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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    WORLD HEALTH ORGANIZATION



    TOXICOLOGICAL EVALUATION OF SOME
    FOOD COLOURS, ENZYMES, FLAVOUR
    ENHANCERS, THICKENING AGENTS, AND
    CERTAIN FOOD ADDITIVES



    WHO FOOD ADDITIVES SERIES 6







    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.

    CALCIUM AND SODIUM-5'-RIBONUCLEOTIDES

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

         The biochemistry of the constituent nucleotides has already been
    discussed and their relationship to purine biosynthesis and uric acid
    and allantoin formation in mammals is clear (Kojima, 1973).

         Mice given i.v. 500 mg/kg DSRN showed initial behavioural
    depression followed by excitation, no muscular relaxation, depressed
    rotating activity, did not have modified electroshock convulsions,
    decreased dose-dependency (200 and 500 mg/kg i.v.) the convulsive dose
    of metrazol. Doses of 50, 125 and 500 mg/kg i.v. all prolonged loss of
    righting reflex (Kojima, 1973). 10, 25 and 50 mg/kg DSRN i.v. in cats
    produced transient dose dependent hypotension and increased blood flow
    to hind limb. 10 mg/kg intra-arterially increased transiently blood
    flow to hind limbs without affecting ECG. Concentrations up to
    10-5 g/ml had no effect on isolated guinea-pig atrium, 10-4g/ml
    showed positive ino- and chronotropic effects. 100 mg/kg s.c. had no
    effect on intestinal transport in mice as shown by charcoal
    transportation. Concentrations below 10-4g/ml had no effect on
    isolated guinea-pig ileum regarding response to acetyl chlorine,
    histamineor barium chloride 100 mg/kg s.c. in rats had no effect on
    gastric juice secretion, pH or total acidity. 100 mg/kg s.c. in mice
    depressed salivary secretion. 100 mg/kg orally had no diuretic effects
    in rats. 500 mg/kg orally did not affect the analgesic response of
    mice and carrageenin oedema in rats (Kojima, 1973). Mice given i.v.
    500 mg/kg disodium 5'-ribonucleotide showed initial behavioural
    depression followed by excitation, no muscular relaxation, depressed
    rotating activity, did not have modified electroshock convulsions,
    decreased dose-dependency (200 and 500 mg/kg i.v.) the convulsive dose
    of metrazol. Doses of 50, 125 and 500 mg/kg i.v. all prolonged loss
    of righting reflex (Kojima, 1974). 10, 25 and 50 mg/kg disodium
    5'-ribonucleotide i.v. in cats produced transient dose dependent
    hypotension and increased blood flow to hind limb. 10 mg/kg
    intra-arterially increased transiently blood flow to hind limbs
    without affecting ECG. Concentrations up to 10 mg/l had no effect on
    isolated guinea-pig atrium, 100 mg/l showed positive ino- and
    chronotropic effects. 100 mg/kg s.c. had no effect on intestinal
    transport in mice as shown by charcoal transportation. Concentrations
    below 0.1 g/l had no effect on isolated guinea-pig ileum regarding
    response to acetyl choline, histamine or barium chloride. 100 mg/kg
    s.c. in rats had no effect on gastric juice secretion, pH or total
    acidity. 100 mg/kg s.c. in mice depressed salivary secretion,
    100 mg/kg orally had no diuretic effects in rats. 500 mg/kg orally did
    not affect the analgesic response of mice and carrageenan oedema in

    rats (Kojima, 1973). Three healthy volunteers (males) were given low
    purine diets containing 250-4 000 mg disodium 5'-ribonucleotide daily.
    The higher level raised the serum uric acid level and urinary uric
    acid output but the 2 g level did not raise serum uric acid level
    above the accepted normal range. No adverse effects were reported
    (Cooper et al., 1972).

    TOXICOLOGICAL STUDIES

    Special studies on reproduction

    Rat

         Four groups of 10 male and 20 females were given 0, 0.1%, 1% and
    2% DSRN daily in their diet over three generations. No adverse effects
    have been noted in parent animals as regards mortality, mating
    performances, body weight change, food consumption, pregnancy rate,
    duration of gestation and at autopsy. Litter parameters as assessed by
    loss, size, pup weights, pup mortality and incidence of abnormalities
    were unaffected by any dose level. Organ weights and skeletal staining
    and histology of F3 pups on 2% showed no evidence of treatment
    related effects (Palmer et al., 1971).

    Special studies on teratogenicity

    Mouse

         One group of 14 pregnant mice received daily 2 g/kg bw DSRN
    during the 8-13th day of pregnancy. No significant effects on the
    fetuses were noted (Kaziwara et al., 1971).

    Rat

         One group of 9 pregnant rats received daily 2 g/kg bw DSRN during
    days 9-15 of pregnancy. No significant effects on the fetuses were
    noted (Kaziwara et al., 1971).

    Monkey

         Two pregnant cynomolgus monkeys received daily 500 mg/kg bw DSRN
    and another three pregnant animals received daily 1000 mg/kg DSRN
    during days 21-31 of pregnancy. No significant effects were noted on
    fetuses (Kaziwara et al., 1971).

    Acute toxicity
                                                                        

                                  LD50
    Animal         Route          mg/kg bw            Reference
                                                                        

    Mouse          Oral and       10 000              Usui et al., 1971

    Rat            parenteral
                                                                        

    Short-term studies

    Rat

         Five groups of 10 male rats were given 0, 0.2%, 0.4%, 0.8% and 2%
    disodium 5'-ribonucleotide in their diet daily for six months. No
    significant abnormalities were seen regarding behaviour, body weight
    gain, food intake, haematology, urinalysis, macroscopic and
    histological findings (Usui et al., 1971).

    Dog

         Three groups of one male and one female beagle were given 2%, 5%
    and 10% of disodium 5'-ribonucleotide in their diet for 4-6 weeks
    without adverse effects (Noel et al., 1970).

    Long-term studies

    Rat

         Three groups of 10 male and 10 female rats each received 0, 1%
    and 2% DSRN in their diet daily for 24 months. No significant
    abnormalities were noted regarding behaviour, body weight gain, food
    intake, haematology, urinalysis, macroscopic and histological findings
    (Usui et al., 1971).

    Dog

         Four groups of four male and four female beagles received 0,
    0.1%, 1% and 2% DSRN in their diet daily for two years. No dog died
    nor were any significant abnormalities noted as regards body weight
    gain, haematology, clinical biochemistry, ophthalmoscopy and
    urinalysis. Terminal macroscopy, histology or organ weight studies
    showed no adverse effects (Rivett et al., 1971).

    OBSERVATIONS IN MAN

         Three healthy volunteers (males) were given low purine diets
    containing 250-4000 mg DSRN daily. The higher level raised the serum
    uric acid level and urinary uric acid output but the 2 g level did not
    raise serum uric acid level above the accepted range. No adverse
    effects were reported (Kojima, 1973).

    Comments:

         Inosinates, guanylates and ribonucleotides 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
    purine.

    EVALUATION

         Acceptable daily intake not specified1

    REFERENCES

    Cooper, A. J. et al. (1972) Huntingdon Research Centre, Unpublished
         report

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

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

              

    1  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.

    Noel et al. (1970) Personal Communication from HRC

    Palmer, A. K., Lovel, M. R. & Spicer, E. J. F. (1971) Report No.
         4554/71/710 by HRC to Takeda

    Rivett, K. F. et al. (1971) Report No. 4500/71/656 by HRC to Takeda

    Usui, T. et al. (1970) Personal communication from HRC


    See Also:
       Toxicological Abbreviations