ethyl isobutyrate              N            )
    0187    Propyl isobutyrate             N            )No safety concern
    0188    Butyl isobutyrate              N            )
    0189    Hexyl isobutyrate              N            )

    0190    Heptyl isobutyrate             N            )
    0191    trans-3-Heptenyl
            2-methylpropanoate             N            )
    0192    Octyl isobutyrate              N            )No safety concern
    0193    Dodecyl isobutyrate            N            )
    0194    Isobutyl isobutyrate           N            )
    0195    Methyl isovalerate             N            )
    0196    Ethyl isovalerate              R            )
                                                                      

                                                                      

    No.     Flavouring agent         Specifications1    Conclusion based
                                                        on current levels
                                                        of intake
                                                                      
    0197    Propyl isovalerate             N            )
    0198    Butyl isovalerate              N            )No safety concern
    0199    Hexyl 3-methylbutanoate        N            )

    0200    Octyl isovalerate              N            )
    0201    Nonyl isovalerate              N            )
    0202    3-Hexenyl 3-methylbutanoate    N            )No safety concern
    0203    2-Methylpropyl 3-
            methylbutyrate                 N            )
    0204    2-Methylbutyl 3-
            methylbutanoate                N,T          )

    0205    Methyl 2-methylbutyrate        N            )
    0206    Ethyl 2-methylbutyrate         N            )
    0207    n-Butyl 2-methylbutyrate       N            )No safety concern
    0208    Hexyl 2-methylbutanoate        N            )
    0209    Octyl 2-methylbutyrate         N            )

    0210    Isopropyl 2-methylbutyrate     N,T          )
    0211    3-Hexenyl 2-methylbutanoate    N,T          )
    0212    2-Methylbutyl 2-
            methylbutyrate                 N            )No safety concern
    0213    Methyl 2-methylpentanoate      N,T          )
    0214    Ethyl 2-methylpentanoate       N            )

    0215    Ethyl 3-methylpentanoate       N,T          )No safety concern
    0216    Methyl 4-methylvalerate        N            )
                                                                      
    Esters of aliphatic acyclic
    primary alcohols with aliphatic
    linear saturated carboxylic acids

    0117    Propyl formate                 N            )
    0118    Butyl formate                  N            )
    0119    n-Amyl formate                 N            )No safety concern
    0120    Hexyl formate                  N            )
    0121    Heptyl formate                 N,T          )

    0122    Octyl formate                  N            )
    0123    cis-3-Hexenyl formate          N            )
    0124    Isobutyl formate               N            )No safety concern
    0125    Methyl acetate                 N            )
    0126    Propyl acetate                 N            )
                                                                      

                                                                      

    No.     Flavouring agent         Specifications1    Conclusion based
                                                        on current levels
                                                        of intake
                                                                      
    0127    Butyl acetate                  R            )
    0128    Hexyl acetate                  N            )
    0129    Heptyl acetate                 N            )No safety concern
    0130    Octyl acetate                  N            )
    0131    Nonyl acetate                  N            )

    0132    Decyl acetate                  N            )
    0133    Lauryl acetate                 N            )
    0134    cis-3-Hexenyl acetate          N            )
    0135    trans-3-Heptenyl acetate       N            )
    0136    10-Undecen-1-yl acetate        N            )No safety concern
    0137    Isobutyl acetate               N            )
    0138    2-Methylbutyl acetate          N            )
    0140    2-Ethylbutyl acetate           N,T          )
    0141    Methyl propionate              N            )
    0142    Propyl propionate              N            )

    0143    Butyl propionate               N            )
    0144    Hexyl propionate               N            )No safety concern
    0145    Octyl propionate               N            )
    0146    Decyl propionate               N            )
    0147    cis-3- & trans-2-Hexenyl
            propionate                     N            Postponed2

    0148    Isobutyl propionate            N            )
    0149    Methyl butyrate                N            )
    0150    Propyl butyrate                N            )No safety concern
    0151    Butyl butyrate                 N            )
    0152    n-Amyl butyrate                N            )

    0153    Hexyl butyrate                 N            )
    0154    Heptyl butyrate                N,T          )
    0155    Octyl butyrate                 N,T          )No safety concern
    0156    Decyl butyrate                 N,T          )
    0157    cis-3-Hexenyl butyrate         N            )

    0158    Isobutyl butyrate              N            )
    0159    Methyl valerate                N            )
    0160    Butyl valerate                 N            )No safety concern
    0161    Propyl hexanoate               N            )
    0162    Butyl hexanoate                N            )

    0163    n-Amyl hexanoate               N            )
    0164    Hexyl hexanoate                N            )
    0165    cis-3-Hexenyl hexanoate        N,T          )No safety concern
    0166    Isobutyl hexanoate             N,T          )
    0167    Methyl heptanoate              N            )
                                                                      

                                                                      

    No.     Flavouring agent         Specifications1    Conclusion based
                                                        on current levels
                                                        of intake
                                                                      

    0168    Propyl heptanoate              N,T          )
    0169    Butyl heptanoate               N,T          )
    0170    n-Amyl heptanoate              N            )No safety concern
    0171    Octyl heptanoate               N,T          )
    0172    Isobutyl heptanoate            N,T          )

    0173    Methyl octanoate               N            )
    0174    n-Amyl octanoate               N            )
    0175    Hexyl octanoate                N            )No safety concern
    0176    Heptyl octanoate               N,T          )
    0177    Octyl octanoate                N,T          )

    0178    Nonyl octanoate                N,T          )
    0179    Methyl nonanoate               N            )
    0180    Methyl laurate                 N            )No safety concern
    0181    Butyl laurate                  N            )
    0182    Isoamyl laurate                N,T          )

    0183    Methyl myristate               N            )No safety concern
    0184    Butyl stearate                 N,T          )
                                                                      
    Esters derived from branched-chain
    terpenoid alcohols and aliphatic
    acyclic carboxylic acids

    0053    Citronellyl formate            N            )
    0054    Geranyl formate                N            )
    0055    Neryl formate                  N            )No safety concern
    0056    Rhodinyl formate               N            )
    0057    Citronellyl acetate            N            )

    0058    Geranyl acetate                R            )
    0059    Neryl acetate                  N            )
    0060    Rhodinyl acetate               N            )No safety concern
    0061    Citronellyl propionate         N            )
    0062    Geranyl propionate             N            )

    0063    Neryl propionate               N            )
    0064    Rhodinyl propionate            N,T          )
    0065    Citronellyl butyrate           N            )No safety concern
    0066    Geranyl butyrate               N            )
    0067    Neryl butyrate                 N            )
                                                                      

                                                                      

    No.     Flavouring agent         Specifications1    Conclusion based
                                                        on current levels
                                                        of intake
                                                                      

    0068    Rhodinyl butyrate              N            )
    0069    Citronellyl valerate           N,T          )
    0070    Geranyl hexanoate              N,T          )No safety concern
    0071    Citronellyl isobutyrate        N            )
    0072    Geranyl isobutyrate            N,T          )

    0073    Neryl isobutyrate              N            )
    0074    Rhodinyl isobutyrate           N            )
    0075    Geranyl isovalerate            N,T          )No safety concern
    0076    Neryl isovalerate              N            )
    0077    Rhodinyl isovalerate           N,T          )

    0078    3,7-Dimethyl-2,6-octadien-
            1-yl 2-ethylbutanoate          N,T          No safety concern
                                                                      

    B.      Flavouring agent considered for specifications only

                                                                      

    No.     Flavouring agent         Specifications1
                                                                      

    0218    Citric acid                    R
                                                                      

    3.  Contaminants

                                                                      
    Contaminant                            Conclusions
                                                                      
    Aflatoxins B, G, and M                 Potencies were estimated as
                                           described in the report
                                                                      

    4.  Food additives considered for specifications only

                                                                      
    Food additive                          Specifications
                                                                      
    Agar                                         R
    Alginic acid                                 R
    Aluminium powder                             R
    Ammonium alginate                            R
    Anoxomer                                     W
                                                                      

