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. 7) in 1963.

         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.



         Propylene glycol is rapidly absorbed after oral administration
    and appears in the blood-stream. After a dose of 8 ml/kg bw had been
    administered to dogs approximately 24 hours were required for complete
    elimination from the blood-stream (Hanzlik et al., 1939a). Propanediol
    phosphate occurs in brain and liver (Rudney, 1954a) and may be
    metabolized by dephosphorylation followed by oxidation Huff & Rudney,

         Propanediol and propanediol phosphate are intermediates in the
    catabolism of acetone to acetate and formate: propanediol added to a
    liver slice preparation is converted to lactic acid (Rodney, 1954b).
    Liver alcohol dehydrogenase oxides the glycol to lactaldehyde (Huff,
    1961). Propylene glycol is glycogenic in the fasted rat (Opitz, 1958).
    Definite increases in liver glycogen occurred after giving 1 ml/kg bw,
    but 0.5 ml produced no change (Hanzlik et al., 1939b). Dogs given
    propylene glycol excreted 25 to 50% unchanged in the urine (Hanzlik et
    al., 1939a; Lehman & Newman, 1937). In experiments on three human
    subjects, 20 to 25% of the dose (1 ml/kg bw) was excreted in the urine
    within 10 hours (Hanzlik et al., 1939a). The propylene glycol content
    of the saliva was about three times as high as that in the blood.

         In the body, propylene glycol stearate esters undergo enzymatic
    hydrolysis and absorption in a similar manner to stearate glycerides
    (Long et al., 1958).


    Acute toxicity

    Animal         Route      LD50            References
                              (per kg bw)

    Rat            oral       21.0 ml         Laug et al., 1939;
                              26.3 ml         Smyth et al., 1941;
                              33.5 ml         Weatherby & Haag, 1938

    Mouse          oral       23.9 ml         Laug et al., 1939;
                              22.0 ml         Latven & Moliter, 1939

    Guinea-pig     oral       18.9 ml         Laug et al., 1939;
                              18.3 ml         Smyth et al., 1941

    Rabbit         oral       18.5 ml         Lehman & Newman, 1937

         In the rat, a single large oral dose produced minimal microscopic
    changes in the kidney. The liver showed slight congestion and
    hyperaemia (Laug et al., 1939).

         The intravenous lethal dose for dogs was 25 ml/kg bw, and the
    anaesthetic dose was 21.2 ml/kg (Hanzlik et al., 1939a).

    Short-term studies


         Six rats wore given 3.58% propylene glycol in the drinking-water
    for 11 weeks. One rat died at the tenth week, one was ill and others
    were beginning to lose weight (Holck, 1937).

         When all the carbohydrate in the diet of a group of four rats was
    replaced by propylene glycol, giving a concentration of 48.5%, all the
    animals died within a month. When three-quarters of the carbohydrate
    was replaced by propylene glycol, giving a concentration of 31%, all
    the animals in another group died within 14 weeks. With half-and-half
    proportions of carbohydrate and propylene glycol, giving a
    concentration of 25%, the rats in a third group grew more slowly than
    those in a control group, and at five-and-a-half months their weight
    was less. With 13% propylene glycol in the diet, there was no
    mortality during the feeding period of five months and weight gain was
    about the same as in the controls. Paired-fed rats given 12.8%
    propylene glycol in the diet and the same level of carbohydrate grew
    faster and attained a greater weight than the control animals. Part of

    this difference might have been due to the greater caloric value of
    the propylene glycol. The spontaneous activity of rats fed large doses
    of propylene glycol was somewhat greater than that of the control
    group. Propylene glycol had no effect on the respiratory quotient of
    rats (Hanzlik et al., 1939b).

         Paired-fed rats kept for 127 to 163 days on a diet in which
    one-quarter of the carbohydrate had been replaced by the caloric
    equivalent of propylene glycol (total propylene glycol intake 89.2 to
    130.7 g) grew better than the controls (Winkle & Newman, 1941).

         Rats in groups of five tolerated up to 10% of propylene glycol in
    the drinking-water over about one-eighth of the normal life span
    (corresponding to a daily intake of 10 to 13 g/kg bw but when the
    drinking-water contained 25% or 50% of propylene glycol they died
    within nine days (Weatherby & Haag, 1938; Seidenfeld & Hanzlik, 1932).

         Groups of 10 rats were each given six weeks of treatment with 5%
    or 10% propylene glycol in their drinking-water. Liver weights were
    significantly increased. The red cell count was significantly
    decreased. There was considerable hyperglycaemia and a slight decrease
    in blood urea (Vaille et al., 1971).


         Doses of 1, 2, 3, 4 or 8 ml of propylene glycol per kg bw were
    administered daily by stomach tube to 11 young rabbits over a period
    of 50 days. A satisfactory growth rate was established (Braun &
    Carland, 1936).

         Seven rabbits were given 5% propylene glycol in drinking-water
    for eight weeks, the mean amount ingested daily being 14.8 ml per
    rabbit. There was induction of hyperglycaemia in this species (Vaille
    et al., 1971).


         Four dogs consumed 5% of propylene glycol in drinking-water for
    five to nine months. The average daily intake of propylene glycol was
    5.1 ml/kg bw. All dogs remained in good health and no significant
    changes were noted in the functional efficiency of tho liver and
    kidneys (galactose excretion, uric acid excretion, rose bengal test,
    phenolsulfonphthalein test). Histopathological examination showed no
    changes in the livers and kidneys. No alterations in serum calcium
    were observed (Winkle & Newman, 1941).

