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    Toxicological evaluation of some food
    additives including anticaking agents,
    antimicrobials, antioxidants, emulsifiers
    and thickening agents



    WHO FOOD ADDITIVES SERIES NO. 5







    The evaluations contained in this publication
    were prepared by the Joint FAO/WHO Expert
    Committee on Food Additives which met in Geneva,
    25 June - 4 July 19731

    World Health Organization
    Geneva
    1974

              

    1    Seventeenth Report of the Joint FAO/WHO Expert Committee on
    Food Additives, Wld Hlth Org. techn. Rep. Ser., 1974, No. 539;
    FAO Nutrition Meetings Report Series, 1974, No. 53.

    The monographs contained in the present volume are also issued by the
    Food and Agriculture Organization of the United Nations, Rome, as
    FAO Nutrition Meetings Report Series, No. 53A












    ISBN 92 4 166005 8





    (C) FAO and WHO 1974

    CONTENTS

    INTRODUCTION

    ALLOCATION OF ACCEPTABLE DAILY INTAKES (ADI)

    TOXICOLOGICAL EVALUATION: ANTICAKING AGENTS

    TOXICOLOGICAL EVALUATION: ANTIMICROBIALS

    TOXICOLOGICAL EVALUATION: ANTIOXIDANTS AND SYNERGISTS

    TOXICOLOGICAL EVALUATION: EMULSIFIERS

    TOXICOLOGICAL EVALUATION: THICKENING AGENTS

    TOXICOLOGICAL EVALUATION: MISCELLANEOUS FOOD ADDITIVES

    THE MONOGRAPHS

         ANTICAKING AGENTS

         Calcium, Potassium, Sodium Ferrocyanide
         Salts of Myristic, Palmitic and Stearic Acids
         Silicon Dioxide and Certain Silicates

         ANTIMICROBIALS

         Acetic Acid and its Potassium and Sodium Salts
         Benzoic Acid and its Potassium and Sodium Salts
         Cupric Sulfate
         Diethyl Pyrocarbonate
         Formic Acid
         Hexamethylenetetramine
         Hydrogen Peroxide
         p-Hydroxybenzoate, Butyl
         p-Hydroxybenzoate, Ethyl, Methyl, Propyl Esters
         Nitrate, Potassium and Sodium Salts
         Nitrite, Potassium and Sodium Salts
         Propionic Acid and its Calcium, Potassium and Sodium Salts
         Sodium Diacetate
         Sorbic Acid and its Calcium, Potassium and Sodium Salts
         Sulfur Dioxide and Sulfites

         ANTIOXIDANTS

         Ascorbic Acid and its Potassium and Sodium Salts
         Ascorbyl Palmitate and Stearate
         Butylated Hydroxyanisole
         Butylated Hydroxytoluene

         Citric Acid and its Calcium, Potassium and Sodium salts
         Ethylenediaminetetraacetate, Disodium and Calcium Disodium Salts
         Gallates, Dodecyl, Octyl and Propyl
         Guaiac Resin
         Isoascorbic Acid and its Sodium Salt
         Isopropyl Citrate Mixture and Monoisopropyl Citrate
         Nordihydroguaiaretic Acid
         Stearyl Citrate
         Thiodipropionic Acid and Dilauryl Ester
         Alpha-Tocopherol and Mixed Toxopherols Concentrate

         EMULSIFIERS

         Acetic and Fatty Acid Esters of Glycerol
         Ammonium Salts of Phosphatidic Acids
         Cholic and Desoxycholic Acid and their Salts
         Citric and Fatty Acid Esters of Glycerol
         Diacetyl Tartaric and Fatty Acid Esters of Glycerol
         Esters of Glycerol and Thermally Oxidized Soybean
           Fatty Acids
         Hydroxylated Lecithin
         Lactic and Fatty Acid Esters of Glycerol
         Lecithin
         Mixed Tartaric, Acetic and Fatty Acid Esters of Glycerol
         Mono- and Diglycerides
         Polyglycerol Esters of Fatty Acids
         Polyglycerol Esters of Interesterified Ricinoleic Acid
         Polyoxyethylene (20) Sorbitan Monoesters of Lauric
            Oleic, Palmitic and Stearic Acid and Triester of Stearic Acid
         Polyoxyethylene (8) and Polyoxyethylene (40) Stearates
         Propylene Glycol Alginate
         Propylene Glycol Esters of Fatty Acids
         Sorbitan Monoesters of Palmitic and Stearic Acids and
           Triesters of Stearic Acid
         Sucrose Esters of Fatty Acids, and Sucroglycerides

