IPCS INCHEM Home



    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    WORLD HEALTH ORGANIZATION





    SAFETY EVALUATION OF CERTAIN FOOD
    ADDITIVES AND CONTAMINANTS



    WHO FOOD ADDITIVES SERIES: 44





    Prepared by the Fifty-third meeting of the Joint FAO/WHO
    Expert Committee on Food Additives (JECFA)





    World Health Organization, Geneva, 2000
    IPCS - International Programme on Chemical Safety

    ANNEX 4

    ACCEPTABLE DAILY INTAKES, OTHER TOXICOLOGICAL INFORMATION, AND
    INFORMATION ON SPECIFICATIONS

    1. Food additives
                                                                                   

    Substance                    Specificationsa    ADI and other toxicological 
                                                    recommendations
                                                                               

    Glazing agent

    Hydrogenated poly 1-decene   R                  No ADI allocatedb 

    Sweetening agent

    Erythritol                   N                  ADI 'not specified'c 

    Thickener

    Curdlan                      N                  ADI 'not specified' 
                                                    (temporary)c,d

    Miscellaneous substances

    gamma-Cyclodextrin           R                  ADI 'not specified'c

    Sodium iron EDTA             R                  Considered to be safe in 
                                                    food fortification
                                                    programmese

    Sodium sulfate               N,T                ADI not specifiedc,f
                                                                               

    a New specifications prepared; R, existing specifications revised; T, the
      existing, new or revised specifications are tentative and information
      is needed.

    b Data were insufficient for establishing an ADI.

    c ADI 'not specified' is applied to a food substance of very little 
      toxicity which, on the basis of the available chemical, biological,
      toxicological, and other data and the total dietary intake of
      the substance arising from its use at the levels necessary to
      achieve the desired effect and from its acceptable background level 
      in food, does not, in the opinion of the Committee, represent a
      hazard to health. For this reason and for reasons stated in the 
      individual evaluations, the establishment of an ADI in numerical
      form is deemed unnecessary.

    d Applies to food additive uses

    e The Committee concluded that sodium iron EDTA (ethylene diamine 
      tetraacetate) could be considered to be safe when used in 
      supervised food fortification programmes in response to a need 
      for iron supplementation of the diet of a population as determined
      by public health officials. Such programmes would provide a daily
      iron intake of approximately 0.2 mg/kg bw.

    f Temporary ADI pending consideration of the 'tentative' qualification
      of the specifications 
    

        2. Substances evaluated by the procedure for the safety
        evaluation of flavouring agents
                                                                                                    

    Flavouring agent                               No.     Specificationsa   Conclusions based
                                                                             on current intake
                                                                                                    

    Aliphatic and aromatic sulfides and thiols 

    Subgroup i: Simple sulfides (thioethers)

    Methyl sulfide                                 452     N                 No safety concern

    Methyl ethyl sulfide                           453     N                 No safety concern

    Diethyl sulfide                                454     N                 No safety concern

    Butyl sulfide                                  455     N                 No safety concern

    (1-Butenyl-1)methyl sulfide                    457     N,T               No safety concern

    Bis(methylthio)methane                         533     N,T               No safety concern

    Allyl sulfide                                  458     N,T               No safety concern

    Methyl phenyl sulfide                          459     N                 No safety concern

    Benzyl methyl sulfide                          460     N                 No safety concern

    Subgroup ii: Acyclic sulfides with oxidized side-chains

    3-(Methylthio)propanol                         461     N,T               No safety concern

    4-(Methylthio)butanol                          462     N,T               No safety concern

    3-(Methylthio)-1-hexanol                       463     N                 No safety concern

    2-Methylthioacetaldehyde                       465     N,T               No safety concern

    3-(Methylthio)propionaldehyde                  466     N,T               No safety concern

    3-(Methylthio)butanal                          467     N,T               No safety concern

    2. (continued)
                                                                                                    

    Flavouring agent                               No.     Specificationsa   Conclusions based
                                                                             on current intake
                                                                                                    

    4-(Methylthio)butanal                          468     N,T               No safety concern

    3-Methylthiohexanal                            469     N                 No safety concern

    2-(Methylthio)methyl-2-butenal                 470     N,T               No safety concern