    Long-term studies


         Groups of 10 rats (males and females) were fed for two years on
    diets containing 2.45% or 4.9% of propylene glycol, corresponding to a
    daily intake of 0.9 or 1.8 ml/kg bw. There was no influence on growth,
    food utilization or survival. The histopathological examination of the
    liver, kidney, lung, heart, spleen, lymph nodes, pancreas, stomach,
    intestine and adrenals showed no lesions attributable to the glycol,
    although slight chronic liver damage was reported (Morris et al.,

         Groups of 30 male and 30 female rats were fed for two years on
    diets containing 0, 6250, 12 500, 25 000 and 50 000 ppm (0%, 0.625%,
    1.25%, 2.50%, and 5%) of propylene glycol. The highest level
    corresponds to 2.5 g/kg per day. There were no statistically
    significant effects on death rate, weight gain or food consumption.
    There were no significant effects on haemoglobin or differential white
    cell counts after two years, nor on haematocrit values, red cell and
    white cell counts and reticulocyte counts after one year of treatment.
    Urine cell counts, urine concentrating power and urinary capacity were
    not affected in rats on the two higher dosage levels after 13, 30 or
    52 weeks. At the end of the two-year trial, there were no significant
    effects on absolute or relative weights of organs (brain, heart,
    liver, spleen, stomach, small intestine, caecum, kidneys, adrenals,
    gonads), and no histopathological effects or neoplasia attributable to
    the substance (Gaunt et al., 1972).


         Groups of five male and five female beagles were given propylene
    glycol, in the diet, at dosage levels of 2.0 and 5.0 g/kg for two
    years. In control groups, the calorific equivalent of dextrose was
    given. At the 5 g/kg level, there were findings suggestive of an
    increased erythrocyte destruction with a compensatory increased rate
    of haematopoiesis: slightly reduced cell count, haemoglobin and
    haematocrit values, slightly increased bilirubin, and increased
    incidence of anisocytosis, poikilocytosis and reticulocytosis. There
    was no evidence of damage to spleen or bone marrow. Dosage with
    2 g/kg per day produced no adverse effect. Liver function tests
    (bromosulfthalein retention, serum alkaline phosphatase, serum
    glutamate-oxalacetate and glutamate-pyruvate transaminases, liver
    glycogen and lipids) and liver histology were not significantly
    affected by either dose level of propylene glycol (Weil et al., 1971).


         Propylene glycol had no effect upon basal metabolism (Hanzlik et
    al., 1939a).


         Conversion to lactic acid has been shown to be the normal
    metabolic pathway. This observation, together with the results of the
    long-term studies, was used as the basis for the evaluation.


    Level causing no toxicological effect

         In the rat and in the dog: 2500 mg/kg bw.

    Estimate of acceptable daily intake for man

         0 to 25 mg/kg bw.


    Braun, H. A. & Cartland, G. F. (1936) J. Amer. pharm. Ass., 25, 746

    Gaunt, I. F., Carpanini, F. M. D., Grasso, P. & Lansdown, A. B. G.
         (1972) Fd. Cosmet. Toxicol., 10, 151

    Hanzlik, P. J., Lehman, A. J., Winkle, W. van, jr & Kennedy, N. K.
         (1939a) J. Pharmacol. exp. Ther., 67, 114

    Hanzlik, P. J., Newman, H. W., Winkle, W. van, jr, Lehman, A. J. &
         Kennedy, N. K. (1939b) J. Pharmacol. exp. Ther., 67, 101

    Holck, H. G. O. (1937) J. Amer. med. Ass., 109, 1517

    Huff, E. (1961) Biochim. biophys. Acta (Amst.), 48, 506

    Huff, E. & Rudney, H. (1959) J. biol. Chem., 234, 1060

    Latven, A. R. & Moliter, H. (1939) J. Pharmacol. exp. Ther., 65, 89

    Laug, E. P., Calvery, H. O., Morris, H. J. & Woodward, G. (1939)
         J. industr. Hyg., 21, 173

    Lehman, A. J. & Newman, H. W. (1937) J. Pharmacol. exp. Ther., 60, 312

    Long, C. L., Domingues, F. J., Studer, V., Lowry, J. R., Zeitlin, B.
         R., Baldwin, R. R. & Thiessen, R., jr (1958) Arch. Biochem.,
         77, 428

    Morris, H. J., Nelson, A. A. & Calvery, H. O. (1942) J. Pharmacol.
         exp. Ther., 74, 266

    Opitz, K. (1958) Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak., 234,

    Rudney, H. (1954a) J. biol. Chem., 210, 353

    Rudney, H. (1954b) J. biol. Chem., 210, 361

    Seidenfeld, M. A. & Hanzlik, P. J. (1932) J. Pharmacol. exp. Ther.,
         44, 109

    Smyth, H. F., jr, Seaton, J. & Fischer, L. (1941) J. industr. Hyg.,
         23, 259

    Vaille, Ch., Debray, Ch., RozÚ, Cl., Souchard, M. & Martin, E. (1971)
         Ann. Pharmac. franšais, 29, 577

    Weatherby, J. H. & Haag, H. B. (1938) J. Amer. pharm. Ass., 27, 466

    Weil, C. S., Woodside, M. D., Smyth, M. F. & Carpenter, C. P. (1971)
         Fd. Cosmet. Toxicol., 9, 479

    Winkle, W. van, jr & Newman, H. W. (1941) Food Res., 6, 509

    See Also:
       Toxicological Abbreviations