                                                                      
    Food additive                          Specifications
                                                                      

    Calcium alginate                             R
    Calcium propionate                           R
    Carbon dioxide                               R
    Carthamus red                                R,T
    Carthamus yellow                             R
    Citric acid                                  R

    Diacetyltartaric and fatty
    acid esters of glycerol (DATEM)              R

    Enzyme-hydrolyzed
    carboxymethyl cellulose                      N,T
    Enzyme-treated starches                      W
    Ethyl hydroxyethyl cellulose                 R

    Gellan gum                                   R
    Gum arabic                                   R

    Isoamyl acetate (amyl acetate)               R

    Microcrystalline wax                         R
    Mixed carotenoids                            R
    Modified starches                            R

    Petroleum jelly                              R,T
    Potassium alginate                           R
    Potassium propionate                         R
    Propionic acid                               R,T
    Propylene glycol                             R
    Propylene glycol alginate                    R
    Propylene glycol esters of
    fatty acids                                  R

    Sodium alginate                              R
    Sodium propionate                            R
    Sulfur dioxide                               R

    Talc                                         R
    Tartaric, acetic and fatty acid
    esters of glycerol, mixed                    S,T
    Turmeric                                     W
                                                                      

    1  N, new specifications prepared; O, no specifications prepared; R,
    existing specifications revised; S, specifications exist, revision not
    considered or not required; T, the existing, new or revised
    specifications are tentative and comments are invited; W, existing
    specifications withdrawn; NR, specifications not reviewed.

    2  Evaluation deferred pending consideration of other alpha, beta-
    unsaturated carbonyl compounds.  One of the predicted main metabolites
    of trans-2-hexenyl propionate is trans-2-hexenol, which should be
    oxidized to the alpha, beta-unsaturated substance, trans-2-hexenal.

    ANNEX 5


    APPLICATION OF A THRESHOLD OF TOXICOLOGICAL
    CONCERN IN THE SAFETY EVALUATION OF
    CERTAIN FLAVOURING SUBSTANCES


    Ian C. Munro, PhD, FRCPath
    CanTox Inc.
    Mississauga, Ontario
    Canada


    Professor Robert Kroes
    Prins Hendriklaan 63,
    3721 AP Bilthoven
    The Netherlands


    This paper was considered at the forty-ninth meeting of the Joint
    FAO/WHO Expert Committee on Food Additives. The conclusions of the
    Committee relating to its consideration of the paper are provided in
    the report, which has been published in the WHO Technical Report
    Series. The opinions expressed herein are those of the authors.

    ANNEX 5

    APPLICATION OF A THRESHOLD OF TOXICOLOGICAL CONCERN IN
    THE SAFETY EVALUATION OF CERTAIN FLAVOURING SUBSTANCES

    Table of Contents

    1.  EXPLANATION

    2.  THE CONCEPT OF A THRESHOLD OF TOXICOLOGICAL CONCERN AND ITS
        APPLICATION IN SAFETY EVALUATION OF FLAVOURING SUBSTANCES
        2.1 The practical problem
        2.2 Concepts in the derivation and application of a Threshold
            Value
        2.3 The scientific basis for the Threshold Value of 1.5 g/person
            per day specified at Step B5

    3.  APPLICATION OF A THRESHOLD OF TOXICOLOGICAL CONCERN TO FLAVOURING
        SUBSTANCES
        3.1 Additional factors that reduce the theoretical risk

    4.  SUMMARY

    5.  REFERENCES

    APPENDIX I

    1.  EXPLANATION

        At its forty-sixth meeting (JECFA, 1997) the Joint FAO/WHO Expert
    Committee on Food Additives (JECFA) further considered the proposed
    safety evaluation procedure for flavouring substances published in
    Annex 5 of WHO Food Additives Series 35 (JECFA, 1996) "A Procedure for
    the Safety Evaluation of Flavouring Substances" and applied this
    procedure to the evaluation of 47 flavouring substances. The Committee
    noted that one step in the safety evaluation procedure (Step B5;
    Figure 1 (the steps have been renumbered since the original
    publications)) involved the application of a decision criterion, based
    on the concept of a threshold of toxicological concern, to flavouring
    substances lacking sufficient toxicity or metabolic data to be
    evaluated using other steps in the procedure. This decision criterion
    is intended to be applied to flavouring agents that lack such data but
    that have a daily intake equal to or less than the threshold intake
    value of 1.5 g/person per day specified at Step B5. At the
    forty-sixth meeting, one substance, allyl-2-furoate, which lacked
    sufficient hydrolysis and toxicity data and was thus eligible for
    evaluation using Step B5, was not evaluated. The Committee deferred
    application of the decision criterion pending a complete evaluation of
    the scientific basis for the 1.5 g/person per day threshold value.
    The Committee recommended that the scientific issues involved in the
    development and application of Step B5 of the safety evaluation
    procedure be considered as soon as possible and that allyl-2-furoate
    be considered for evaluation using this step.

    2.  THE CONCEPT OF A THRESHOLD OF TOXICOLOGICAL CONCERN AND
    ITS APPLICATION IN SAFETY EVALUATION OF FLAVOURING SUBSTANCES

    2.1  The practical problem

    There are approximately 2500 chemically defined flavouring substances
    in use in Europe and the USA. Of these substances, approximately 1500
    have been evaluated by FEMA's Expert Panel and are recognized by the
    US Food and Drug Administration (FDA) to be Generally Recognized As
    Safe (GRAS) substances, meaning they are considered safe for their
    intended use. Without exception, flavouring substances are volatile
    organic chemicals. The vast majority of flavouring ingredients have
    simple, well-characterized structures with a single functional group
    and low relative molecular mass (<300 g/mol). More than 700 of the
    1323 chemically defined flavouring substances used in food in the USA
    are simple aliphatic acyclic and alicyclic alcohols, aldehydes,
    ketones, carboxylic acids and related esters, lactones, ketals, and
    acetals. Other structural categories include aromatic (e.g.,
    cinnamaldehydes and anthranilates), heteroaromatic (e.g., pyrazines
    and pyrroles) and heterocyclic (e.g., furanones and alicyclic
    sulfides) substances with characteristic organoleptic properties. For
    most flavouring substances, the structural differences within chemical
    classes are small. Incremental changes in carbon chain length and the
    position of a functional group or hydrocarbon chain typically describe
    the structural variation in groups of related flavouring substances. 

    Figure 1;V040JE14.BMP

    These systematic changes in structure provide the basis for
    understanding the effect of structure on the chemical and biological
    properties of a substance.

        Within structural groups of flavouring substances, many substances
    have considerable toxicology data; subchronic studies exist for many
    substances or their metabolic products, and several representative
    members of structural groups have chronic toxicity studies. At the
    forty-sixth meeting, the Committee was able to use information on
    metabolism, toxicity and intake on individual substances within a
    group to conclude, using all but Steps B5 of the safety evaluation
    procedure outlined in Figure 1, that esters of ethyl alcohol and
    isoamyl alcohol do not pose a safety concern at current levels of
    intake. In addition, the Committee considered that the allyl ester
    flavouring substances (with the exception of allyl-2-furoate which was
    not evaluated) likewise do not pose a safety concern. Allyl-2-furoate
    is one of a few flavouring substances currently in commercial use that
    lacks toxicity and metabolic data and, because the Committee expressed
    the view that evidence also was lacking for its rapid and complete
    hydrolysis to allyl alcohol and furoic acid, it was not evaluated at
    Step B4 along with the other allyl esters. However, allyl-2-furoate is
    a candidate substance for consideration using Step B5 because it has
    an exposure well below the 1.5 g/person per day decision criterion
    specified at Step B5 of the safety evaluation procedure. This paper
    elaborates the scientific principles underpinning the decision
    criterion specified at Step B5 and discusses the implications of
    applying the threshold of toxicological concern concept to the safety
    evaluation of flavouring substances.

