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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


    PROPYL p-HYDROXYBENZOATE

    Synonyms                      Propylparaben

    Chemical name                 Propyl p-hydroxybenzoate; n-propyl ester
                                  of p-hydroxybenzoic acid

    Empirical formula             C10H12O3

    Structural formula

    MOLECULAR STRUCTURE 7

    Molecular weight              180.21

    Definition                    Propyl p-hydroxybenzoate, after drying
                                  for 2 hours at 80, contains not less
                                  than 99 per cent. of C10H12O3.

    Description                   Propyl p-hydroxybenzoate is a white,
                                  almost odourless, crystalline solid.

    Use                           As an antimicrobial agent.

    Biological Data

         This additive was evaluated by the Joint FAO/WHO Expert Committee
    on Food Additives in its Sixth Report (FAO/WHO, 1962). Since its
    publication some new experimental work has been carried out on these
    compounds. This and other work not included in the Sixth Report is
    presented and discussed in this monograph.

    Biochemical aspects

         Dogs fed 1000 mg/kg body-weight excreted 58 per cent. in the
    urine and dogs given 50 mg/kg body-weight i.v. excreted 94 per cent.
    The ester was detectable in the plasma only soon after administration
    (Sokol, 1952; Jones et al., 1956).

         Two grams propyl ester was given daily to human volunteers for 50
    days. No unhydrolyzed ester could be detected in the urine
    (Sabalitschka & Neufeld-Crzellitzer, 1954).

         At high doses, propyl p-hydroxybenzoate was found to be a useful
    anaesthetic for frogs and tadpoles (Kopsch, 1949).

    Acute toxicity

                                                                          

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

    Mouse     oral              8 000               Sokol, 1952
    Mouse     (free ester)        400               Sokol, 1952
                                                                          

    Short-term studies

         Rat. Feeding experiments with n mixture of 40 per cent. ethyl
    ester and 60 per cent. propyl ester were reported under ethyl
    p-hydroxybenzoate (Heyden, 1939; Heyden, 1940). Rats ware fed on a
    vitamin A deficient diet with a mixture of propyl ester and methyl
    ester added at various concentrations. No additional pathological
    effects were noted (Cremer, 1935).

         Guinea-pig.  Mixed propyl and methyl esters were fed to
    animals on scorbutic diets. No additional pathological effects were noted
    (Cremer, 1935). For details see the methyl ester.

         Dog. Dogs were fed 0.7 g/kg body-weight for 90 days without
    ill effects or macroscopic changes (Ghirardi, 1940).

         Rabbit. 0.25-0.30 per cent. solutions had no local
    anaesthetic effect on the cornea (Adler-Hradecky & Kelentey, 1960).

         Man. The propyl ester has been used therapeutically at doses
    of 800 mg/kg body-weight over 3 days for the treatment of moniliasis
    (Rossier & Wegmann, 1953).

    Long-term studies

         Rat. Experiments were conducted with a mixture consisting of
    40 per cent. ethyl ester and 60 per cent. propyl ester. For details and
    results see ethyl p-hydroxybenzoate. It was concluded that the
    mixture, when fed at a level of 1500 mg/kg body-weight, did not
    produce any pathological changes, with the exception of a significant
    decrease in growth rate from the 4th to the 8th month. No influence in
    weight gain was seen at the 150 mg/kg body-weight level (Heyden,
    1942).

    Comments

         The long-term studies in rats are adequate for an assessment.
    However,  further biochemical studies in man and animals are desirable
    and further studies on local anaesthetic activity should also be
    undertaken.

    Evaluation

         Applicable to the methyl, ethyl and propyl esters.

    Level causing no toxicological effect

         Rat. 20 000 ppm in the diet, equivalent to 1000 mg/kg
    body-weight/day

    Estimate of acceptable daily intake for man

                                       mg/kg body-weight1

       Unconditional acceptance               0-2

       Conditional acceptance                 2-7

    REFERENCES

    Adler-Hradecky, C. & Kelentey, B. (1960) Arch. int. Pharmacodyn.,
    128, 135

    Cremer, H. (1935) Z. Lebensmitt-Untersuch., 70, 136

    Ghirardi, G, E. (1940) Arch, ital. Sci. farmcol., 9., 282

    Heyden, -. (1939) Unpublished report from Applied Research
    Incorporated

    Heyden, -. (1940) Unpublished report from Applied Research
    Incorporated

    Heyden, -. (1942) Unpublished report from Applied Research
    Incorporated



                   

    1 Sum of ethyl, methyl and propyl esters of p-hydroxybenzoic acid.

    Jones, P. S., Thigpen, D., Morrison, J. L. & Richardson, A. P. (1956)
    J. Amer. pharm. Ass,. sci. Ed., 45, 270

    Kopsch, P. (1949) Anat. Anz.,97, 158

    Rossier P. H. & Wegmann, T. (1953) Wien. Med. Wschr., 19/20, 358

    Sabalitschka, T. & Neufeld-Crzellitzer, R. (1954) Arzneimittel-
    Forsch., 4, 575

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

    


    See Also:
       Toxicological Abbreviations