         THICKENING AGENTS

         A.   CELLULOSES

         Microcrystalline Cellulose
         Modified Celluloses

         B.   VEGETABLE GUMS

         Arabic Gum
         Carob Bean Gum
         Guar Gum
         Karaya Gum
         Tragacanth Gum

         C.   MODIFIED STARCHES AND DEXTRINS

         Acetylated Distarch Adipate
         Acetylated Distarch Glycerol
         Acetylated Distarch Phosphate
         Acid-treated Starches
         Alkali-treated Starches
         Amylose and Amylopectin
         Bleached Starches
         Distarch Glycerol
         Distarch Phosphate
         Enzyme-treated Starches
         Hydroxypropyl Distarch Glycerol
         Hydroxypropyl Distarch Phosphate
         Hydroxypropyl Starch
         Monostarch Phosphate
         Oxidized Starches
         Phosphated Distarch Phosphate
         Starch Acetate
         Starch Sodium Succinate
         White and Yellow Dextrins

         D.   OTHERS

         Agar
         Alginic Acid and its Ammonium, Calcium, Potassium
           and Sodium Salts
         Carrageenan and Furcellaran
         Pectin

         MISCELLANEOUS

         Calcium Acetate, Chloride, Gluconate and Sulfate
         Food-Grade Mineral Oil
         L-Glutamic Acid and its Ammonium, Calcium, Monosodium
           and Potassium Salts
         Lactic Acid and its Ammonium, Calcium, Potassium and
           Sodium Salts
         Oxystearin
         Phosphoric Acid, Polyphosphates and their Calcium,
           Magnesium, Potassium and Sodium Salts
         Polyvinyl Pyrrolidone
         1,2 - Propylene Glycol
         Sorbitol
         Stearoyl Lactylic Acid, Calcium and Sodium Salts
         Tartaric Acid and its Potassium, Potassium-Sodium and
           Sodium Salts

    ANNEX 1.    Reports and other documents resulting from previous
      meetings of the Joint FAO/WHO Expert Committee on Food Additives

    ANNEX 2.    Membership of the Seventeenth Joint FAO/WHO Expert
      Committee on Food Additives

    INDEX
    

    INTRODUCTION

         The monographs contained in this document are the result of the
    deliberations of the Joint FAO/WHO Expert Committee on Food Additives
    which met in Geneva from 25 June to 4 July 1973. Since the report1 of
    this meeting contains comments on the same substances, these
    monographs should be read or consulted in conjunction with the report.

         The present monographs follow the standard format adopted by the
    Expert Committee on Food Additives when dealing with the toxicological
    evaluation of food additives. Each monograph attempts to provide, in a
    condensed form, as full an account as possible of all the biochemical
    and toxicological data made available to the Expert Committee on Food
    Additives at the time of the meeting.

         All the substances examined at this meeting have been evaluated
    in previous meetings. Monographs formerly published on the same
    compounds have been incorporated, in a revised form, into the
    monographs contained in this document. References to previous
    monographs are found in the introductory explanation at the beginning
    of each monograph and a comprehensive list of earlier publications is
    provided in Annex 1 of this document.

         As a number of food additives are closely related chemically and
    toxicologically, the Committee at its seventeenth meeting adopted the
    same position that has been adopted in its seventh and later reports,
    that of a system of grouping additives for purposes of evaluation.
    When a given food additive is related to two or more groups, its level
    in the diet must not exceed the maximum acceptable level for either
    group. In order to facilitate the location of each substance under
    each grouping, an extensive index has been included at the end of this
    document. The index contains the names of the compounds included under
    the general title in each monograph plus a number of synonyms. An
    asterisk (*) indicates the title of the monograph containing the
    biochemical and toxicological data for each compound included in this
    document.

              

    1    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; Wld Hlth Org. techn.
    Rep. Ser., 1974, No. 539.

         Any new information and comments on the biological data and their
    evaluation should be addressed to:

         Division of Environmental Health
         Food Additives Unit
         World Health Organization
         Avenue Appia
         1211 Geneva 27
         Switzerland

    ALLOCATION OF ACCEPTABLE DAILY INTAKES (ADI)

         The acceptable daily intake (ADI) for man, expressed on a body
    weight basis, is the amount of a food additive that can be taken daily
    in the diet, even over a lifetime, without risk.