    2,8-Dithianon-4-ene-4-carboxaldehyde           471     N,T               No safety concern

    Methyl 3-methylthiopropionate                  472     N                 No safety concern

    Methylthiomethyl butyrate                      473     N,T               No safety concern

    Methyl 4-(methylthio)butyrate                  474     N                 No safety concern

    Ethyl 2-(methylthio)acetate                    475     N,T               No safety concern

    Ethyl 3-methylthiopropionate                   476     N                 No safety concern

    Ethyl 4-(methylthio)butyrate                   477     N                 No safety concern

    3-(Methylthio)propyl acetate                   478     N,T               No safety concern

    Methylthiomethyl hexanoate                     479     N,T               No safety concern

    Ethyl 3-(methylthio)butyrate                   480     N,T               No safety concern

    3-(Methylthio)hexyl acetate                    481     N,T               No safety concern

    1-Methylthio-2-propanone                       495     N,T               No safety concern

    1-(Methylthio)-2-butanone                      496     N                 No safety concern

    4-(Methylthio)-2-butanone                      497     N,T               No safety concern

    2. (continued)
                                                                                                    

    Flavouring agent                               No.     Specificationsa   Conclusions based
                                                                             on current intake
                                                                                                    
    4-(Methylthio)-4-methyl-2-pentanone            500     N,T               No safety concern

    Di(butan-3-one-1-yl) sulfide                   502     N,T               No safety concern

    ortho-(Methylthio)phenol                       503     N,T               No safety concern

    4-(Methylthio)-2-oxobutanoic acid              501     N                 No safety concern

    2-(Methylthiomethyl)-3-phenyl propenal         505     N                 No safety concern

    Subgroup iii: Cyclic sulfides

    2,5-Dimethyl-2,5-dihydroxy-1,4-dithiane        562     N,T               No safety concern

    2,5-Dihydroxy-1,4-dithiane                     550     N                 No safety concern

    2-Methyl-4-propyl-1,3-oxathiane                464     N,T               No safety concern

    4,5-Dihydro-3(2H)thiophenone                   498     N,T               No safety concern

    2-Methyltetrahydrothiophen-3-one               499     N,T               No safety concern

    1,4-Dithiane                                   456     N,T               No safety concern

    2-Methyl-1,3-dithiolane                        534     N                 No safety concern

    Trithioacetone                                 543     N,T               No safety concern

    Subgroup iv: Thiols

    Methyl mercaptan                               508     N,T               No safety concern

    Propanethiol                                   509     N,T               No safety concern

    2-Propanethiol                                 510     N,T               No safety concern

    2. (continued)
                                                                                                    

    Flavouring agent                               No.     Specificationsa   Conclusions based
                                                                             on current intake
                                                                                                    

    1-Butanethiol                                  511     N                 No safety concern

    2-Methyl-1-propanethiol                        512     N,T               No safety concern

    3-Methylbutanethiol                            513     N,T               No safety concern

    2-Pentanethiol                                 514     N,T               No safety concern

    2-Methyl-1-butanethiol                         515     N                 No safety concern

    3-Methyl-2-butanethiol                         517     N                 No safety concern

    1-Hexanethiol                                  518     N,T               No safety concern

    2-Ethylhexanethiol                             519     N,T               No safety concern

    Prenythiol                                     522     N                 No safety concern

    Thiogeraniol                                   524     N,T               No safety concern

    Cyclopentanethiol                              516     N,T               No safety concern

    2,3, and 10-Mercaptopinane                     520     N,T               No safety concern

    Allyl mercaptan                                521     N,T               No safety concern

    1-para-Menthene-8-thiol                        523     N,T               No safety concern

    Benzenethiol                                   525     N                 No safety concern

    Benzyl mercaptan                               526     N                 No safety concern

    Phenylethyl mercaptan                          527     N                 No safety concern

    2. (continued)
                                                                                                    

    Flavouring agent                               No.     Specificationsa   Conclusions based
                                                                             on current intake
                                                                                                    
    ortho-Toluenethiol                             528     N,T               No safety concern

    2,6-Dimethylthiophenol                         530     N                 No safety concern

