The evaluations contained in this publication were prepared by the
    Joint FAO/WHO Expert Committee on Food Additives which met in Rome,
    4-13 June 19741

    World Health Organization     Geneva     1975


    1  Eighteenth Report of the Joint FAO/WHO Expert Committee on
    Food Additives, Wld Hlth Org. techn. Rep. Ser., 1974, No. 557.
    FAO Nutrition Meetings Report Series, 1974, No. 54.




         IMP derives from dephosphorylation of ATP (Adonosine-5-
    triphosphate) to AMP and deamination. Further conversion to
    hypoxanthine is slow compared with the conversion of ATP to IMP. The
    greater portion of IMP in living tissue is derived from de novo
    purine synthesis, less derives from ingested dietary purines or
    nucleotides. IMP is the first purine formed in the complex synthesis
    of purine nucleotides. Uric acid is the metabolic end-product in man
    and allantoin in many mammals. Some two-thirds of uric acid appears
    in urine, the rest is excreted in the gut and further degraded
    (Kojima, 1973). Pharmacological studies on IMP showed no effect on the
    S-A or A-V nodes in the Langendorff preparation of the rat heart
    (Versporille, 1966). Intravenous administration produced hypotension
    in the rabbit and dog (Flössner, 1934) but had no effect on heart rate
    and ECG of the rabbit (Yabo, 1964; Hara et al., 1966). A 1% solution
    decreased the mobility of isolated guinea-pig intestine (Hara et al.,
    1966). Isolated guinea-pig uterus showed a biphasic response to the
    application of IMP (Flössner, 1934). Topical IMP enhances the
    electrical response of the chordotympani to topical MSG in rats and
    cats (Adachi, 1964; Sato et al., 1965). Intravenous IMP had no
    significant effect on blood electrolytes in the rabbit (Hara et al.,

         Male and pregnant (day 10 or 18 of gestation) rats were given by
    gavage 25 mg/kg bw of 814C labelled IMP. Radioactivity in plasma
    reached maximum levels one-half to two hours after treatment and
    slowly decreased to practically zero after 24 hours, the half-life
    being about five hours. About 70% of total activity appeared in the
    urine, 6-7% in faeces, none in expired air, between 0-2% remained in
    organs, 8-17% in the organ-free carcass of males and 18 day pregnant
    females 24 hours after treatment. The fetuses contained about 0.77%
    activity 24 hours after treatment (Ohara et al., 1973). Groups of five
    male rats (control 10) given 0%, 1% and 4% IMP for five or 10 days in
    a purine-free basal diet showed levels of uric acid in serum and
    urine hardly different from controls. Most of the exogenously ingested
    IMP was rapidly excreted in the urine as allantoin. Only liver
    hypoxanthine-guanine phosphoribosyl transferase and adenine
    phosphoribosyl transferase activity were increased and also the ratio
    of liver uricase/xanthine oxidase activity, suggesting metabolism by
    shunt pathways for exogenously ingested IMP (Hashimoto et al., 1973).

         I.v. 500 mg/kg IMP in mice caused behavioural excitement,
    increased reflex response, no muscular relaxation, depressed rotating
    activity during the first hour, did not modify electroshock

    convulsions but decreased dose-dependently metrazol convulsive dosage.
    Doses of 50-500 mg/kg i.v. prolonged loss of righting reflex.
    10-50 mg/kg i.v. in cats had no effect on B.P., heart rate, ECG, blood
    flow of hind limbs. 100 mg/kg s.c. IMP had no effect on intestinal
    transport as measured by charcoal transportation in mice. 10-4 g/ml
    IMP did not affect the contractile response of guinea-pig ileum to
    acetylchlorine, histamine or barium chloride but 10-2 decreased
    motility. 100 mg/kg s.c. IMP had no effect on gastric juice volume in
    the rat but slightly increased pH. 100 mg/kg in mice depressed
    salivary secretion. Rats given 100 mg/kg intragastric IMP showed no
    diuresis. Oral 500 mg/kg IMP had no effect on analgesic response of
    mice or carrageenin oedema in rats (Kojima, 1973).


