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    FAO Nutrition Meetings
    Report Series No. 40A,B,C
    WHO/Food Add./67.29




    TOXICOLOGICAL EVALUATION OF SOME
    ANTIMICROBIALS, ANTIOXIDANTS, EMULSIFIERS,
    STABILIZERS, FLOUR-TREATMENT AGENTS, ACIDS AND BASES





    The content of this document is the result of the deliberations of the
    Joint FAO/WHO Expert Committee on Food Additives which met at Rome,
    13-20 December, 19651 Geneva, 11-18 October, 19662




                   

    1 Ninth Report of the Joint FAO/WHO Expert Committee on Food
    Additives, FAO Nutrition Meetings Report Series, 1966 No. 40; 
    Wld Hlth Org. techn. Rep. Ser., 1966, 339

    2 Tenth Report of the Joint FAO/WHO Expert Committee on Food
    Additives, FAO Nutrition Meetings Report Series, 1967, in press; 


    Food and Agriculture Organization of the United Nations
    World Health Organization
    1967

    CONTENTS

    INTRODUCTION

    NOTES ON THE BIOLOGICAL DATA

    NOTES TO THE READER

    ACCEPTABLE DAILY INTAKES FOR MAN OF SOME ANTI MICROBIALS, ANTIOXIDANTS
    AND ANTIOXIDANT SYNERGISTS

    ACCEPTABLE DAILY INTAKES FOR MAN OF SOME EMULSIFIERS AND STABILIZERS

    ACCEPTABLE TREATMENT LEVELS FOR SOME FLOUR-TREATMENT AGENTS

    ACCEPTABLE DAILY INTAKES FOR MAN OF SOME ACIDS AND BASES

    ACCEPTABLE DAILY INTAKES FOR SOME OTHER FOOD ADDITIVES

    THE MONOGRAPHS

    ANTIMICROBIALS, ANTIOXIDANTS AND ANTIOXIDANT SYNERGISTS

    Benzoic acid
    Benzoate, Potassium
    Benzoate, Sodium
    Benzoate, Butyl p-Hydroxy
    Benzoate, Ethyl p-Hydroxy
    Benzoate, Methyl p-Hydroxy
    Benzoate, Propyl p-Hydroxy
    Butylated Hydroxytoluene
    Diethyl Pyrocarbonate
    EDTA, Calcium disodium
    EDTA, Disodium
    Hydrogen Peroxide
    Isopropyl Citrate Mixture
    Monoisopropyl Citrate see Isopropyl Citrate Mixture
      Propionic acid
    Propionate, Calcium
    Propionate, Sodium
    Sorbic acid
    Sorbate, Calcium
    Sorbate, Potassium
    Sulfur Dioxide
    Potassium Metabisulfite
    Sodium Hydrogen Sulfite
    Sodium Metabisulfite
    Sodium Sulfite

    EMULSIFIERS AND STABILIZERS

    Acetic acid and fatty acid esters of glycerol
    Cellulose, Hydroxypropyl Methyl
    Cellulose, Methyl Ethyl
    Cellulose, Sodium Carboxymethyl
    Cholic acid (and Na salt)
    Cholic acid, Desoxy- (and Na salt)
    Citric acid and fatty acid esters of glycerol
    Diacetyltartaric acid and fatty acid esters of glycerol
      Diglyceride, acetylated, citrated, lactated or tartrated see Acetic
      acid, Citric acid, etc.
    Lactic acid and fatty acid esters of glycerol
    Mixed tartaric acid and acetic acid and fatty acid esters of glycerol
    Polyglycerol esters of fatty acids
    Propylene glycol esters of fatty acids

    FLOUR TREATMENT AGENTS

    Azodicarbonamide
    Chlorine
    Iodate, Calcium
    Iodate, Potassium
    Nitrogen Oxides
    Peroxides, Acetone
    Peroxide, Calsium
    Persulfate, Ammonium
    Persulfate, Potassium
    Stearyl Tartrate

    ACIDS

    Acetic acid
    Adipic acid
    Monocalcium phosphates
    Citric acid
    Fumaric acid
    Gluconic acid see Glucono-delta-lactone
    Glucono-delta-lactone (Glucosic acid)
    Hydrochloric acid
    DL-Lactic acid
    DL-Malic acid

    BASES

    Carbonate, Ammonium
    Carbonate, Calcium
    Carbonate, Magnesium
    Carbonate, Potassium

    Carbonate, Sodium
    Carbonate, Ammonium Hydrogen
    Carbonate, Potassium Hydrogen
    Carbonate, Sodium Hydrogen
    Hydroxide, Ammonium
    Hydroxide, Calcium
    Hydroxide, Magnesium
    Hydroxide, Potassium
    Hydroxide, Sodium
    Oxide, Calcium
    Oxide, Magnesium

    OTHERS

    Mannitol
    Polyvinylpyrrolidone
    Sorbitol
    

    INTRODUCTION

         The monographs contained in this report are the result of the
    deliberations of the ninth1 and tenth2 sessions of the Joint FAO/WHO
    Expert Committee on Food Additives. Therefore the monographs should be
    consulted together with these reports.