    2-Naphthalenethiol                             531     N,T               No safety concern

    2-Ethylthiophenol                              529     N,T               No safety concern

    Subgroup v: Thiols with oxidized side-chains

    2-Mercaptopropionic acid                       551     N                 No safety concern

    Ethyl 2-mercaptopropionate                     552     N,T               No safety concern

    Ethyl 3-mercaptopropionate                     553     N                 No safety concern

    3-Mercaptohexyl acetate                        554     N                 No safety concern

    3-Mercaptohexyl butyrate                       555     N                 No safety concern

    3-Mercaptohexyl hexanoate                      556     N,T               No safety concern

    1-Mercapto-2-propanone                         557     N,T               No safety concern

    3-Mercapto-2-butanone                          558     N,T               No safety concern

    2-Keto-4-butanethiol                           559     N,T               No safety concern

    3-Mercapto-2-pentanone                         560     N,T               No safety concern

    3-Mercapto-3-methyl-1-butanol                  544     N,T               No safety concern

    3-Mercaptohexanol                              545     N                 No safety concern

    2. (continued)
                                                                                                    

    Flavouring agent                               No.     Specificationsa   Conclusions based
                                                                             on current intake
                                                                                                    
    2-Mercapto-3-butanol                           546     N,T               No safety concern

    alpha-Methyl-beta-hydroxypropyl                547     N                 No safety concern
    alpha-methyl-beta-mercaptopropyl sulfide 

    4-Methyoxy-2-methyl-2-butanethiol              548     N,T               No safety concern

    3-Methyl-3-mercaptobutyl formate               549     N                 No safety concern


    para-Mentha-8-thiol-3-one                      561     N,T               No safety concern

    Sodium 3-mercapto-oxopropionate                563     N                 No safety concern

    Subgroup vi: Dithiols

    1,2-Ethanedithiol                              532     N                 No safety concern

    1,3-Propanedithiol                             535     N                 No safety concern

    1,2-Propanedithiol                             536     N,T               No safety concern

    1,2-Butanedithiol                              537     N                 No safety concern

    1,3-Butanedithiol                              538     N                 No safety concern

    2,3-Butanedithiol                              539     N                 No safety concern

    1,6-Hexanedithiol                              540     N                 No safety concern

    1,8-Octanedithiol                              541     N                 No safety concern

    1,9-Nonanedithiol                              542     N                 No safety concern

    2. (continued)
                                                                                                    

    Flavouring agent                               No.     Specificationsa   Conclusions based
                                                                             on current intake
                                                                                                    
    Subgroup vii: Simple disulfides

    Dimethyl disulfide                             564     N                 No safety concern

    Methyl propyl disulfide                        565     N,T               No safety concern

    Propyl disulfide                               566     N                 No safety concern

    Diisopropyl disulfide                          567     N                 No safety concern

    Methyl 1-propenyl disulfide                    569     N,T               No safety concern

    Propenyl propyl disulfide                      570     N,T               No safety concern

    Methyl 3-methyl-1-butenyl disulfide            571     N,T               No safety concern

    Allyl methyl disulfide                         568     N,T               No safety concern

    Allyl disulfide                                572     N,T               No safety concern

    Dicyclohexyl disulfide                         575     N,T               No safety concern

    Methyl phenyl disulfide                        576     N                 No safety concern

    Methyl benzyl disulfide                        577     N                 No safety concern

    Benzyl disulfide                               579     N,T               No safety concern

    Phenyl disulfide                               578     N                 No safety concern

    Subgroup viii: Disulfides with oxidized side-chains

    2-Methyl-2-(methyldithio) propanal             580     N,T               No safety concern

    Ethyl 2-(methyldithio) propionate              581     N,T               No safety concern

    2. (continued)
                                                                                                    

    Flavouring agent                               No.     Specificationsa   Conclusions based
                                                                             on current intake
                                                                                                    
    Subgroup ix: Trisulfides

    Dimethyl trisulfide                            582     N,T               No safety concern

    Methyl ethyl trisulfide                        583     N,T               No safety concern

    Methyl propyl trisulfide                       584     N,T               No safety concern

    Dipropyl trisulfide                            585     N,T               No safety concern