    2.2  Concepts in the derivation and application of a threshold value

        With the possible exception of so-called genotoxic carcinogens,
    the concept of a threshold in toxicological responses is universally
    accepted and endorsed by the World Health Organization (IPCS, 1987,
    1994). In fact, the threshold concept forms the basis for the process
    of establishing Acceptable Daily Intakes (ADIs) that carry with them
    no appreciable risk to human health (IPCS, 1987; SCF, 1996). The idea
    that a generic threshold value or range of values might be established
    that would preclude the need for toxicity data on chemicals having
    human intakes below these thresholds was proposed over 30 years ago by
    Frawley (1967). This approach provides an attractive alternative to
    the conventional regulatory philosophy of rigorously testing each new
    chemical substance regardless of expense or level of human exposure.
    Two factors, pragmatism and scientific knowledge, have influenced the
    evolution of the threshold concept. The scientific information base is
    now sufficiently mature to consider application of a threshold of
    toxicological concern as a concept that is both practical and
    scientifically defensible. On a purely pragmatic level, it is
    recognized that humans are exposed to thousands of substances through
    the food supply and the number of substances increases logarithmically
    with declining concentration (Hall, 1975).

        It is neither practical nor scientifically defensible to test all
    these substances by conventional toxicological procedures, and to
    insist this be done would create a resource problem of immense
    proportions. Another more important factor that justifies an approach
    using a threshold of toxicological concern, is that in the past 10 to
    15 years a great deal of knowledge has accumulated about the potential
    human risks from chemicals in general and especially for those which
    are carcinogenic. On the basis of accumulated knowledge, it is
    theoretically possible to establish a range of threshold values
    representing the full spectrum of toxicological end-points including
    both carcinogenic and non-carcinogenic effects. In regard to
    non-carcinogenic responses, Munro  et al. (1996) have developed a
    database of over 600 chemicals arranged into three chemical structural
    groups from which they were able to plot the distribution of
    no-observed-effect levels (NOELs) and estimate the 5th centile NOELs
    for each structural class. From these 5th centile NOELs, generic human
    exposure thresholds were calculated for each of the structural
    classes. It was proposed by Munro  et al. (1996) that these human
    exposure threshold values could be used along with data on intake,
    metabolism and, as required, toxicity data, to evaluate the safety of
    flavouring substances. This procedure is outlined in the report of the
    forty-fourth meeting of JECFA (JECFA, 1995) and was further discussed
    and applied to the safety evaluation of flavours during the
    forty-sixth meeting of the Committee (JECFA, 1997). Step B5 of the
    safety evaluation procedure proposes the application of a threshold
    value of 1.5 g/person per day which is much lower than the threshold
    values developed by Munro  et al. (1996). Table 1 presents the 5th
    centile NOELs and corresponding human exposure thresholds that were
    derived from the Munro  et al. (1996) database for the three
    structural classes referred to in Annex 5 to WHO Food Additives Series
    35 (JECFA, 1996). It should be noted that the 1.5 g/person per day
    threshold value is 60 times lower than the human exposure threshold
    for structural Class III, the class with the highest presumptive
    toxicity. That is because the 1.5 g/person per day threshold value,
    proposed at Step B5, is derived from the distribution of risks for
    carcinogenic chemicals calculated using linear extrapolation models.
    This methodology is considerably more conservative than that used to
    derive the human exposure threshold values for non-carcinogenic
    end-points (see footnote to Table 1). Since Step B5 is intended to be
    applied to substances that lack adequate toxicity and metabolic data
    to be evaluated at previous steps in the safety evaluation procedure,
    the additional conservatism used in selecting this lower value is
    justified.

        Because of concerns, raised by others (SCF, 1996), that the 5th
    centile NOELs for specific toxicological end-points such as
    reproductive effects, neurotoxicity and immunotoxicity might result in
    human exposure thresholds lower than 1.5 g/person per day, this
    matter was examined. Table 1 presents the NOELs and corresponding
    human exposure thresholds for 100 substances reported in the RTECS
    database (RTECS, 1987) to cause developmental abnormalities. The human
    exposure threshold for this group of substances is 2076 g/person per
    day, 1384 times higher than the 1.5 g/person per day value. In

    addition, the 5th centile NOEL for 31 neurotoxic organophosphate
    insecticides included in structural class III of the Munro  et al. 
    (1996) database produced a corresponding human exposure threshold of
    18 g/person per day, 12 times greater than the threshold value
    proposed at Step B5. It might be expected that such neurotoxic
    compounds would have a low human exposure threshold because they are
    specifically designed to be highly potent toxins. Moreover, the
    measure of neurotoxicity selected to establish the NOELs in most cases
    was cholinesterase inhibition, an extremely sensitive end-point. Most
    importantly, organophosphates would not be used as flavouring
    substances. A list of the 100 substances reported to cause
    developmental abnormalities and of the 31 neurotoxic organophosphates,
    along with their NOELs, is given in Annex I.


    Table 1.  Comparison of various human exposure threshold values

                                                                         

    Category               5th Centile NOEL   Human exposure threshold1
                           (mg/kg bw/day)      (g/person/day)
                                                                         

    Structural Class I           3.0                     1800
    Structural Class II          0.91                    540
    Structural Class III         0.15                    90
    Developmental
    abnormalities2               3.46                    2076
    Neurotoxic compounds3        0.03                    18
                                                                         

    Step B5 Decision Criterion4                     1.5 g/person/day
                                                                         

    1  The human exposure threshold was calculated by multiplying the
    5th centile NOEL by 60 (assuming a 60 kg individual) dividing by a
    safety factor of 100, and multiplying by 1000 to convert from
    milligrams to micrograms. (Munro et al., 1996)
    2  Substances are from the RTECS database and were indicated to
    cause developmental abnormalities. The NOELs were presented by
    RTECs as the TDLo which is defined as the lowest dose of a
    substance reported to produce any non-significant adverse effects.
    (RTECS, 1987)
    3  For organophosphates, end-point measured was typically
    cholinesterase inhibition.
    4  See text for details.
                                                                   

    For the evaluation of the sensitivity of immunotoxicity as an
    end-point, the data of Luster  et al. (1992, 1993) were used to
    conduct a comparison of NOELs and LOELs based on immunotoxic
    end-points with corresponding NOELs and LOELs based on non-immunotoxic
    end-points. Twenty-four substances meeting the criteria of
    immunotoxicity used by Luster  et al. (1992, 1993) were identified
    that also had corresponding non-immunotoxic end-point NOELs or LOELs.

    A list of these substances is provided in Appendix I. Six of these
    substances had immunotoxic NOELs with corresponding non-immunotoxic
    NOELs. Twelve of these substances had no immunotoxic NOELs but had
    immunotoxic LOELs with corresponding non-immunotoxic LOELs. Five
    additional substances had immunotoxic NOELs with corresponding
    non-immunotoxic LOELs and one substance had an immunotoxic LOEL with a
    corresponding non-immunotoxic NOEL. For these last 6 substances, NOELs
    were compared with LOELs divided by a conservative factor of 10 to
    adjust for differences between NOELs and LOELs (Dourson  et al., 
    1996). For example, tetraethyl lead has an immune end-point NOEL of
    0.5 mg/kg bw per day and a non-immune end-point LOEL of 0.0012 mg/kg
    bw per day. The LOEL was divided by 10 (0.00012 mg/kg bw per day) for
    comparison with the NOEL. In order to perform the comparison of
    immunotoxic end-point sensitivity with non-immunotoxic end-point
    sensitivity, the immunotoxic NOEL/LOEL was divided by the
    corresponding non-immunotoxic NOEL/LOEL resulting in a ratio. The
    resulting ratios of the 24 comparisons are shown graphically in Figure
    2. The majority of the substances (17/24) had non-immunotoxic NOELs or
    LOELs that were lower (i.e., more sensitive) than the corresponding
    immunotoxic NOELs or LOELs. Two substances had similar NOELS/LOELS and
    5 substances had immunotoxic NOELs or LOELs that were less than
    10-fold lower than their non-immuntoxic counterparts. These data
    demonstrate that immunotoxicity is not a more sensitive end-point than
    other forms of toxicity.