         An ADI is allocated only to substances for which the available
    data include either the results of adequate short-term and long-term
    toxicological investigations or satisfactory information on the
    biochemistry and metabolic fate of the compound, or both.

         An ADI may be allocated temporarily, pending the provision of
    additional data within a stated period of time. This measure implies
    that the toxicological data are adequate to ensure the safety in use
    of the additive during the time for which the temporary ADI applies.
    If the additional data requested do not become available within the
    stated period, the temporary ADI may be withdrawn at a future meeting
    of the Committee.

         An ADI without an explicit indication of the upper limit of
    intake ("not limited") may be assigned to substances of very low
    toxicity, especially those that are food constituents or that may be
    considered as foods or normal metabolites in man. An additive having a
    "not limited" ADI must meet the criteria of good manufacturing
    practice - for example, it should have proven technological efficacy
    and be used at the minimum level of efficacy, it should not conceal
    inferior food quality or adulteration, and it should not create a
    nutritional imbalance.

         There may be circumstances in which the ADI is not applicable.
    Thus it may be exceeded for special dietary purposes - for example, in
    the case of modified celluloses, to reduce the energy content of the
    diet. On the other hand, the ADI for glutamic acid and glutamates does
    not extend to foods for infants under three months old.

         In previous reports a conditional ADI was allocated to a number
    of substances, often in addition to an unconditional ADI. Variations
    in the rules for applying conditional ADIs have given rise to some
    confusion. For this reason, the Committee considers that the
    allocation of conditional ADIs should be abandoned.

         ADIs are intended as guides only and may be exceeded, after
    consultation with experts, in circumstances in which there may be
    important advantages in doing so. In the opinion of the Committee, an
    ADI provides a sufficiently large safety margin to ensure that there
    need be no undue concern about occasionally exceeding it provided the
    average intake over longer periods of time does not exceed it.

         "No ADI allocated" is applicable in the absence of sufficient
    information to establish safety, or of adequate specifications.

         "Not to be used" is applicable where there is sufficient
    information on which to base such a decision.

    TOXICOLOGICAL EVALUATION: ANTICAKING AGENTS
                                                                        

                                                      Acceptable daily
    Substances                                        intake for man
                                                      (mg/kg bw)
                                                                        

    Calcium, potassium, sodium ferrocyanide           0-0.0251

    Salt of myristic, palmitic, and
      stearic acids (aluminum, ammonium,
      calcium, magnesium, potassium,
      sodium)                                         Not limited

    Silicon dioxide and certain silicates
      (aluminum, calcium, sodium alumino
      silicate)                                       Not limited

    Magnesium silicate (talc and magnesium
      trisilicate)                                    Not limited1
                                                                        

    1    Temporary acceptance.

    TOXICOLOGICAL EVALUATION: ANTIMICROBIALS
                                                                        

                                                      Acceptable daily
    Substances                                        intake for man
                                                      (mg/kg bw)
                                                                        

    Acetic acid and its potassium and                 Not limited
      sodium salts
    Benzoic acid and its potassium and                0-5
      sodium salts1
    Diethyl pyrocarbonate2                            Not to be used
    Formic acid                                       0-3
    Cupric sulfate                                    No ADI3
    Hexamethylenetetramine                            0-0.15
    Hydrogen peroxide                                 No ADI4
    p-Hydroxybenzoate, butyl                          No ADI
                                                       allocated5
    p-Hydroxybenzoate, ethyl6                         0-10
    p-Hyroxybenzoate, methyl6                         0-10
    p-Hydroxybenzoate, propyl6                        0-10
    Nitrate, potassium and sodium salts7              0-5
    Nitrite, potassium and sodium salts8              0-0.29
    Propionic acid and its calcium, potassium,
      and sodium salts                                Not limited
    Sodium diacetate                                  0-15
    Sorbic acid and its calcium, potassium
      and sodium salts10                              0-25
    Sulfur dioxide and sulfites (sodium and
      potassium metabisulfites, sodium sulfite,
      sodium hydrogen sulfite)11                      0-0.7
                                                                        

    1    As sum of benzoic acid and sodium and potassium benzoate
    (expressed as benzoic acid).

    2    The treatment level allocated in previous reports is withdrawn.

    3    Maximum acceptable daily load = 0.5 mg/kg bw expressed as Cu.

    4    This substance is to be used only as an emergency measure when
    better methods of milk preservation are not available.