    Allyl methyl trisulfide                        586     N,T               No safety concern

    Diallyl trisulfide                             587     N,T               No safety concern

    Diallyl polysulfide                            588     N,T               No safety concern

    Subgroup x: Heterocyclic disulfides

    3,5-Dimethyl-1,2,4-trithiolane                 573     N,T               No safety concern

    3-Methyl-1,2,4-trithiane                       574     N,T               No safety concern

    Subgroup xi: Thioesters

    S-Methyl thioacetate                           482     N,T               No safety concern

    Ethyl thioacetate                              483     N                 No safety concern

    Methyl thiobutyrate                            484     N,T               No safety concern

    Propyl thioacetate                             485     N                 No safety concern

    S-Methyl 2-methylbutanethioate                 486     N,T               No safety concern

    S-Methyl 3-methylbutanethioate                 487     N,T               No safety concern

    2. (continued)
                                                                                                    

    Flavouring agent                               No.     Specificationsa   Conclusions based
                                                                             on current intake
                                                                                                    
    S-Methyl 4-methylpentanethioate                488     N,T               No safety concern

    S-Methyl hexanethioate                         489     N,T               No safety concern

    Allyl thiopropionate                           490     N,T               No safety concern

    Prenyl thioacetate                             491     N                 No safety concern

    Methylthio 2-(acetyloxy)propionate             492     N                 No safety concern

    Methylthio 2-(propionyloxy)propionate          493     N                 No safety concern

    3-Acetyl-3-mercaptohexyl acetate               494     N                 No safety concern

    S-Methyl benzothioate                          504     N,T               No safety concern

    cis-and trans-Menthone-8-thioacetate           506a    N                 No safety concern
                                                   and 
                                                   506b

    Subgroup xii--Sulfoxides

    Methylsulfinylmethane                          507     N,T               No safety concern

    Aliphatic primary alcohols, aldehydes, carboxylic acids, acetals and esters containing additional
    oxygenated functional groups

    2-Oxobutyric acid                              589     N,T               No safety concern

    Methyl 2-hydroxy-4-methylpentanoate            590     N,T               No safety concern

    Methyl 2-oxo-3-methylpentanoate                591     N,T               No safety concern

    2. (continued)
                                                                                                    

    Flavouring agent                               No.     Specificationsa   Conclusions based
                                                                             on current intake
                                                                                                    
    Citronelloxyacetaldehyde                       592     N,T               No safety concern

    3-Oxobutanal dimethyl acetal                   593     N                 No safety concern

    Ethyl 3-hydroxybutyrate                        594     N,T               No safety concern

    Ethyl acetoacetate                             595     N                 No safety concern

    Butyl acetoacetate                             596     N,T               No safety concern

    Isobutyl acetoacetate                          597     N,T               No safety concern

    Isoamyl acetoacetate                           598     N,T               No safety concern

    Geranyl acetoacetate                           599     N,T               No safety concern

    Methyl 3-hydroxyhexanoate                      600     N,T               No safety concern

    Ethyl 3-hydroxyhexanoate                       601     N                 No safety concern

    Ethyl 3-oxohexanoate                           602     N                 No safety concern

    Ethyl 2,4-dioxohexanoate                       603     N,T               No safety concern

    3-(Hydroxymethyl)-2-heptanone                  604     N,T               No safety concern

    1,3-Nonanediol acetate (mixed esters)          605     N,T               No safety concern

    Levulinic acid                                 606     N                 No safety concern

    Ethyl levulinate                               607     N                 No safety concern

    Butyl levulinate                               608     N                 No safety concern

    2. (continued)
                                                                                                    

    Flavouring agent                               No.     Specificationsa   Conclusions based
                                                                             on current intake
                                                                                                    
    1,4-Nonanediol diacetate                       609     N,T               No safety concern

    Hydroxycitronellol                             610     N,T               No safety concern

    Hydroxycitronellal                             611     N                 No safety concern

    Hydroxycitronellal dimethyl acetal             612     N                 No safety concern

    Hydroxycitronellal diethyl acetal              613     N,T               No safety concern

    Diethyl malonate                               614     N                 No safety concern

    Butyl ethyl malonate                           615     N,T               No safety concern

