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    WHO/Food Add./24.65
    FAO Nutrition Meetings
    Report Series No. 38A




    SPECIFICATIONS FOR IDENTITY AND 
    PURITY AND TOXICOLOGICAL EVALUATION 
    OF SOME ANTIMICROBIALS AND 
    ANTIOXIDANTS





    The content of this document is the result of the deliberations of the
    Joint FAO/WHO Expert Committee on Food Additives which met 8-17
    December 1964a





                   

    a Eighth Report of the Joint FAO/WHO Expert Committee on Food
    Additives, Wld Hlth Org. techn. Rep. Ser., 1965, 309; FAO
    Nutrition Meetings Report Series 1965, 38.


    PROPYL GALLATE

    CHEMICAL NAMES          Propyl gallate; 
                            n-propyl ester of 3,4,5-trihydroxybenzoic
                            acid

    EMPIRICAL FORMULA       C10H12O5

    STRUCTURAL FORMULA

    MOLECULAR STRUCTURE 3

    MOLECULAR WEIGHT        212.21

    DEFINITION              Propyl gallate contains not less then 99% of
                            C10H12O5 after drying at 110C for 4 hours.

    DESCRIPTION             A white to creamy-white, crystalline, odourless
                            solid, with a slightly bitter taste.  1 g is
                            soluble in 300 ml of water or in 3.5 ml of
                            ethanol; freely soluble in fat.

    USE                     As an antioxidant; more effective combined with
                            citric acid as synergist.

    OCTYL GALLATE

    CHEMICAL NAME           Octyl gallate; 
                            n-octyl ester of 3,4,5-trihydroxybenzoic acid

    EMPIRICAL FORMULA       C15H22O5

    STRUCTURAL FORMULA

    MOLECULAR STRUCTURE 4

    MOLECULAR WEIGHT        282.34

    DEFINITION              Octyl gallate contains not less than 98.5% of
                            C15H22O5 after drying at 60C for 4 hours.

    DESCRIPTION             A white to creamy-white, odourless solid, which
                            may have a slightly bitter taste.  1 g is
                            soluble in 2.5 ml of ethanol.  It is insoluble 
                            in water but freely soluble in fats.

    USE                     As an antioxidant; more effective combined with
                            citric acid as synergist.

    DODECYL GALLATE

    CHEMICAL NAMES          Dodecyl gallate; 
                            n-dodecyl (or lauryl) ester of 
                            3,4,5-trihydroxybenzoic acid

    SYNONYM                 Lauryl gallate

    EMPIRICAL FORMULA       C19H30O5

    STRUCTURAL FORMULA

    MOLECULAR STRUCTURE 5

    MOLECULAR WEIGHT        338.45

    DEFINITION              Dodecyl gallate contains not less than 98.5% of
                            C19H30O5 after drying at 60C for 4 hours.

    DESCRIPTION             A white or creamy-white, odourless solid, which
                            may have a slightly bitter taste.  1 g is
                            soluble in 3.5 ml of ethanol.  Insoluble in
                            water but freely soluble in fats.

    USE                     As an antioxidant; more effective combined with
                            citric acid as synergist.

    Biological Data

    Biochemical aspects

    The available evidence indicates that the esters are hydrolysed in the
    body.  Most of the gallic acid is converted into 4-O-methyl gallic
    acid.  Free gallic acid or a conjugated derivative of 4-O-methyl
    gallic acid is excreted in the urine.  Conjugation of the 4-O-methyl
    gallic acid with glucuronic acid was demonstrated.1

    Rats fed a low-methionine, low-choline diet containing 1% gallic acid
    developed fatty livers which could be prevented by added choline or
    methionine.2

    The detailed metabolic pathways for propyl gallate have bean
    described.3  There is no evidence to suggest that other esters of
    gallic acid differ greatly in their metabolism from the pattern
    described for propyl gallate.

    Acute Toxicity

                                                                                     

                       Animal    Route                  LD50          Reference
                                                      (mg/kg 
                                                     body-weight)
                                                                                 

    Propyl gallate     Rat       oral                  3800               4
                       Rat       oral                  3600               5
                       Rat       intraperitoneal       380                4
                       Mouse     oral                  2000-3500          5

    Octyl gallate      Rat       oral                  4700               6
                       Rat       intraperitoneal       60-80              7

    Dodecyl gallate    Rat       oral                  6500               6
                       Bat       intraperitoneal       100-120            7
                                                                                 
    
    Short-term studies

    Rat.  Levels of propyl gallate of 1.2% and 2.3% in the diet caused
    interference with weight gain, the bitter taste of the gallate
    apparently making the diet unpalatable.  The higher dose level caused
    some deaths (about 40%) during the first month; the survivors
    continued to eat the diet for 10-16 months and showed retarded growth,
    but no pathological lesions.  The animals that died exhibited renal
    damage.4

    Weanling rats were given diets containing 2.5% and 5% dodecyl gallate.
    All animals fed the smaller quantity were dead within 10 days, and all
    animals fed the larger quantity died within 7 days.8

    Rats fed for 70 days on a diet containing 7% fat and 0.2% dodecyl
    gallate showed no effect on body-weight.9

    Weanling rats were fed diets which contained 20% lard and 0%, 0.1%,
    0.2%, O.3%, 0.4% and 0.5% propyl gallate for 6 weeks.  There was no
    effect on body-weight, liver weight, liver weight to body-weight
    ratio, left adrenal weight, total liver lipid, composition of liver
    polyunsaturated fatty acids, liver cholesterol, adrenal cholesterol or
    serum sodium.10