        Overall, it may be considered that the threshold of toxicological
    concern concept is highly conservative since the decision criterion of
    1.5 g/person per day, shown in Table 1, is 1200-fold below the 5th
    centile NOEL for the most toxic threshold NOEL (for neurotoxic
    chemicals) and 6000 times lower than the 5th centile for Class III
    substances.

    FIGURE 2

    2.3  The scientific basis for the threshold value of 1.5
    g/person per day specified at Step B5

        Over the past several years, an immense amount of information has
    accumulated on the range of carcinogenic potencies for chemicals that
    have been tested in animals. For these chemicals, the distribution of
    potencies in experimental animals and projected human risk (calculated
    using linear risk assessment models) are well established and highly
    unlikely to be altered by further cancer bioassays (Krewski  et al., 
    1990). In fact, the Carcinogenic Potency Database (CPD) compiled by
    Gold  et al. (1984) that was used to derive the decision criterion of
    1.5 g per day specified at Step B5, now contains nearly 500
    substances reported to be carcinogenic in animals. It is reasonable to
    assume that the addition to that data-base of several more "genotoxic"
    carcinogens, should they be discovered, would be unlikely to alter the
    distribution of known risks for identified carcinogens. Scientists may
    never be prepared to say they know all they would like to know about
    the distribution of risks of existing animal carcinogens. On the other
    hand, it can be estimated with considerable confidence, based on data
    available today, that a substance which has not been tested for
    carcinogenicity and that is consumed in an amount below the threshold
    value specified at Step B5 will not present a risk of human cancer
    greater than one in one million (10-6).

        With these thoughts in mind, it is now important to look at the
    theoretical and practical aspects of the concept of threshold of
    concern and how it can be applied to flavouring substances in the
    context of JECFA safety evaluations.

        The Carcinogen Potency Database (CPD) contains data on
    approximately 3700 long-term animal studies of 975 chemicals (Gold 
     et al. 1986a,b,c; 1989). These include studies conducted by the US
    National Toxicology Program as well as studies conducted in other
    laboratories that have been published in the literature. Of the 975
    chemicals tested, 955 were tested in rats and/or mice and 492 produced
    an increase in tumour incidence (342 in rats and 278 in mice). Gold
     et al. have put an enormous effort into compiling this database and
    ensuring its quality. The reader is referred to a series of papers by
    Gold  et al. and others, published in Environmental Health
    Perspectives, which document the validity of this database (Gold 
     et al., 1984, 1986a,b,c, 1989; Peto  et al., 1984; Sawyer  et 
     al., 1984).

        For each compound, the CPD may include experiments with different
    species, strains, sexes, dosing regimens, routes of administration, or
    other experimental conditions (Gold  et al., 1984). In most
    experiments, two or more dose levels were used in addition to an
    unexposed control; in some cases, however, only a single exposed group
    was employed. Although a rigorous evaluation of the quality of
    individual experiments is not possible, the CPD does include
    information on the original investigators' conclusions regarding the
    overall strength of evidence for carcinogenicity.

        The CPD also contains a measure of carcinogenic potency (the
    TD50) computed as described by Peto  et al. (1984) and Sawyer 
     et al. (1984). In order to obtain some degree of comparability among
    different studies, all TD50 values are expressed in units of mg/kg bw
    per day and are adjusted to a 2-year standard rodent lifetime. In
    cases where exposure is not constant throughout the study period, a
    time-weighted average dose is used for purposes of modelling
    dose-response. When individual animal data are available, the TD50
    values are adjusted for intercurrent mortality; otherwise, the crude
    proportions of animals with tumours are used to estimate carcinogenic
    potency without adjusting for mortality from other causes. Finally,
    the TD50 is estimated on the basis of an essentially linear one-hit
    dose-response model.

        The CPD represents an extremely useful source of information on
    experiments with chemical carcinogens. The database includes
    experiments on highly potent rodent carcinogens such as
    2,3,7,8-tetrachlorodibenzo- p-dioxin and aflatoxin B1, as well as
    less potent agents such as metronidazole and DDT. Gold  et al. (1984)
    noted that TD50 values included in the CPD vary by 10 million-fold.

        Rulis (1986) used the Gold  et al. (1984, 1986a,b,c, 1989)
    database when he and others at FDA derived a threshold of regulation
    for packaging materials. What was done, in essence, was to transform
    the distribution of lowest TD50 for each carcinogen that was tested
    by the oral route to a distribution of 10-6 risks. While numerous
    mathematical models including the linearized multistage model could
    have been used to perform this transformation, Rulis (1986) used the
    slope (2TD50)-1 of a straight line joining the TD50 and the origin
    as an estimator of the slope in the low-dose region. Although the
    linearized multistage model could have been used since it has the
    advantage of allowing for curvature in the dose-response curve, linear
    extrapolation from the TD50 is computationally simple, extremely
    conservative, and requires only published potency values from the CPD.

        To illustrate the differences between these two approaches,
    Krewski  et al. (1990) considered the data on bladder tumours in mice
    exposed to the experimental carcinogen 2-acetyl-aminofluorene (2-AAF),
    shown in Figure 3. As indicated in Table 2, the TD50 for bladder
    tumours based on the fitted multistage model is 17.2 mg/kg bw per day,
    leading to a slope of (2TD50)-1 = 0.0291 (mg/kg per day) -1. Because
    over 3300 animals were involved in this experiment, the 95% lower
    confidence limit on the TD50 and the corresponding upper confidence
    limit on the slope are close to the best estimates obtained from the
    fitted model. Due to the high degree of curvature in the dose-response
    curve for bladder tumours, however, the upper confidence limit on the
    slope based on linear extrapolation from the lower confidence limit on
    the TD50 is more than 75-fold greater than the slope derived from the
    linearized multistage model.

    FIGURE 3

    Table 2.  Low-dose slopes for bladder tumors in mice exposed to
    2-AAF for 24 months based on linear extrapolation from the TD50

                                                                    

    Source of TD50              TD50            Slope of (2TD50)-1
                                (mg/kg/day)     (mg/kg/day)
                                                                    

    Fitted multistage model
      Best estimate             17.2            0.0291
      95% Confidence limit      16.71           0.02982

    Fitted one-hit model
      Best estimate             96.0            0.0052
      95% Confidence limit      77.42           0.00652

    95% Confidence limit on
    the linear term in 
    multistage model (q1*)                      0.00042
                                                                    

    1 Lower confidence limit
    2 Upper confidence limit

                                                                    


        These data show that when there is significant upward curvature in
    the dose-response curve, the methodology employed by Rulis (1986) to
    calculate a dose associated with a 10-6 risk will produce a value
    substantially lower than when these risk-specific doses are calculated
    using the linearized multistage model. This point also has been made
    by Hoel & Portier (1994), who noted that examination of the shape of
    the dose-response curve for 315 chemicals found to produce cancer in
    the NCI/NTP program indicates that tumour site data were more often
    consistent with a quadratic response than a linear response,
    suggesting that the use of linear dose-response models will often
    overestimate risk. It may therefore be concluded that the methodology
    used by Rulis (1986) (Federal Register, 1993, 1995) to estimate the
    distribution of 10-6 risks for carcinogens in the Gold  et al. CPD
    was appropriately conservative.

        The next step in the process of establishing a threshold value
    involves the selection of an appropriate exposure, which is based on
    the distribution of 10-6 risks. This value must be both highly
    protective of human health and of sufficient practical value to reduce
    the number of compounds requiring formal toxicological testing. Two
    steps need to be considered here: the first involves the selection of
    an appropriate risk standard that will ensure that any threshold value
    selected will have an acceptably high probability of health

    protection. The second step involves being pragmatic enough in the
    selection of a threshold value that it still is of sufficient
    magnitude to be of practical value. Of course, the protection of human
    health is of greater concern than the practical value.

        Initially Rulis (1986, 1989) proposed, for illustration, a
    threshold value of 0.15 g/person per day. Based on the distribution
    of 10-6 risks from the CPD, this value would intersect the
    distribution at the 85th centile, meaning that only 15% of carcinogens
    in the database would present a risk greater than 10-6 at an intake
    of 0.15 g/day. This analysis indicates that, at an intake of 0.15
    g/person per day, 85% chemicals in the CPD known to induce cancer in
    rodents would fail to show a significant increase in risk for the
    exposed population. This is demonstrated graphically in Figure 4,
    modified from Rulis (1989).