    Special studies on reproduction


         One control and three test groups of 10 male and 20 female rats
    were used in a three generation study at dietary levels of 0%, 0.5%,
    1% and 2% IMP. Test animals were on their diets for 60 days before
    mating. No effects on mating performance, pregnancy rate or duration
    of gestation were noted. Body weight gain was better than in controls
    for male test animals in all generations. Litter size, pup weight, pup
    mortality and incidence of abnormalities were unaffected by treatment.
    Organ weight analysis, histopathology and skeletal staining of F3B
    revealed no consistent pattern related to treatment (Palmer et al.,

    Special studies on teratogenicity


         One group of nine pregnant rats was given daily 100 mg/kg IMP
    during days 9-15 of pregnancy. No significant teratogenic findings
    were noted in the fetuses examined (Kaziwara, 1971).


         Two groups of 13-18 female Japanese white rabbits received
    200 mg/kg or 2000 mg/kg bw IMP in their diet during days 6-18 of
    gestation. Sixteen female rabbits acted as controls. Four to five
    females of each group were delivered spontaneously and pups observed
    to day 30. All other dams were killed at day 29 of gestation. No
    significant effects were noted on implantation sites, number of
    live or dead fetuses, body weight of live fetuses and external
    abnormalities. The mortality of fetuses in the 0.2 g/kg group was
    lower than other groups. All groups showed some delay in ossification
    but no specific skeletal abnormalities were found which appeared to be

    due to IMP. Daily administration of 2000 mg/kg bw IMP by gavage had no
    adverse effect on pup development (Jojima et al., 1973).

    Acute toxicity
    Animal    Route             (mg/kg bw)       Reference
    Mouse     oral              12 000-14 000    Hara et al., 1966

              oral (male)       17 600           Ichimura & Muroi, 1973

              oral (female)     19 800           Ichimura & Muroi, 1973

              s.c.              6 200-7 000      Hara et al., 1966

              s.c. (male)       5 480            Ichimura & Muroi, 1973

              s.c. (female)     5 630            Ichimura & Muroi, 1973

              i.p.              5 400-5 600      Hara et al., 1966

              i.p. (male)       6 300            Ichimura & Muroi, 1973

              i.p. (female)     6 200            Ichimura & Muroi, 1973

              i.v.              3 300-3 900      Hara et al., 1966

              i.v. (male)       3 950            Ichimura & Muroi, 1973

              i.v. (female)     4 600            Ichimura & Muroi, 1973

    Rat       oral              16 000           Usui et al., 1971

              oral (male)       17 100           Ichimura & Muroi, 1973

              oral (female)     15 900           Ichimura & Muroi, 1973

              s.c. (male)       3 900            Ichimura & Muroi, 1973

              s.c. (female)     4 340            Ichimura & Muroi, 1973

              i.p. (male)       5 400            Ichimura & Muroi, 1973

              i.p. (female)     4 850            Ichimura & Muroi, 1973

              i.v. (male)       2 730            Ichimura & Muroi, 1973

              i.v. (female)     2 870            Ichimura & Muroi, 1973

    Short-term studies


         Eight groups of 10 male rats received daily in their diet either
    0.10, 100 or 1000 mg/kg bw of naturally derived or synthetically
    prepared IMP for 90 days. No adverse effects were noted on weight
    gain, organ weights, haematological parameters and histopathologically
    (Hara et al., 1966).

         In another experiment three groups of 10 male rats, given 0%,
    0.1% or 1% of IMP in their diet for three and six months, showed no
    significant abnormalities regarding their behaviour, body weight gain,
    food intake, haematology, urinalysis, macroscopic and histological
    findings (Usui et al., 1971).

         A further six months study in one control and four treatment
    groups each of eight male and eight female Sprague-Dawley rats at
    levels of 0%, 0.5%, 1.0%, 2.0% and 4.0% during 12 weeks followed by
    levels of 0%, 0.75%, 1.5%, 3.0% and 6.0% from week 13 to 25 showed no
    significant abnormalities in any treatment group with regard to
    behaviour, body weight gain, food intake, haematology and urinalysis.
    Some animals in higher dosage groups showed renal medullary
    calcification. Organ weights were normal but the relative mean weight
    of kidney and spleen in the 6% groups were significantly raised
    (Yonetani et al., 1973).