    5    Evaluation not possible with data provided.

    6    As sum of ethyl, methyl, and propyl esters of p-hydroxybenzoic
    acid.

    7    As sodium nitrate.

    8    As sodium nitrite.

    9    Temporary acceptance.

    10   As sum of sorbic acid and calcium, potassium, and sodium
    sorbates (expressed as sorbic acid).

    11   As SO2.

    TOXICOLOGICAL EVALUATION: ANTIOXIDANTS AND SYNERGISTS
                                                                        

                                                      Acceptable daily
    Substances                                        intake for man
                                                      (mg/kg bw)
                                                                        

    Ascorbic acid and its potassium and
      sodium salts                                    0-151
    Ascorbyl palmitate and stearate2                  0-1.25
    Butylated hydroxyanisole                          0-0.53
    Butylated hydroxytoluene                          0-0.53
    Citric acid and its calcium, potassium, and
      sodium salts                                    Not limited
    Ethylenediaminetetraacetate, disodium and
      calcium disodium salts4                         0-2.5
    Gallates, dodecyl, octyl, propyl5                 0-0.2
    Guaiac resin                                      0-2.5
    Isoascorbic acid and its sodium salt              0-5
    Isopropyl citrate mixture and monoisopropyl
      citrate6                                        0-14
    Nordihydroguaiaretic acid                         No ADI
                                                        allocated7
    Stearyl citrate                                   0-50
    Thiodipropionic acid and dilauryl ester8          0-3
    alpha-Tocopherol and mixed tocopherols
      concentrate9                                    0-2
                                                                        

    1    This figure is in addition to the ascorbic and acid present
    naturally in foods.

    2    As ascorbyl stearate or ascorbyl palmitate, or the sum of both.

    3    As BHA, BHT, or the sum of both. Temporary acceptance.

    4    As CaNa2EDTA (no excess of Na2EDTA should remain in foods).

    5    As sum of dodecyl, octyl, and propyl gallate. Temporary
    acceptance. (n-Octyl gallate should not be used in beverages.)

    6    As monoisopropyl citrate.

    7    Evaluation not possible with data provided.

    8    As thiodipropionic acid.

    9    As alpha-tocopherol.

    TOXICOLOGICAL EVALUATION: EMULSIFIERS
                                                                        

                                                      Acceptable daily
    Substances                                        intake for man
                                                      (mg/kg bw)
                                                                        

    Acetic and fatty acid esters of glycerol          Not limited
    Ammonium salts of phosphatidic acid               0-151
    Cholic and desoxycholic acid and their salts      0-1.25
    Citric and fatty acid esters of glycerol          Not limited
    Diacetyl tartaric and fatty acid esters of
      glycerol                                        0-50
    Esters of glycerol and thermally oxidized         Decision
      soybean fatty acid                               postponed2
    Hydroxylated lecithin                             No ADI
                                                       allocated3
    Lactic and fatty acid esters of glycerol          Not limited
    Lecithin                                          Not limited
    Mixed tartaric, acetic and fatty acid
      esters of glycerol4                             Not limited
    Mono- and diglycerides                            Not limited
    Polyglycerol esters of fatty acids                0-255
    Polyglycerol esters of interesterified
      ricinoleic acid                                 0-7.5
    Polyoxyethylene (20) sorbitan esters of lauric,
      stearic, palmitic and oleic acids and
      triesters of stearic acid6                      0-25
    Polyoxyethylene (8) and polyoxyethylene (40)
      stearate7                                       0-25
    Propylene glycol alginate8                        0-25
    Propylene glycol esters of fatty acids9           0-25
    Sorbitan esters of palmitic and stearic acids
      and triesters of stearic acid10                 0-25
    Sucrose esters of fatty acids and sucroglycerides 0-2.52

                                                                        

    1    Temporary acceptance.

    2    Previously allocated temporary ADI is withdrawn.

    3    Evaluation not possible with data provided.

    4    Provided that the total food additive intake of tartaric acid
    does not exceed 30 mg/kg.

    5    As polyglycerol esters of palmitic acid.

    6    As total polyoxyethylene (20) sorbitan esters.

    7    As total of polyoxyethylene (8) and (40) stearates.

    8    The contribution from propylene glycol alginate to total
    dietary propylene glycol intake from all sources should be included in
    the ADI for propylene glycol.