    FIGURE 4

        Subsequent to the report of Rulis (1989), Munro (1990) held a
    workshop to evaluate factors that influence the selection of an
    appropriate threshold value. The workshop first reanalysed the Gold
     et al. (1984) database using the original database of 343 rodent
    carcinogens and confirmed the observations of Rulis (1986, 1989) that
    a dietary intake of 0.15 g/day intersected the distribution of 10-6
    risks at approximately the 85th centile. In addition, the workshop
    extended the analysis to include additional carcinogens added to the
    original Gold  et al. (1984) database, bringing the total to 492
    rodent carcinogens (Gold  et al., 1989). This reanalysis with a
    broader set of data produced essentially the same distribution of 
    1  10-6 risks as was originally published by Rulis (1986, 1989). The
    workshop participants also noted that inherent in the acceptance of
    any threshold value was the assumption that every new untested
    substance was a likely carcinogen and could be as potent as the most
    potent 15% of carcinogens in the CPD.

        Recognizing that not every new substance would turn out to be a
    carcinogen, the workshop (Munro, 1990) constructed a table of risk
    avoidance probabilities (Table 3). 

        This table shows the effect of various assumptions regarding the
    proportion of chemicals that are presumed carcinogens on the
    probability that a 10-6 risk standard will not be exceeded. It should
    be noted that as this proportion decreases, the probability of not
    exceeding a specific risk standard increases dramatically. Thus, for
    example, while there is a 63% chance that the risk will not exceed
    10-6 with a value of 1.5 g/person per day when 100% of new chemicals
    are assumed to be carcinogenic, the probability that the risk will be
    less than 10-6 is 96% when only 10% of new chemicals are assumed to
    be carcinogenic. Moreover, if one invokes a less conservative risk
    standard of 10-5 (Table 3, right side), then the probability of not
    exceeding that risk at a threshold value of 1.5 g/person per day
    exceeds 96% even if it is assumed that 50% of new chemicals are
    potential carcinogens. It also should be remembered that, in theory,
    the probability of an untested substance having a potency greater than
    the median of the distribution of TD50s from the CPD (Gold  et al., 
    1989) is 50%. In reality, however, it is most unlikely that a
    genotoxic carcinogen with a potency equal to or greater than the
    median carcinogen in the Gold  et al. (1989) database would be
    discovered from the existing inventory of flavouring substances, given
    existing knowledge of structure-activity relationships in
    carcinogenesis.



        Table 3.  Probability of a target risk not being exceeded at various threshold values

                                                                                      
    Threshold value            Percentage of chemicals presumed carcinogenic
    (g/day)           100%    50%     20%     10%      100%     50%     20%    10%
                                                                                      
                              10-6 Target risk                 10-5 Target level
                                                                                      

         0.15           86     93      97      99        96      98      99     >99
         0.3            80     90      96      98        94      97      99     99
         0.6            74     87      95      97        91      96      98     99
         1.5            63     82      93      96        86      96      97     99
         3.0            55     77      91      95        80      90      96     98
         6.0            46     73      89      95        74      87      95     97
                                                                                      

    (Modified from Munro, 1990).
    

        Taking the above factors into consideration and keeping in mind
    that the calculated 10-6 risks based on the Gold  et al. (1989)
    database were derived using a highly conservative methodology, Rulis
    (1989) reexamined his previous selection criteria for a threshold
    value and those of Munro (1990) and concluded that a threshold value
    of 1.5 g/person per day would provide a high degree of health
    protection. This threshold value was subsequently adopted by FDA as
    the threshold of regulation (Federal Register, 1993, 1995) and FDA
    noted that such an exposure level would result in a negligible risk
    even in the event that a substance of unknown toxicity was later shown
    to be a carcinogen.

    3.  APPLICATION OF A THRESHOLD OF TOXICOLOGICAL CONCERN TO 
    FLAVOURING SUBSTANCES

        The Scientific Committee for Food (SCF, 1996) has made the point
    that the decision to accept any particular threshold value is both a
    scientific and a risk management decision. The role of the scientist
    is to ensure that risk managers are provided with the full range of
    uncertainties surrounding selection of any threshold value. In the
    foregoing sections it was pointed out that the threshold concept
    should not be interpreted as providing absolute certainty of no risk.
    Threshold of toxicological concern is a probabilistic methodology that
    involves acceptance of a negligible risk standard. Such a standard is
    commonly used by toxicologists in the establishment of ADIs, and, in
    fact, IPCS (1987) has defined the ADI as "an estimate by JECFA of the
    amount of a food additive, expressed on a body weight basis, that can
    be ingested daily over a lifetime  without appreciable health risk". 
    JECFA has noted that it uses the risk assessment process when setting
    an ADI, i.e., the level of "no apparent risk" is set on the basis of
    quantitative extrapolation from animal data to human beings typically
    using a NOEL from the animal studies divided by a 100-fold safety
    factor (IPCS, 1987). When ADIs (or such similar limits e.g., TLVs,
    RfD, etc.) are established, there is a residual, usually
    unquantifiable, element of risk (Purchase & Auton, 1995; Baird 
     et al., 1996; SCF, 1996; Sielken & Valdez-Flores, 1996). This is a
    reflection of the inability to determine precisely the NOEL from
    empirical data, statistical uncertainties associated with the
    sensitivity of experimental models, completeness of data, or the
    magnitude of safety factors needed to account for any residual
    uncertainty (Dourson & Stara, 1983).

        The threshold of toxicological concern likewise does not carry
    with it the absolute certainty that an untested chemical present in
    food below the decision criterion specified at Step B5 will present a
    less than 10-6 risk. Rather there is a high probability (i.e. about
    95%) that the cancer risk from such a chemical will be less than
    10-6. It is this residue of uncertainty that has produced a concern
    about the possibility, albeit remote, that a highly potent genotoxic
    carcinogen might inadvertently be considered acceptable using the
    threshold concept (SCF, 1996).

    3.1  Additional factors that reduce the theoretical risk

        When the threshold concept is applied to flavouring substances,
    two additional factors significantly reduce the probability of risk of
    cancer below one in one million. The first of these relates to very
    low levels of exposure to flavouring substances. As exposure
    decreases, the probability of not exceeding a 10-6 risk substantially
    increases, approaching 97 to 99% at an order of magnitude below the
    1.5 g/person per day value (Table 3). Therefore, application of a
    threshold of toxicological concern to substances having very low
    exposures (i.e., less or much less than the threshold value) carries
    with it a much higher probability of no appreciable risk. It also must
    be kept in mind that exposure to the vast majority of flavouring
    substances tends to be overestimated because these materials are
    volatile and appreciable amounts are lost during food preparation,
    storage, etc. These issues regarding exposure to flavouring substances
    are discussed in Annex 5 of WHO Food Additives Series 35 (JECFA,
    1996).

        The second factor involves a consideration of chemical structure.
    The use of chemical structure for predicting toxicity for food
    chemicals, especially flavouring substances, has long been recognized
    by JECFA (IPCS, 1987), and JECFA has noted that use of
    structure-activity is most highly developed in the area of
    carcinogenesis. The use of structural alerts in combination with a
    knowledge of chemistry and metabolism offers a way of identifying
    potential carcinogens (Ashby & Tennant 1988, 1991; Williams, 1990;
    Tennant  et al., 1990; Klopman & Rosenkranz, 1994). The examination
    of many chemicals for genotoxic, mutagenic and carcinogenic activities
    has led to the preparation of a series of structural alerts that
    provide the basis for potential reaction with DNA and possible
    carcinogenic potential of the substance. The existence of reactive
    moieties on known rodent carcinogens implies that potential mutagenic
    activity and, in many cases, the carcinogenic activity of untested
    chemicals might be identified by an examination of structure (Ashby &
    Tennant, 1988, 1991; Tennant & Ashby, 1991).