         In another experiment, six male and six female Sprague-Dawley
    rats were given 0%, 1%, 4% and 8% IMP in the diet for 52 weeks. The
    only adverse effects noted were slight depression of body weight gain
    of the 8% groups. More renal calcifications were found in the 4% and
    8% females compared with others, probably related to urine osmolarity.
    The 8% males and 2% and 8% females showed more severe nephrosis than
    the others (Yonetani et al., 1973).


         Two groups of one male and one female beagle were given 3.6-3.9%
    or 8% of IMP for four to six weeks without any adverse effects (Noel
    et al., 1971).

    Long-term studies


         Five groups of 14 male and 14 female Sprague-Dawley rats were
    given for 95 weeks 0%, 1%, 2%, 4% and 8% IMP in their diet. No
    significant changes were seen in behaviour, body weight gain, food
    intake, haematology, blood chemistry, urinalysis, histopathology or
    mortality (Yonetani et al., 1973).


         One control and three test groups each of four male and four
    female beagles were given 0, 0.5, 1 and 2 g/kg IMP in their diet for
    two years. No significant abnormalities were found clinically in body
    weight gain, food consumption or ophthalmoscopy. Haematology,
    biochemistry and urinalysis were normal. Dogs on 2 g/kg/day had
    significantly raised allantoin levels in the serum but these were not
    dose related. Exhaustive histopathology showed no significant
    abnormalities (Rivett et al., 1973).


         Three healthy volunteers were given 1, 1.5, 2 and 2.5 g IMP for
    seven consecutive days on a constant purine diet. Serum uric acid and
    urinary uric acid excretion doubled without signs of ill effects
    (Kojima, 1973).


         Inosinates, guanylates and ribonuoleotides are substances
    normally present in all tissues and their role in purine metabolism as
    well as their breakdown in the majority of mammals, but not man, to
    uric acid and allantoin is well known. The various products have been
    studied adequately in long-term, reproduction and teratology tests.
    Ingestion of large amounts of these compounds by man can increase the
    serum uric acid level and urinary uric acid excretion and this needs
    to be considered in relation to people with gouty diathesis and those
    taking uric-acid retaining diuretics. Hence, specific mention of the
    addition of these substances on the label may be indicated. The
    changes in dietary purine intake from the use of flavour enhancers are
    no greater than those likely to be occasioned by changes in
    consumption of those dietary items which are the main contributors of


         Acceptable daily intake not specified.*


    *    The statement "ADI not specified" means that, on the basis of the
    available data (toxicological, biochemical, and other), the total
    daily intake of the substance, arising from its use or uses at the
    levels necessary to achieve the desired effect and from its acceptable
    background in food, does not in the opinion of the Committee,
    represent a hazard to health. For this reason, and for the reasons
    stated in individual evaluations, the establishment of an acceptable
    daily intake (ADI) in mg/kg bw is not deemed necessary.


    Adachi, A. (1964) J. Physiol. Soc. Jap., 26, 347

    Flössner, O. (1934) Arch. Exptl. Path. Pharmakol., 174, 245

    Hara, S. et al. (1966) J. Tokyo Med. Coll., 24, 553

    Hashimoto, S. et al. (1973) Report from Life Sciences Laboratories,
         Ajinomoto Co., Japan

    Ichimura, M. & Muroi, K. (1973) Report from Life Sciences
         Laboratories, Ajinomoto Co., Japan

    Jojima, M. et al. (1973) Report from Life Sciences Laboratories,
         Ajinomoto Co., Japan

    Kaziwara, K., Mizutani, M. & Ihara, T. (1971) J. Takeda Res. Lab., 30
         (2), 314

    Kojima, K. (1973) Toxicology, 2 (In press)

    Noel, P. R. B. et al. (1971) Personal communication, HRC

    Ohara, V., Matsuzawa, Y. & Takeda, J. (1973) Report from Life Sciences
         Laboratories, Ajinomoto Co., Japan

    Rivett, K. F. et al. (1973) Unpublished data of HRC

    Sato, M. et al. (1965) Jap. J. Physiol., 15, 53

    Usui, T. et al. (1971) J. Takeda Res. Lab., 30 (3), 614

    Versprille, A. (1966) Arch. Ges. Physiol., 291, 261

    Yabo, S. (1964) Folia Pharmacol. Japon., 60, 194

    Yonetani, S. et al. (1973) Unpublished data

    See Also:
       Toxicological Abbreviations