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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


    ADIPIC ACID

    Chemical name                 Hexanedioic acid; 1,4-butanedicarboxylic
                                  acid

    Empirical formula             C6H10O4

    Structural formula            COOH
                                  '
                                  (CH2)4
                                  '
                                  CCOH

    Molecular weight              146.14

    Definition                    Adipic acid contains not less than 99.6
                                  per cent. and not more than the
                                  equivalent of 101 per cent. of
                                  C6H10OT4.

    Description                   Adipic acid occurs as white, odourless
                                  crystals or crystalline powder, with an
                                  acid taste.

    Use                           As an acidulant.

    Biological Data

    Biochemical aspects

         Adipic acid is oxidized in vitro by isolated rat liver
    mitochondria (Lang & Bässler, 1953). The capacity of man and animals
    to utilize adipic acid is limited to a relatively small amount. In
    balance studies, groups of 10 and 4 rats, previously fed for 20-25
    weeks on a normal diet or on an adipic acid diet, were given 400 mg or
    800 mg adipic acid daily for 14 days. Both groups excreted 2.4-6 per
    cent. of the dose independent of the previous feeding regime. No
    metabolite of adipic acid could be detected in the urine (Lang &
    Bartsch, 1953).

         Four rabbits given 4-6 g adipic acid excreted 57 per cent. of the
    dose in the urine in 4 days (Enders, 1941). A dog given a total of
    23.1 g of disodium adipate during 3 days excreted 58 per cent in the
    urine (Verkade et al., 1937). Man could metabolize not more than 2-5 g
    adipic acid per day. The utilization increased with decreasing dose
    (Weitzel, 1941; Weitzel 1947). Small amounts of adipic acid have been
    frequently found in the normal human urine (Hanson, 1943). Feeding of
    adipic acid to man did not influence the excretion of oxalic acid
    (Kabelitz, 1343).

         Rats given 250 mg/kg body-weight 14C-labelled adipic acid
    oxidized up to 70 per cent. of the dose to 14CO2.  The tissues from
    the sacrificed rats showed very little radioactivity, the highest
    activity appearing in the kidneys.   Some adipic acid was excreted in
    the urine; in addition other radioactive substances (urea, glutamic
    acid, citric acid and ß-keto adipic acid) were found in the urine
    (Rusoff et al., 1960).

    Acute toxicity

                                                                       

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

    Mouse      oral (free acid)    1 900            Horn et al., 1957

               i.p. (disodium      4 000            Rhone-Poulenc, 1965
               salt)

    Rat        i.p. (free acid)    275              Horn et al., 1957
                                                                       

    Short-term studies

         Rat. Repeated large doses of 638-1332 mg/kg body-weight, when
    given to immature rats depressed the rats of weight gain (Foulger,
    1943). Five young rats given 2430 mg/kg. body-weight daily for 4 weeks
    gained the same weight as controls. Three adult rats fed the same dose
    for a similar period of time maintained steady body-weight, appeared
    healthy and had a normal blood urea level at the end of the
    experiment.  Analysis of the body lipids showed no retention of adipic
    acid in the body (Enders, 1941).

         Groups of 18 young male rats were fed 0, 200, 400 and 800 mg
    adipic acid per rat per day for 5 weeks. The highest level produced
    significant growth depression with severe diarrhoea in the first 2-3
    weeks. In another experiment groups of 15 male and female young rats
    were fed 0, 400 and 800 mg per rat per day of adipic acid for 33
    weeks. Toxic effects i.e. apathy, change in the fur, severe diarrhoea,
    growth depression and high mortality rate occurred especially in the
    first weeks of the experiment at the highest level only.
    Histopathological examination of the animals showed no abnormalities
    at levels of 0 and 400 mg/day. At the highest level enlarged hepatic
    nuclei and polynucleated cells, with increased number and size of
    Kupffer cells, were observed. The gut showed chronic inflammation with
    much regenerative activity and mucosal damage. In a third experiment,
    a protein-deficient diet was given together with 0, 50, 100, 200 and
    400 mg per day for 19 weeks. At the highest level mortality rate was
    increased and growth significantly depressed (Lang & Bartsch, 1953).

         Rabbit. Slight nephropathic action was demonstrated in fasting
    rabbits given 2 or 4 disodium adipate by s.c. injection. Phthalein dye
    excretion was slightly reduced and urinary non-protein nitrogen and
    creatinine were raised for 48 hours after injection (Rose et al.,
    1925).

    Long-term studies

         Groups of 20-39 male and female rats received 0, 0.1, 1, 3 and 5
    per cent. adipic acid for 2 years. Body-weight was initially depressed
    significantly in males at the 3 per cent. and 5 per cent. levels and
    the 5 per cent. group had the lowest weights and slightly reduced food
    consumption. There was no significant difference in survival among the
    various test groups from controls. Autopsy findings and tumour
    incidence were not significantly different from controls and on
    histopathological examination the major organs were found normal (Horn
    et al., 1957). Data concerning the reproduction of the animals are not
    given in the paper.

    Comments

         The long-term studies are satisfactory but were carried out in
    one species only. Reproduction was not investigated in these
    experiments, though a short-term experiment showed no apparent
    deleterious effect. Parenterally administered disodium adipate appears
    to be nephrotoxic to the rabbit.

    Evaluation

    Level causing no toxicological effect

         Rat. 10 000 ppm in the diet, equivalent to 500 mg/kg
    body-weight/day.

    Estimate of acceptable daily intake for man

                                  mg/kg body-weight

       Conditional acceptance            0-5

    Further work required

    Studies of kidney function in man.

    REFERENCES

    Enders, A. (1941)Arch. exp. Pathol. Pharmacol., 197, 597

    Foulger, J. H. (1943) Haskell Laboratory of Industrial Toxicology
    (Unpublished Report)

    Hanson, H. (1943) Z. ges. inn, Med.., 113, 226

    Horn, H. J., Holland, E. G. & Hazleton, L. W. (1957) Agr. Food
    Chem., 5, 759

    Kabelitz, G. (1943) Klin. Wschr., 22, 439

    Lang, K. & Bartsch, A. R. (1953) Biochem. Z., 323, 462

    Lang, K. & Bässler, K. H. (1953) Biochem., Z., 323, 456

    Rhône-Poulenc (1965) Unpublished report

    Rose, W.C. et al., (1925) J. Pharmacol. exp. Ther., 25, 59

    Russoff, I. I. et al. (1960) Toxicol. appl. Pharmacol., 2, 316

    Verkade, P. E., Lee, J van der & Alphen, A. J. S. van (1937) 
    Hoppe-seylers Z. physiol. Chem., 250, 47

    Weitzel, G. (1941) Berl. Verhdl. Sächs. Akad. Wiss. Math. -Phys.
    Kl., 93, 9

    Weitzel, G. (1947) Hoppe-Seylers Z. physiol. Chem., 282, 185
    


    See Also:
       Toxicological Abbreviations
       Adipic acid (ICSC)
       Adipic acid (WHO Food Additives Series 12)
       ADIPIC ACID (JECFA Evaluation)
       Adipic Acid (SIDS)