        Structure-activity relationships have been successfully applied to
    congeneric substances (i.e., individual substances within a
    structurally related group of substances) for which no toxicity data
    are available (Klopman & Rosenkranz, 1994). Congeners that are
    potential human carcinogens and mutagens possess electrophilic
    functional groups with the ability to react directly with DNA. These
    electrophilic sites may be reactive functional groups on the congener
    or those formed during metabolic activation. Conversely, these
    functional groups may be lost during metabolic detoxication of the
    substance. Although the carcinogenic and mutagenic potency of
    congeneric substances may differ, structural alerts within the group
    of congeners are indicative of carcinogenic or mutagenic potential
    (Klopman & Rosenkranz, 1994). A list of the functional groups
    identified by Ashby & Tennant (1988, 1991) and Tennant  et al. (1990)
    as structural alerts is given in Table 4.

    Table 4.  A list of functional groups  identified by Ashby & Tennant
    (1988, 1991) and  Tennant et al. (1990) as structural alerts for DNA
    reactivity

                                                                     
    a)  alkyl esters of phosphonic or sulfonic acids
    b)  aromatic nitro-groups
    c)  aromatic azo-groups (reduction to amine)
    d)  aromatic ring N-oxides
    e)  aromatic mono- and di-alkyl amino groups
    f)  alkyl hydrazines
    g)  alkyl aldehydes
    h)  N-methylol derivatives
    i)  monohaloalkanes
    j)  N and S mustards, beta-haloethyl-
    k)  N-chloramines
    l)  propiolactones and propiosulfones
    m)  aromatic and aliphatic aziridinyl derivatives
    n)  aromatic and aliphatic substituted primary alkyl halides
    o)  urethane derivatives (carbamates)
    p)  alkyl N-nitrosamines
    q)  aromatic amines and N-hydroxy derivatives
    r)  aliphatic epoxides and aromatic oxides
    s)  center of Michael reactivity
    t)  halogenated methanes (C(X)4)
    u)  aliphatic nitro groups
                                                                     

        Most flavouring agents are simple aliphatic and aromatic
    substances containing functional groups that are efficiently
    metabolized via detoxication pathways, and very few flavouring agents
    and/or their  in vivo metabolites contain structural alerts. The
    absence of structural alerts in a flavouring agent provides added
    assurance that it will not present an appreciable risk at or below the
    decision criterion of 1.5 g/person per day. For those that do contain
    significant structural alerts, such as aliphatic epoxides, additional
    data have been generated to facilitate evaluation.

    4.  SUMMARY

        The application of the decision criterion at Step B5 of the safety
    evaluation procedure provides a means of evaluating those flavouring
    substances that have extremely low exposures but lack metabolic and
    toxicity data. It is recognized that application of a threshold of
    toxicological concern is a departure from traditional toxicological
    evaluation but, nonetheless, is based on highly conservative
    methodology and assumptions which, taken together, ensure that
    flavouring substances meeting the proposed criteria will present, at
    most, an insignificant risk.

    The following factors taken together ensure the absence of any
    appreciable theoretical risk from the use of flavouring substances
    evaluated using this procedure:

    1. The decision criterion is based on carcinogenesis data, an
    extremely sensitive end-point in susceptible animal species with
    accepted relevance to humans.

    2. The CPD presents a worse case situation since chemicals were
    generally tested over a lifetime by daily administration at the
    maximum tolerated dose (MTD), and the procedures used by Gold  et 
     al. (1984) to establish the TD50s involved numerous conservative
    assumptions.

    3. The methods used by Rulis (1986, 1989) and others (Krewski  et 
     al., 1990; Munro, 1990) to calculate the distribution of 10-6
    risks, upon which the threshold value of 1.5 g/person per day is
    based, are highly conservative since they involved the use of linear
    extrapolation from the lowest TD50 for each substance in the database.

    4. It is unlikely that any untested flavouring agent would turn out to
    be a genotoxic carcinogen, and the possibility that a carcinogen would
    be accepted using the threshold concept can be substantially reduced
    by the application of structural alert methodology.

    5. Many flavouring substances are consumed in amounts considerably
    below the threshold value of 1.5 g/person per day and this
    substantially increases the probability, already in the range of 90 to
    95%, that they will not present any significant theoretical risk.

    6. Toxicity end-points such as developmental toxicity, neurotoxicity
    and immunotoxicity demonstrate considerably higher human exposure
    thresholds than the threshold value of 1.5 g/person per day specified
    at Step B5 making it highly unlikely that these non-cancer end-points
    are a relevant concern in applying the threshold concept.

        Taken together, these factors provide a sound basis for concluding
    that flavouring substances with intakes below the 1.5 g/person per
    day threshold of toxicological concern specified at Step B5 can be
    safely consumed.


    ACKNOWLEDGEMENT

    The authors are deeply indebted to Dr. Alan Rulis for reviewing this
    paper and providing many useful suggestions.

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        Table 1.  NOELS for organophosphate insecticides1

                                                                                                                             
    Agent                         Species      End-point observed                                  NOEL (mg/kg bw per day)
                                                                                                                             

    Acephate                      rat          decreased body weight gain (parents and pups)                  2.5
    Azinphos methyl               rat          inhibition of plasma ChE activity                              0.18
    Coumaphos                     rat          inhibition of RBC and plasma ChE activity                      0.4
    Crufomate                     rat          inhibition of RBC ChE activity                                 3
    Diazinon                      mouse        decreased body weight gain                                    722
    Dichlorvos                    rat          inhibition of ChE activity (specific end-point
                                               not indicated)                                                 0.23
    Dimethoate                    rat          inhibition of brain, RBC and plasma ChE activity               0.05
    Disulfoton                    rat          inhibition of brain, RBC and plasma ChE activity               0.05
    Ethephon                      rat          inhibition of plasma and RBC ChE activity                     15
    Ethion                        rat          inhibition of plasma ChE activity in females                   0.2
    Ethyl-p-nitrophenylphenyl
    phosphorothioate              rat          inhibition of brain, RBC  and plasma ChE activity              0.25
    Express                       rat          decreased body weight gain                                     1
    Fenamiphos                    rabbit       decreased maternal body weight gain                            0.1
    Fenchlorphos                  rat          inhibition of ChE (form not specified)                        15
    Fonofos                       rat          inhibition of RBC and plasma ChE activity                      0.5
    Glufosinate ammonium          rat          increased absolute and relative kidney
                                               weight in males                                                0.42
    Glyphosate                    rat          increased incidence of renal tubular
                                               dilation in F3b pups                                          10
    Malathion                     rat          inhibition of brain ChE activity                               5
    Merphos                       rat          inhibition of RBC ChE activity in females                      0.1
    Merphos oxide                 rat          inhibition of brain ChE activity                               0.25
    Methamidophos                 rat          clinical signs typical of ChE inhibition                       1
    Methidithion                  rat          inhibition of brain and RBC ChE activity                       0.2
    Methyl parathion              rat          decreased haemoglobin, haematocrit and RBCs                    0.025
    Naled                         rat          decreased body weight gain                                     0.2
    Parathion                     rat          decreased body weight gain                                     1.8
    Phosmet                       rat          inhibition of RBC and plasma ChE activity                      2
    Phosphamidon                  rat          decreased body weight gains                                    6.2
    Pirimiphos-methyl             rat          inhibition of plasma ChE activity                              0.5
                                                                                                                             

    Table 1.  Continued...