    Dimethyl succinate                             616     N                 No safety concern

    Diethyl succinate                              617     N                 No safety concern

    Fumaric acida                                  618     R,T               No safety concern

    (-)-Malic acid                                 619     R,T               No safety concern

    Diethyl malate                                 620     N,T               No safety concern

    Tartaric acid (+-,-, , meso-)                 621     R                 No safety concern

    Diethyl tartrate                               622     N                 No safety concern

    Adipic acid                                    623     R                 No safety concern

    Diethyl sebacate                               624     N                 No safety concern

    Dibutyl sebacate                               625     N                 No safety concern

    2. (continued)
                                                                                                    

    Flavouring agent                               No.     Specificationsa   Conclusions based
                                                                             on current intake
                                                                                                    
    Ethylene brassylate                            626     N                 No safety concern

    Aconitic acid                                  627     N,T               No safety concern

    Ethyl aconitate (mixed esters)                 628     N,T               No safety concern

    Triethyl citratea                              629     R,T               No safety concern

    Tributyl acetylcitrate                         630     N,T               No safety concern

    3-Methyl-2-oxobutanoic acid and                631     N,T               No safety concern
    sodium salt

    3-Methyl-2-oxopentanoic acid and               632     N,T               No safety concern
    sodium salt

    4-Methyl-2-oxopentanoic acid and               633     N,T               No safety concern
    sodium salt

    2-Oxopentandioic acid                          634     N                 No safety concern

    3-Hydroxy-2-oxopropionic acid                  635     N                 No safety concern
                                                                                                    

    N, new specifications prepared; R, existing specifications revised; T, the existing new or revised
    specifications are tentative and information is needed.

    a The ADI for this substance was maintained.
    

    3.  Peanut and soya bean oils

         The Committee reviewed available information on the potential
    allergenicity of peanut and soya bean oils. It concluded that distinct
    processes that would consistently yield safe products have not been
    defined, since:

    *    the processes by which the peanut and soya bean oils tested
         clinically in humans were refined were not clearly described;

    *    data on the protein content of those oils that had been
         clinically tested were not available; and

    *    the quality of the analytical procedures, including validation,
         for the determination of the concentration of residual protein in
         the oils was not clearly described.

         Further information is required.

    4.  Contaminants

    4.1  Lead

         The provisional tolerable weekly intake (PTWI) of 25 g/kg bw was
    maintained. The Committee considered the results of a quantitative
    risk assessment and concluded that the concentrations of lead found
    currently in food would have negligible effects on the
    neurobehavioural development of infants and children. It noted,
    however, examples of foods with high levels of lead remain in
    commerce. The simulation model that is presented in the report could
    be used to evaluate the effects of potential intervention procedures.
    A complete risk assessment of lead should also take into account other
    sources of exposure.

    4.2  Methylmercury

         The PTWI of 3.3 g/kg bw was maintained. The Committee considered
    data on intake, quantitative relationships between daily intake of
    methylmercury and concentrations in blood and hair, and
    epidemiological studies in progress. The information available was
    insufficient to evaluate neurodevelopmental effects on the children of
    mothers who had a low intake of methylmercury. No clear indication of
    consistent risk was detected in the epidemiological studies. The
    Committee noted that fish, the major source of methylmercury in the
    diet, is an important component of nutrition, especially in certain
    regions and ethnic groups, and recommended that the nutritional
    benefits of fish be weighed against the possibility of harm when
    limits on the concentration of methyl-mercury in fish or on fish
    consumption are being considered. 

    4.3  Zearalenone

         A PMTDI of 0.5 g/kg bw was established.