         The opinions recorded are based upon scientific evidence made
    available to the members at the time of the meeting. Every effort was
    made to obtain all the information on each substance but it is almost
    inevitable that some work has been missed. The committee offered its
    apologies to these whose work may not have been taken into
    consideration.

         Specifications on these food additives will be forwarded as
    working papers to the participants at the Fourth Session of the Codex
    Committee on Food Additives September 1967, and to interested
    organizations, and will also be available on request from the Joint
    FAO/WHO Food Standards Branch (Codex Alimentarius), FAO, Rome.


                   

    1 FAO Nutrition Meetings Report Series, 1966, No. 40; Wld Hlth
    Org. techn. Rep. Ser., 1966, 339

    2 FAO Nutrition Meetings Report Series, in press; Wld Hlth Org.
    techn. Rep. Ser., in press

    NOTES ON THE BIOLOGICAL DATA

         The Committee agreed that the monographs dealing with the
    evaluation of the biological data should be drafted along the lines
    adopted in the previous reports. The Committee at its tenth session
    also agreed to support in principle the recommendations made by the
    Scientific Group on Procedures for Investigating Intentional and
    Unintentional Food Additives.1

    Acceptable Daily Intake

         The Committee decided to retain the method of expressing the
    acceptable daily intake that had been adopted in earlier reports and,
    in appropriate cases, to continue to divide the over-all zone of
    acceptability into two parts. For detailed discussion see the Seventh
    Report.2 The first part of the over-all acceptable daily intake zone
    has been termed the unconditional zone of acceptability, and this
    represents levels of use that are effective technologically, at least
    for some purposes, and can be safely employed without further expert
    advice. The second part consists of a conditional zone of
    acceptability and represents levels of use that can be employed safely
    but at which it is thought desirable that some degree of expert
    supervision and advice should be readily available.

    Acceptable Treatment Level

         In regard to the flour-treatment agents, the main toxicological
    and nutritional considerations are concerned with treated flour rather
    than with the food additive itself. The Committee followed the
    procedure adopted in the Seventh Report2 for benzoyl peroxide,
    chlorine dioxide and potassium bromate and recommended levels of flour
    treatment for this group of additives instead of setting an acceptable
    level of daily intake.

    Grouping of related food additives

         As a number of food additives are closely related chemically and
    toxicologically, the Committee adopted a system of grouping of food
    additives. The acceptable daily intake is expected to cover all the
    specified members of the group that may be included in the diet. In
    some cases, a given food additive may be related to two groups, in
    which case the level in the diet must not exceed the maximum
    acceptable level for either group. The problem is not as complicated
    as it may appear at first sight, since many of the substances in a
    group of additives are likely to be used as alternatives to each
    other.

                   

    1 Wld Hlth Org. techn. Rep. Ser., 1967, 348
    2 FAO Nutrition Meetings, Report Series, 1964, 35; Wld Hlth 
    Org. tech. Rep. Ser., 1964, 281

    Request for further work

         Previous monographs have often listed further work that seemed to
    be desirable. However, it is only in relatively few cases that the
    studies requested have been done, although in some cases the work may
    be urgently needed in the interests of the consumer. The Committee at
    its ninth session, therefore agreed to request, in the monographs,
    only work that is urgently needed in the interests of safety. All
    other suggestions for further work that may seem desirable, but not so
    urgently needed, are included under the heading "Comments".

         The Committee draws the attention of manufacturers and users of
    food additives to the fact in future, if a statement about farther
    work being required is included in a monograph, this matter should
    be given urgent attention. If the additive in question is one that is
    already in use, its continued use will be supported by the Committee
    only if the further work required has been carried out and the results
    justify continuance of the use of the additive. If no action is taken
    to provide the further evidence that is required, it will be assumed
    that neither the manufacturers nor the users are interested in
    continuing the use of the additive. In this case, the Committee may
    well decide to recommend the prohibition of its use. If the food
    additive is a new substance not yet in use and if further work has
    been required, a conditional intake level may be established for a
    limited period to allow the results of this additional work to be
    submitted and studied.