                                                                                                                             
    Agent                         Species      End-point observed                                     NOEL (mg/kg bw per day)
                                                                                                                             

    Quinalphos                    mouse        inhibition of plasma ChE activity                              0.03
    Tetrachlorvinphos             rat          inhibition of RBC ChE activity                                 6
    Tetraethyl dithio
    pyrophosphate                 rat          inhibition of RBC and plasma ChE activity                      0.5
                                                                                                                             

    1 Data taken from the EPA (IRIS) database and WHO 1969 Integrated Risk Information System
    2 NOEL divided by a factor of 3 (see Munro et al., 1996 for explanation)

    Table 2.  Substances reported to cause developmental abnormalities (from RTECS)

                                                                                                                                          
           Chemical                                                                                            Species     Dose (TDLo)1
                                                                                                                           mg/kg bw
                                                                                                                                          

    1      1,3,4-Thiadiazole, 2,2'-(methylenediimino)bis-                                                      rat         1
    2      1-6-Hexanediamine                                                                                   rat         1840
    3      1-Piperazinepropanol, 4-(6-((6-methoxy-8-quinolyl)amino)hexyl)-alpha-methyl-, maleate (1:2)         rat         90
    4      11H-Pyrido(2,1-b)quinazolone-2-carboxylic acid, 11-oxo-                                             rat         4400
    5      1H-Indazole-3-carboxylic acid, 1-(2,4-dichlorobenzyl)-                                              rat         175
    6      1H-Isoindole-1,3(2H)-dione,4,5,6,7-tetrahydro-2-(7-fluoro-3,4-dihydro-3-oxo-4-;
           (2-propynyl)-2H-1,4-benzoxazin-6-yl)-                                                               rat         300
    7      2,7-Naphthalenedisulfonic acid, 3,3'((3,3'-dimethyl-4,4'biphenylylene)bis(azo))
           bis(5-; amino-4-hydroxy-, tetrasodium salt)                                                         rat         150
    8      2-Propanone, 1,1,3,3-tetrachloro-                                                                   rabbit      130
    9      2-Pyridinemethanol,alpha-(3-(2,6-dimethyl-1-piperidinyl)propyl)-alpha-phenyl-,;
           monohydrochloride, Z-(+-)-                                                                          rabbit      650
    10     3-Biphenylcarboxylic acid, 2',4'-difluoro-4-hydroxy-                                                rabbit      520
    11     4-Thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid,6-((aminophenylacetyl)amino)-;
           3,3-dimethyl-7-oxo-,(2,2-dimethyl-1-oxopropoxy)methyl ester,hydrochloride                           mouse       1200
    12     4-Thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid,6-(2-amino-2-phenylacetamido)-;
           3,3-dimethyl-7-oxo-,trihydrate,D-(-)-                                                               rat         2800
    13     4H-Pyrido(1,2-a)pyrimidin-4-one,9-methyl-3-(1H-tetrazol-5-yl)-, potassium salt                      rat         2750
    14     4H-s-Triazolo(3,4-c)thieno(2,3-e)(1,4)-diazepine,6-(o-chlorophenyl)-8-ethyl-1-methyl-               rabbit      13
    15     5-Isoxazoleacetic acid, 3,4-bis(4-methoxyphenyl)-                                                   rat         1650
    16     7H-Pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid,2,3-dihydro-9-fluoro-3-methyl-;
           10-(4-methyl-1-piperazinyl)-7-oxo-,hemihydrate,(S)-                                                 rat         8910
    17     9H-Purine-6-thiol, 9-beta-D-ribofuranosyl-                                                          rat         87.5
    18     Acetamide, 2,2-dichloro-N-(beta-hydroxy-alpha-(hydroxymethyl)-p-(methylsulfonyl)phenethyl)-,;
           D-threo-(+)                                                                                         rat         150
    19     Acetamide, N,N-dimethyl-                                                                            rabbit      3900
    20     Acetic acid, (2,4-dichlorophenoxy)-                                                                 rat         0.22
    21     Acetic acid, (3,5,6-trichloro-2-pyridyloxy)-                                                        rat         2000
    22     Acetic acid, oxo((3-(1H-tetrazol-5-yl)phenyl)amino)-,butyl ester                                    rat         24000
    23     Acetonitrile, amino-, bisulfate                                                                     rat         200
    24     Acridine, 9,9-dimethyl-10-(3-(N,N-dimethylamino)propyl)-,tartrate                                   mouse       175
    25     Alanine, 3-(3,4-dihydroxyphenyl)-, L-                                                               rat         500
                                                                                                                                          

    Table 2.  Continued...

                                                                                                                                          
           Chemical                                                                                            Species     Dose (TDLo)1
                                                                                                                           mg/kg bw
                                                                                                                                          

    26     Alanine, N-((5-chloro-8-hydroxy-3-methyl-1-oxo-7-isochromanyl)carbonyl)-3-phenyl-,;
           sodium salt, (-)-                                                                                   rat         5
    27     Alosenn                                                                                             rat         5500
    28     Anthranilic acid, N-(2,3-xylyl)-                                                                    mouse       8
    29     Arsine oxide, dimethylhydroxy-                                                                      rat         300
    30     Benzamide, N-(2-piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)-, monoacetate                     rabbit      390
    31     Benzenesulfonamide, 4-amino-N-(4,5-dimethyl-2-oxazolyl)-,mixt. with 5-((3,4,5-;
           trimethoxyphenyl)methyl)-2,4-pyrimidinediamine                                                      rat         3360
    32     Benzenesulfonamide, 4-amino-N-(4,6-dimethoxy-2-pyrimidinyl)-                                        rat500
    33     Benzenesulfonic acid, thio-,S,S'-(2-(dimethylamino)trimethylene) ester                              rat         660
    34     Benzhydrol, 2-chloro-alpha-(2-(dimethylamino)ethyl)-,hydrochloride                                  mouse       120
    35     Benzoic acid, 3,4,5-trimethoxy-beta-(dimethylamino)-beta-ethylphenethyl ester,; maleate (1:1)       rabbit      6500
    36     Benzyl alcohol, 4-amino-alpha-((tert-butylamino)methyl)-3,5-dichloro-,monohydrochloride             rat         4.4
    37     Biphenyl, 3,3',4,4'-tetramethyl-                                                                    mouse       640
    38     Butyric acid, 4-(p-bis(2-chloroethyl)aminophenyl)-                                                  mouse       3
    39     Butyrophenone, 4-(4-(p-chlorophenyl)-4-hydroxypiperidino)-4'-fluoro-                                rat         5.04
    40     Cadmium                                                                                             rat         23
    41     Carbazic acid, 3-(1-phthalazinyl)-, ethyl ester, monohydrochloride                                  mouse       70
    42     Chlordane                                                                                           rat         880
    43     Cortisone                                                                                           mouse       500
    44     Dibenzo(b,e)(1,4)dioxin, 2,3,7,8-tetrabromo-                                                        mouse       0.216
    45     Dibenzo-p-dioxin, 2,7-dichloro-                                                                     rat         5
    46     Disulfide, bis(thiocarbamoyl)                                                                       mouse       105
    47     Ethane, 1,1,1-trichloro-2,2-bis(p-methoxyphenyl)-                                                   rat         2000
    48     Ethane, 2-(o-chlorophenyl)-2-(p-chlorophenyl)-1,1,1-trichloro-                                      rat         250
    49     Ethanone, 1-(7-(2-hydroxy-3-((1-methylethyl)amino)propoxy)-2-benzofuranyl)-, hydrochloride          rat         1400
    50     Ethanone, 2-((4-(2,4,dichloro-3-methylbenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)-;
           1-(4-methylphenyl)-                                                                                 rat         2000
    51     Folic acid, methyl-                                                                                 rat         500
    52     Gallic acid, propyl ester                                                                           rat         45000
    53     Glutamic acid, N-(p-((1-(2-amino-4-hydroxy-6-pteridinyl)ethyl)amino)benzoyl)-L-                     rat         20
    54     Gossypol acetic acid                                                                                mouse       480
    55     Hydrocinnamic acid, alpha-hydrazino-3,4-dihydroxy-alpha-methyl-, L-                                 rat         2100
                                                                                                                                          

    Table 2.  Continued...