    5.  Food additives considered for specifications only
                                                                                  

    Food additive                                             Specificationsa
                                                                              

    alpha-Acetolactate decarboxylase from Bacillus            R
    brevis expressed in B. subtilis

    Adipic acid                                               R

    alpha-Amylase from B. megaterium expressed                R
    in B. subtilis

    alpha-Amylase from B. stearothermophilus expressed        R
    in B. subtilis

    Argon                                                     N

    Calcium hydrogen sulfite                                  W

    Carob bean gum                                            R

    Carotenes, algae                                          S

    Carotenes, vegetable                                      S

    Chymosin A from Escherichia coli K-12 containing the      R
    prochymosin A gene

    Chymosin B from Aspergillus niger var. awarmori           R
    containing the prochymosin B gene

    Chymosin B from Kluyveromyces lactis containing           R
    the prochymosin B gene

    Citric acid                                               R

    Ferrous gluconate                                         R

    Ferrous sulfate                                           R

    Ferrous sulfate, dried                                    N

    Fumaric acid                                              R

    Guar gum                                                  R

    Helium                                                    N

    Magnesium gluconate                                       R

    ()-Malic acid                                            R

    Maltogenic amylase from B. stearothermophilus             R
    expressed In B. subtilis

    5.  (continued)
                                                                              

    Food additive                                             Specificationsa
                                                                              
    Nitrogen                                                  R

    Oxygen                                                    N

    Potassium metabisulfite                                   R

    Potassium sulfite                                         R

    Riboflavin from B. subtilis                               R

    Sodium hydrogen sulfite                                   R

    Sodium metabisulfite                                      R

    Sodium sulfite                                            R

    Sodium thiosulfate                                        R

    Sucrose esters of fatty acids                             R

    ()-Tartaric acid                                         R

    (-)-Tartaric acid                                         R

    Thaumatin                                                 R

    Xanthan gum                                               R
                                                                              

    a N, new specifications prepared; R, existing specifications
      revised; S, specifications exist, revision not considered or
      required; W, existing specifications withdrawn
    

        6. Food additives considered for evaluation of national
       intake assessments
                                                                                                        

    Substance                          Conclusions
                                                                                                        

    Annatto extracts (bixin)           Intake estimates based on levels proposed in the draft General
                                       Standard for Food Additivesa and the range of foods in which
                                       use is allowed integrated with national food consumption data
                                       exceeded the ADI of 0-0.065 mg/kg bw (expressed as bixin). 

                                       Intake assessments based on national standards did not exceed
                                       the ADI for most population groups. Data from Brazil, however,
                                       provided evidence that 28% of the population consume annatto
                                       as a condiment and have a chronic intake of about 150% of the ADI. 

                                       The Committee recommended that populations that have a high intake
                                       of annatto extracts continue to be monitored and recommended that
                                       annatto extracts be re-evaluated in 2001.

    Canthaxanthin                      Intake estimates based on levels proposed in the draft General
                                       Standard for Food Additivesa and the range of foods in which use
                                       is allowed integrated with national food consumption data exceeded
                                       the ADI of 0-0.03 mg/kg bw.

                                       Indirect exposure through the use of canthaxanthin as a feed 
                                       additive for food animals is the major source of intake of 
                                       canthaxanthin in food.

                                       Long-term intake based on national standards is unlikely to 
                                       exceed the ADI.

    Erythrosine                        The intake of erythrosine could exceed the ADI of 0-0.1 mg/kg 
                                       bw if the levels proposed in the draft General Standard for 
                                       Food Additivesa are widely adopted at the national level.

                                       Non-food sources of erythrosine, such as pharmaceutical 
                                       products, should be included in intake assessments.

                                       On the basis of national assessments, the long-term intake of 
                                       erythrosine is unlikely to exceed the ADI.

    6. (continued)
                                                                                                        

    Substance                          Conclusions
                                                                                                        

    Iron oxides                        Iron oxides are permitted for use in foods in the draft General 
                                       Standard for Food Additivesa under conditions of Good
                                       Manufacturing Practice.

                                       Intake of iron oxides assessed on the basis of national 
                                       standards is unlikely to exceed the ADI of 0-0.5 mg/kg bw.
                                                                                                        

    a   Intake estimates based on food additive levels in the draft General Standard for Food Additives 
        (GSFA) being developed by the Codex Committee on Food Additives and Contaminants integrated 
        with national food consumption data will give gross overestimates of actual intakes in any
        one country because the levels proposed in the draft GSFA are generally compiled by adopting 
        the highest level of use of any one food category submitted by Member States or nongovernmental 
        organizations. The range of food uses specified in the draft GSFA is also usually
        much wider than in national standards.
        





















    See Also:
       Toxicological Abbreviations