    References

         Authors who have submitted papers relevant to a given monograph
    but who are not mentioned in it may rest assured that their work has
    been consulted. In the interest of brevity, however, the
    bibliographies of some monographs may be restricted to more recent or
    more extensive investigations in the field in question. The pioneering
    achievements of the earlier workers in these fields are fully
    appreciated.

    NOTES TO THE READER

         Further general remarks on the biological data and toxicological
    evaluation in these monographs as well as reference to the other food
    additives considered by the Joint Expert Committee may be found in a
    publication entitled "Explanatory Notes on the Activities of the Joint
    FAO/WHO Expert Committee on Food Additives".1

         Any new information and comments relating: to biological data and
    their evaluation should be addressed to: Food Additives Unit, World
    Health Organization, Avenue Appia, Geneva, Switzerland.


                   

    1 Off-print from Tenth Report of the Joint FAO/WHO Expert Committee
    on Food Additives

    ACCEPTABLE DAILY INTAKES FOR MAN OF SOME ANTIMICROBIALS, ANTIOXIDANTS 
    AND ANTIOXIDANT SYNERGISTS

                                                                         

                                        Over-all daily intake zone1
                                        (mg/kg body-weight)
    Compounds considered                                                 
                                        Unconditional       Conditional
                                                                         

    Benzoic Acid
    Benzoate, Potassium
    Benzoate, Sodium                    0-52                5-102

    Benzoate, Butyl p-Hydroxy                   Decision postponed

    Benzoate, Ethyl p-Hydroxy
    Benzoate, Methyl p-Hydroxy          0-23                2-73
    Benzoate, Propyl p-Hydroxy

    Butylated Hydroxyanisole            0-0.54              0.5-24
    Butylated Hydroxytoluene

    EDTA, Disodium                      0-1.255             1.25-2.55
    EDTA, Calcium disodium

    Hexamethylenetetramine                      Decision postponed

    Hydrogen Peroxide                            Restricted uses

    Isopropyl Citrate Mixture           0-7                 7-20

                                                                         


    1    The first part of the over-all acceptable intake zone is termed
         unconditional and this represents levels which can be safely used
         without further expert supervision and advice. The second part is
         termed conditional and represents levels of use that can be
         safely employed but at which it is thought desirable that some
         degree of expert supervision and advice should be readily
         available.
    2    As sum of benzoic acid and sodium and potassium benzoate
         (calculated as benzoic acid).
    3    As sum of methyl, ethyl, and propyl esters of p-hydroxybenzoic
         acid.
    4    As sum of butylated hydroxytoluene and butylated hydroxyanisole.
    5    As calcium disodium EDTA. The use of disodium EDTA is recommended
         only for accurately chelating calcium.

    ACCEPTABLE DAILY INTAKES FOR MAN OF SOME ANTIMICROBIALS, ANTIOXIDANTS
    AND ANTIOXIDANT SYNERGISTS (continued)

                                                                       

                                        Over-all daily intake zone
                                        (mg/kg body-weight)
    Compounds considered                                               
                                        Unconditional       conditional
                                                                       

    Propionic Acid
    Propionate, Calcium
    Propionate, Sodium                  0-101               10-201

    Sorbic Acid
    Sorbate, Calcium                    0-12.52             12.5-252
    Sorbate, Potassium

    Sulfur dioxide
    Potassium metabisulfite
    Sodium sulfite                      0-0.353             0.35-1.53
    Sodium metabisulfite
    Sodium hydrogen sulfite

    Antimicrobial for certain                Acceptable level of 
    beverages                                   treatment (ppm)

    Diethyl Pyrocarbonate               0-300

                                                                       

    1    As sum of propionic acid and calcium and sodium propionate
         (calculated as propionic acid).
    2    As sum of sorbic acid and calcium and potassium sorbate
         (calculated as sorbic acid).
    3    As sum of sulfur dioxide, sodium sulfite, sodium and potassium
         metabisulfite and sodium hydrogen sulfite (calculated as SO2).

    ACCEPTABLE DAILY INTAKES FOR MAN OF SOME EMULSIFIERS AND STABILIZERS

                                                                       

                                         Over-all daily intake zone1
                                         (mg/kg body-weight)
    Compounds considered                                               
                                         Unconditional    Conditional
                                                                       
    Cellulose, Sodium Carbozymethyl-                      Higher levels
    Cellulose, Hydroxypropyl Methyl-     0-302            for dietetic
    Cellulose, methyl-                                    or calorie
    Cellulose, Methylethyl-                               control 
                                                          purposes

    Acetic acid and fatly acid
    esters of glycerol
    Citric acid and fatty acid
    esters of glycerol
    Lactic acid and fatty acid           0-1003
    esters of glycerol4
    Mixed tartaric and acetic
    and fatty acid esters of
    glycerol5

    Diacetyltartaric acid and fatty
    acids esters of glycerol5            0-25             25-50

    Polyglycerol esters of fatty         0-12.5           12.5-25
    acids

    Propylene glycol esters of fatty     0-206            20-606
    acid.