                                                                                                                                          
           Chemical                                                                                            Species     Dose (TDLo)1
                                                                                                                           mg/kg bw
                                                                                                                                          

    56     Indole-3-acetic acid, 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-                                       rat         1
    57     Isonicotinamide, 2-ethylthio-                                                                       mouse       450
    58     Isothiocyanic acid, butenyl ester                                                                   rat         800
    59     L-Glutamic acid, magnesium salt (1:1), hydrobromide                                                 rat         6000
    60     L-Tyrosine                                                                                          rat         3500
    61     L-Tyrosine, O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-                                              rat         26.25
    62     Linoleic acid (oxidized)                                                                            rat         166000
    63     Lysine, L-                                                                                          rat         81000
    64     Manganese, (ethylenebis(dithiocarbamato))- and zinc acetate (50:1)                                  rat         765
    65     Mannitol, 1,6-dibromo-1,6-dideoxy-, D-                                                              mouse       150
    66     Methanol, 1,3,4-thiadiazol-2-ylminodi-                                                              rat         5
    67     Molybdenum                                                                                          rat         5.8
    68     Morpholine, 4-(3,4,5-trimethoxybenzoyl)-                                                            rat         700
    69     Norleucine, 6-amidino-, monohydrochloride, hydrate                                                  rat         2000
    70     Oxazolo(3,2-d)(1,4)benzodiazepin-6(5H)-one, 10-chloro-11b-(o-chlorophenyl)-2,3,7,11b- ;
           tetrahydro                                                                                          mouse       1800
    71     Phenol, p-amino-                                                                                    rat         2500
    72     Phenothiazine-2-acetic acid, 10-methyl                                                              mouse       180
    73     Phosphonic acid, (1,2-epoxypropyl)-, calcium salt (1:1), (1R,2S)-(-)-                               rat         15400
    74     Phosphorodithioic acid, O,O-dimethyl ester, S-ester with 2-mercapto-N-methylacetamide               rat         120
    75     Phthalic acid, di(methoxyethyl)ester                                                                rat         593
    76     Piperazine, 1-(p-tert-butylbenzyl)-4-(p-chloro-alpha-phenylbenzyl)-                                 rat         320
    77     Piperazine,1-(p-tert-butylbenzyl)-4-(p-chloro-alpha-phenylbenzyl)-,dihydrochloride                  rat         360
    78     Piperidine, 3-((4-methoxyphenoxy)methyl)-1-methyl-4-phenyl-, hydrochloride, (3R-trans)-             rat         210
    79     Piperidine, 1-methyl-4-(N-2-thenylanilino)-, tartrate                                               rat         157
    80     Polychlorinated biphenyl (aroclor 1254)                                                             rat         90
    81     Pregn-4-ene-3,20-dione,9-fluoro-11-beta,17,21-trihydroxy-                                           rabbit      2
    82     Pregna-,4-diene-2,20-dione,9-fluoro-11-beta,16-alpha,17,21-tetrahydroxy-,16,21-diacetate            mouse       3.2
    83     Propionic acid,2-(2,4,5-trichlorophenoxy)-                                                          mouse       1617
    84     Pyrimidine, 2,4-diamino-6-methyl-5-phenyl-                                                          rat         100
    85     Retinoic acid, 4-oxo-,13-cis-                                                                       mouse       100
    86     Retinoic acid, all-trans-                                                                           mouse       15
    87     Rowachol                                                                                            rat         9600
                                                                                                                                          

    Table 2.  Continued...

                                                                                                                                          
           Chemical                                                                                            Species     Dose (TDLo)1
                                                                                                                           mg/kg bw
                                                                                                                                          

    88     Stannane, diacetoxydibutyl-                                                                         rat         15.2
    89     Sulfanilamide, N(sup 1)-(6-methoxy-2-methyl-4-pyrimidinyl)-                                         mouse       3000
    90     Toluene, alpha-(2-(2-butoxyethoxy)ethoxy)-4,5-(methylenedioxy)-2-propyl-                            rat         2130
    91     Tryptophan, N-acetyl-,L-                                                                            rat         27500
    92     Urea, (alpha-(2-methylhydrazino)-p-toluoyl)-, monohydrobromide                                      rabbit      50
    93     Urea, 1-butyl-3-(p-tolylsulfonyl)-                                                                  mouse       1700
    94     Urea, 1-butyl-3-sulfanilyl-                                                                         rat         1000
    95     Uridine, 5'-deoxy-5-fluoro-                                                                         rat         550
    96     ZZL-0820                                                                                            rabbit      325
    97     beta-Escin                                                                                          mouse       36
    98     m-Propionotoluidide,2-methyl-4'-nitro-alpha,alpha,alpha-triflouro-                                  rat         1050
    99     p-Acetophenetidide                                                                                  rat         6000
    100    p-Cresol, 2,6-di-tert-butyl-                                                                        mouse       1200
                                                                                                                                          

    1  TDLo = the lowest dose of a substance reported to produce any non-significant adverse effect (=NOEL).

    Table 3.  Substances with immunotoxic NOELs

                                                                                                                                       
    Substance                        Immune             Non-immune             Non-immune                     Reference
                                      NOEL           NOEL         LOEL         end-point
                                    (mg/kg bw      (mg/kg bw   (mg/kg bw
                                     per day)       per day)    per day)
                                                                                                                                       

    ORAL ADMINISTRATION

    1  p-nitrotoluene                  400            200                      hepatic, splenic               Burns et al., 1994
    2  pentachlorophenol                10              3                      hepatic, renal                 Schwetz et al., 1978
    3  o-phenylphenol                  100             10                      blood (red blood cells)        Luster et al., 1981
    4  hexachlorodibenzo-p-dioxin    0.056          1E-05                      reproductive                   Murray et al., 1979
    5  DPH                             150             50                      teratogenic                    McClain & Langhoff, 1979
    6  tetraethyl lead                 0.5                       0.0012        hepatic,thymus                 Schepers, 1964
    7  benzidine                        11                          2.7        neural, hepatic                Littlefield et al., 1983
    8  nitrobenzene                     30                           60        reproductive                   Kawashima et al., 1995

    NON-ORAL ADMINISTRATION

    1  indomethacin (subcutaneous)       2            1.6                      reproductive/vascular
                                                                               permeability(subcutaneous)     Hoos & Hoffman, 1983
    2  TPA (subcutaneous)               20                         0.32        reproductive (subcutaneous)    Nagasawa et al., 1980
    3  ethyl carbamate 
       (intraperitoneal)                 2             15                      reproductive (subcutaneous)    NTIS, 1968
                                                                                                                                       

    Table 4.  Substances with immunotoxic LOELs

                                                                                                                                        

    Substance                       Immune          Non-immune                 Non-immune                       Reference
                                     LOEL       NOEL          LOEL             end-point
                                  (mg/kg bw    (mg/kg bw      (mg/kg bw
                                   per day)     per day)       per day
                                                                                                                                        

    ORAL ADMINISTRATION

    1  2,3,7,8-TCDD                0.086                      1E-05            reproductive                     Murray et al., 1979
    2  lithium carbonate              50                         98            reproductive, body weight,
                                                                               hepatic, renal                   Ibrahim & Canolty, 1990
    3  m-nitrotoluene                200                         40            hepatic (female)                 NTP, 1992
    4  2,4-diaminotoluene             25                         24            reproductive                     Thysen et al., 1985
    5  dimethylvinyl chloride         50                        125            splenic                          NTP, 1986
    6  ethylene dibromide            125          30                           mortality                        Teramoto et al., 1980
    7  4,4-thiobis
       (6-t-butyl-m-cresol)           10                         45            hepatic                          NTP, 1994


    NON-ORAL ADMINISTRATION
    1  azathioprine
       (intraperitoneal)              10                          1            reproductive (intraperitoneal)   Scott, 1977
    2  benzo(a)pyrene
       (subcutaneous)                 50                         50            reproductive (subcutaneous)      Bui et al., 1986
    3  diethylstilbestrol
       (subcutaneous)                0.2                      1E-05            reproductive (subcutaneous)      McLachlan, 1977
    4  DMB(a)A (subcutaneous)          5                       1.25            reproductive (oral)              Davis et al., 1978
    5  N-nitroso dimethylamine
       (intraperitoneal)             1.5                          5            reproductive (intraperitoneal)   Chaube, 1973
    6  ochratoxin A
       (intraperitoneal)             3.4                     0.0625            renal (gavage)                   NTP, 1989
                                                                                                                                        
    

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    See Also:
       Toxicological Abbreviations