    Propyl gallate was added to the dietary fat of weanling rats at levels
    of 0.02% in the fat for 13 weeks.  The fat content of the diet
    accounted for 30% of its calorific value.  There was a very slight
    inhibition of growth.  The same rats were then placed on a partial
    starvation diet and kept until they died.  The survival time of the
    animals which had received the propyl gallate was considerably reduced
    and the reduction in their total body protein was greater.11

    Guinea-pig.  Propyl gallate fed to guinea-pigs in groups of 20 at a
    level of O.O117% in the diet for 14 months caused no detectable ill
    effects.4

    Dog.  A level of 0.0117% of propyl gallate in the diet was well
    tolerated by a group of 7 dogs over a period of 14 months.4

    Pig.  Diets containing 0.2% of propyl, octyl or dodecyl gallate were
    fed to pigs without demonstrable ill effect; no anaemia was
    observed.12

    Long-term studies

    Rat and mouse.  A level of 5% propyl gallate in the diet in a 2-year
    chronic toxicity test on rats and mice gave rise to patchy hyperplasia
    in the proventiculus.  At a level of 1% no difference was noted
    between test and control animals.5

    Rats in groups of 10 males and 10 females were fed for 2 years on
    diets containing 0%, 0.00117%, 0.0117%, 0.117%, 1.17% and 2.34% of
    propyl gallate.  The groups receiving 1.17% and 2.34% of propyl
    gallate showed stunted growth and evidence of renal damage.  In the
    other groups, there was no detectable effect on haemoglobin,
    erythrocyte or leucocyte levels in the blood, or on the histological
    appearance of the organs examined.4

    Propyl, octyl and dodecyl gallate were fed to rats at concentrations
    of 0.035%, 0.2% and 0.5% in the diet.  Growth was affected only at the
    0.5% level of dodecyl gallate; there was significant retardation,
    particularly in the second generation.  At this level of dodecyl
    gallate, some litters were lost in the second generation because they

    were not sufficiently fed by the mothers.  A slight hypochromic
    anaemia was noticed in the groups on diets containing 0.2% octyl and
    dodecyl gallate.  No abnormalities were observed in the organs or
    tissues of the rats at autopsy.12

    Young rats in groups of 12 males and 12 females were fed diets
    containing 7% fat and 0.2% octyl or dodecyl gallate.  There was no
    significant difference between test and control animals over 3
    generations.6

    Comment on experimental studies reported

    The acute and short-term toxicity studies reported are fairly
    extensive and cover a wide range of animal species.  The results of
    the experiments involving partial starvation are of great interest and
    indicate a higher toxicity of propyl gallate than the other studies.
    Evaluation of these experiments is difficult, however, in the absence
    of comparable studies with other food additives.  Several long-term
    studies have been made and the levels of feeding varied widely.  There
    are some discrepancies in the results reported.  However, the
    long-term studies on rats provide a basis for evaluation.

    Evaluation

    Level causing no significant toxicological effect in the rat

    With one exception, in long-term studies in rats gallates caused no
    demonstrable ill effects when fed at a level of 0.2%; in one
    investigation, however, this level resulted in hypochromic anaemia. 
    It seems likely that this may have been due to interference with iron
    absorption, but the cause was not established.  Haematological effects
    were carefully examined in a number of other investigations and no
    abnormalities were seen.  It seem probable, therefore, that this
    effect was related to the particular circumstances of one study and
    can be properly disregarded in arriving at the level that causes no
    significant effects in the rat.  The level that causes no significant
    toxicological effect in the rat is 100 mg/kg body-weight per day.

    Estimate of acceptable daily intakes for man

                                     mg/kg body-weight

            Unconditional acceptance        0-0.2
            Conditional acceptance          0.2-0.5

    Comment

    Attention should be given to the amounts of other phenolic
    antioxidants in the diet.

    Further Work Considered Desirable

    1. long-term studies in other species than the rat, with special
    attention to possible interference with iron metabolism and
    haematopoiesis.

    2. Metabolic studies in human subjects.

    3. Further studies on the effects of stress on the toxicity of this
    and other food additives.

    References

    1. Booth, A. N., Masri, M. S., Robbins, D. J., Emerson, O. H., Jones,
    F. T. & DeEds, F. (1959) J. biol. Chem., 234, 3014

    2. Booth, A. N., Robbins, D. J. & DeEds, F. (1961) J. Nutr., 75, 104

    3. Dacre, J. O. (1960) J. N.Z. Inst. Chem., 24, 161

    4. Orten, J. M., Kuyper, A. C. & Smith, A. H. (1948) Food Techn., 2,
    308

    5. Lehman, A. J., Fitzhugh, O. G., Nelson, A. A. & Woodward, G. (1951)
    Advanc. Food Res., 3, 197

    6. Sluis. K. J. H. van (1951) Food Manuf., 26, 99

    7. Esch, G. J. van, Genderen, H. van (1954) Netherlands Institute of
    Public Health, Report No. 481

    8. Allen, C. S. & DeEds, F. D. (1951) J. Amer. Oil Chem. Soc., 28, 304

    9. Tollenaar, F. D. (1954) Fette u. Seifen, 56, 41

    10. Johnson, A. R. & Hewgill, F. R. (1961) Aust. J. exp. Biol. med.
    Sci., 39, 353

    11.Buckman, N. D. (1962) Vop. Pitan., 21, 68

    12. Esch, G. J. van (1955) Voeding, 16, 683
    


    See Also:
       Toxicological Abbreviations
       PROPYL GALLATE (JECFA Evaluation)