    Cholic and Desoxycholic acids        0-1.25
    and their salts
                                                                       

    1    The first part of the over-all acceptable daily intake zone is
         termed unconditional and this represents levels which can be
         safely used without further expert supervision and advice.  The
         second part is termed conditional and represents levels of use
         that can be safely employed but at which it is thought desirable
         that some degree of expert supervision and advice should be
         readily available.
    2    As sum of these cellulose derivatives
    3    As sum of these fatty emulsifiers.
    4    The conditional zone of acceptability for the total intake of
         D(-)-lactic acid is 0-100 mg/kg.
    5    The zone of acceptability for the total food additives intake of
         tartaric acid is 0-6 mg/kg (unconditional) and 6-20 mg/kg
         (conditional).
    6    As propylene glycol.

    ACCEPTABLE TREATMENT LEVELS FOR SOME FLOUR-TREATMENT AGENTS

                                                                      

    Name                          Acceptable levels of treatment(ppm)
                                                                      

    Azodicarbonamide              0-45

    Chlorine                      No level set

    Iodate, Calcium               Use not recommended

    Iodate, Potassium             Use not recommended

    Nitrogen Oxides               No level set

    Peroxides, Acetone            No level set

    Peroxide, Calcium             No level set

    Persulfate, Ammonium          No level set

    Persulfate, Potassium         No level set

    Stearyl Tartrate              0-5001
                                                                      

    1    See monograph on Stearyl tartrate

    ACCEPTABLE DAILY INTAKES FOR MAN OF SOME ACIDS AND BASES

                                                                        

                                        Over-all daily intake zone1
                                        (mg/kg body-weight)
    Compounds considered                                                
                                        Unconditional     Conditional
                                                                        

    Acids
    Acetic acid                                           Not limited
    Adipic Acid                                           0-5
    Citric Acid                                           Not limited
    Fumaric Acid                        0-6               6-10
    Glucono-delta-lactone               0-15              15-50
    (gluconic acid)
    Hydrochloric Acid                                     Not limited
    DL-Lactic Acid                                        0-1002
    DL-Malic Acid                                         0-1003
    Monocalcium Phosphates                                Not limited4

    Bases
    Carbonate, Ammonium  )
    Carbonate, Calcium   )
    Carbonate, Magnesium )                                Not limited5
    Carbonate Potassium  )
    Carbonate, Sodium    )
    Carbonate, Ammonium Hydrogen  )
    Carbonate, Potassium Hydrogen )                       Not limited5
    Carbonate Sodium Hydrogen     )
    Hydroxide, Ammonium  )
    Hydroxide Calcium    )
    Hydroxide, Magnesium )                                Not limited5
    Hydroxide Potassium  )
    Hydroxide, Sodium    )
    Oxide Calcium        )                                Not limited5
    Oxide, Magnesium     )
                                                                        

    1    The first part of the over-all acceptable daily intake zone is
         termed unconditional and this represents levels which can be
         safely used without further expert supervision and advice. The
         second part is termed conditional and represents levels of use
         that can be safely employed but at which it is thought desirable
         that some degree of expert supervision and advice should be
         readily available.
    2    Refers to content of D(-)-lactic acid.
    3    Refers to content of D(-)-malic acid.
    4    Subject to limits of phosphorus load given in the Seventh Report
         (Wld Hlth Org. techn. Rep, Ser., 1964, 281, 31).
    5    Provided that use is in accordance with good manufacturing
         practice.

    ACCEPTABLE DAILY INTAKES FOR MAN OF SOME OTHER FOOD ADDITIVES

                                                                     

                                  Over-all daily intake zone1
                                  (mg/kg body-weight)
    Compounds considered                                             
                                  Unconditional       Conditional
                                                                     

    D-Mannitol                    0-50                50-150

    Sorbitol                                Not limited

    Polyvinylpyrrolidone                              0-1
                                                                     


    1    The first part of the over-all acceptable daily intake zone is
         termed unconditional and this represents levels which can be
         safely used without further expert supervision and advice. The
         second part is termed conditional and represents levels of use
         that can be safely employed but at which it is thought desirable
         that some degree of expert supervision and advice should be
         readily available.





















    See Also:
       Toxicological Abbreviations