    9    As propylene glycol.

    10   As total sorbitan esters.

    TOXICOLOGICAL EVALUATION: THICKENING AGENTS
                                                                        
                                                      Acceptable daily
    Substances                                        intake for man
                                                      (mg/kg bw)
                                                                        
    A.   Celluloses

         Hydroxypropyl cellulose1                     0-25
         Hydroxypropyl methyl cellulose1              0-25
         Methyl cellulose1                            0-25
         Methylethyl cellulose1                       0-25
         Microcrystalline cellulose                   Not limited
         Sodium carboxymethyl cellulose1              0-25

    B.   Vegetable gums

         Arabic gum                                   Not limited
         Carob bean gum                               No ADI
                                                        allocated2
         Guar gum                                     Not limited
         Karaya gum                                   No ADI
                                                        allocated2
         Tragacanth gum                               No ADI
                                                        allocated2

    C.   Modified starches and dextrins

         Acetylated distarch adipate                  Not limited
         Acetylated distarch glycerol                 Not limited
         Acetylated distarch phosphate                Not limited
         Acid-treated starches                        Not limited
         Alkali-treated starches                      Not limited
         Amylose and amylopectin                      Not limited
         Bleached starches                            Not limited
         Distarch gylcerol                            Not limited
         Distarch phosphate                           Not limited
         Enzyme-treated starches                      Not limited
         Hydroxypropyl distarch glycerol              Not limited
         Hydroxypropyl distarch phosphate             No ADI
                                                       allocated2
         Hydroxypropyl starch                         Not limited
         Monostarch phosphate                         Not limited
                                                                        

    1    As the sum of total modified celluloses. The ADI may be
    exceeded for dietetic purposes, i.e., when use is primarily intended
    to take advantage of the noncaloric properties of these additives.

    2    Evaluation not possible with data provided.

    TOXICOLOGICAL EVALUATION: THICKENING AGENTS
    (continued)
                                                                        

                                                      Acceptable daily
    Substances                                        intake for man
                                                      (mg/kg bw)
                                                                        

         Oxidized starches                            Not limited1
         Phosphated distarch phosphate                Not limited
         Starch acetate                               Not limited
         Starch sodium succinate                      No ADI
                                                        allocated2
         White and yellow dextrins                    Not limited

    D.   Others

         Agar                                         Not limited
         Alginic acid and its ammonium, calcium,
           potassium, and sodium salts3               0-50
         Carrageenan and furcellaran                  0-75
         Pectin (non-amidated)                        Not limited
         Pectin (amidated)                            0-251
                                                                        

    1    Temporary acceptance.

    2    Evaluation not possible with data provided.

    3    As alginic acid.

    TOXICOLOGICAL EVALUATION: MISCELLANEOUS FOOD ADDITIVES
                                                                        

                                                      Acceptable daily
    Substances                                        intake for man
                                                      (mg/kg bw)
                                                                        

    Calcium acetate, choride gluconate and sulfate    Not limited
    Food-grade mineral oil                            Not limited
    L-glutamic acid, its ammonium, calcium, mono-
      sodium, and potassium salts1                    0-120
    Lactic acid and its ammonium, calcium,
      potassium, and sodium salts                     Not limited2
    Oxystearin                                        0-25
    Phosphoric acid and its salts                     0-703
    Polyvinyl pyrrolidone                             No ADI
                                                        allocated4
    1,2-propylene glycol                              0-25
    Sorbitol                                          Not limited
    Stearoyl lactylic acid, calcium and sodium salts  0-20
    Tartaric acid (and its potassium, sodium, and
      potassium-sodium salts)5                        0-30
                                                                        

    1    As glutamic acid, additional to glutamic acid intake from all
    non-additive dietary sources. ADI not applicable to infants under 12
    weeks of age.

    2    Neither D(-)-lactic acid nor (DL)-lactic acid should be used
    in infant foods.

    3    Total dietary phosphorus load for man. Attention should be paid
    to the reverse relationship with calcium intake.

    4    Evaluation not possible with data provided. Previously
    allocated conditional ADI is withdrawn.

    5    As L(+)-tartaric acid.





















    See Also:
       Toxicological Abbreviations