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


    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


    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.



         This substance has been evaluated for acceptable daily intake by
    the Joint FAO/WHO Expert Committee on Food Additives (see Annex  1, 
    Ref. No. 13) in 1965.

         Since the previous evaluation, additional data have become
    available and are summarized and discussed in the following monograph.
    The previously published monograph has been expanded and is reproduced
    in its entirety below.



         Dogs given 1000 mg/kg bw of the butyl ester excreted only 48.2%
    of the dose in the urine within 48 hours. Metabolic pathways other
    than hydrolysis and subsequent conjugation may account for the poor
    recovery of butyl ester metabolites in balance experiments (Jones et
    al., 1956). Dogs fed 1000 mg/kg bw of butyl ester or given 50 mg/kg bw
    i.v. excreted 40-48% of the ester in the urine as metabolites and 0.5%
    as unchanged ester (Sokol, 1952).

         The metabolism of various alkyl p-hydroxybenzoates (butyl, ethyl,
    methyl and propyl) was investigated in rabbits using oral dose levels
    of 0.4 and 0.8 g/kg and compared with that of p-hydroxybenzoic acid,
    which is a major metabolite of their esters. Metabolism of the esters
    was very rapid and excretion of the free p-hydroxybenzoic acid in the
    urine after administration was much less than that of p-hydroxybenzoic
    acid but output of the acid conjugated with glycine and glucoronic
    acid was much larger. When various alkyl esters were administered,
    those were converted into the free acid (25-39%), glycine conjugate
    (15-29%), ester-type glucuronide (5-8%), ether-type glucuronide
    (10-18%) and the sulfate (7-12%) during 24 hours (Tsukamoto & Terada,


    Special studies on teratogenicity

         An attempt has been made to correlate the potential teratogenic
    activity of three salicylate derivatives, with their ability to
    inhibit acid mucopolysaccharide synthesis. The sodium salt of
    p-hydroxybenzoic acid, a metabolite of the esters did not exhibit
    teratogenic potential (Larsson & Boström, 1965).

    Acute toxicity

                                  LD50            References
    Animal    Route               (mg/kg bw)

    Mouse     Oral (free acid)    5 000           Sokol, 1952

              Oral (Na salt)      950             Matthews et al., 1956

              i.p. (free acid)    230 appox.      Sokol, 1952

              i.p. (Na salt)      230 ± 24        Matthews et al., 1956

    Short-term studies


         Groups of 12 male and 12 female weanling rats were fed dietary
    levels of 0, 2 and 8% of butyl ester for 12 weeks. At the 8% level, 
    no males survived the experimental period, the mortality rate in the 
    females was higher than that of the controls, and the rate of weight 
    gain was markedly affected; the animals at this level also showed 
    depressed and decreased motor activity. However, autopsies with 
    histological examination of animals dying during the test showed only
    pneumonia and pulmonary consolidation, without difference between 
    treated and control animals. Food consumption was unaffected in all 
    groups and necropsy of all survivors showed no difference other than 
    the body weight depression at 8% (Matthews et al., 1956 and Report on 
    Preservatives 1959).

    Long-term studies

         Data are not available.


         Cases of sensitivity have been reported (Schamberg, 1967 - one 
    case; Schorr & Mohajerin, 1966 - one case; Epstein, 1968 - three 
    cases; Wuepper, 1967 - four cases). It has been found that 0.5%  or
    less of p-hydroxybenzoate esters in a skin cream is capable of 
    producing a relentless progression and extension of a dermatitis. 
    Cross sensitivity to all the significant esters (butyl, ethyl, 
    methyl, propyl) is seen in most patients who develop sensitivity to 
    one of them. In a two-year survey of 273 patients with chronic 
    dermatitis, the incidence of positive patch-tests with 5%
    p-hydroxybenzoate was 0.8% (Schorr, 1968).


         The available data do not include any long-term studies and only
    one species has been investigated in short-term experiments. There is
    no information on human metabolism.


         Not possible with the data provided.


    Epstein, S. (1968) Ann. Allergy, 26, 185

    Jones, P.S. et al. (1956) J. Amer. pharm. Ass. sci. Ed., 45, 270

    Larsson, K. S. & Boström (1965) Acta Paediat. Scand., 54, 43

    Matthews, C. et al. (1956) J. Amer. pharm. Ass. sci. Ed., 45, 260

    Report on Preservatives (1959) Food Standards Committee S.O. Code No.

    Schamberg, I. L. (1967) Arch. Derm., 95, 626

    Schorr, W. F. (1968) J. Amer. med. Ass., 204, 859

    Schorr, W. F. & Mohajerin, A. H. (1966) Arch. Derm., 93, 721

    Sokol, H. (1952) Drug Stand., 20, 89

    Tsukamoto, H. & Terada, S. (1964) Chem. Pharm. Bull., 12, 765

    Wuepper, K. D. (1967) J. Amer. med. Ass., 202, 579

    See Also:
       Toxicological Abbreviations