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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    WORLD HEALTH ORGANIZATION



    SUMMARY OF TOXICOLOGICAL DATA OF CERTAIN FOOD ADDITIVES



    WHO FOOD ADDITIVES SERIES NO. 12






    The data contained in this document were examined by the
    Joint FAO/WHO Expert Committee on Food Additives*
    Geneva, 18-27 April 1977




    Food and Agriculture Organization of the United Nations
    World Health Organization



    * Twenty-first Report of the Joint FAO/WHO Expert Committee on Food
    Additives, Geneva, 1977, WHO Technical Report Series No. 617

    ADIPIC ACID

    Explanation

         This substance has been evaluated for acceptable daily intake by
    the Joint FAO/WHO Expert Committee on Food Additives (see Annex I,
    Ref. Nos. 11 and 13) in 1965.

         The previous monograph has been expanded and is reproduced below.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

         Four young dogs were injected subcutaneously with 0.25 g adipic
    acid (sodium salt), twice daily, for a period of five days. Urine was
    collected during this period, and for three days following
    administration of the test compound. Approximately 50% of the adipic
    acid was recovered unchanged, from the urine (Flaschentrager, 1926).

         Rats were administered orally 2.43 g adipic acid/day for two
    successive days. Excretion of unchanged adipic acid in the urine,
    reached a maximum on the second day of administration of the test
    compound, and continued for three more days. Approximately 70% of the
    dose was recovered unchanged in the urine (Enders, 1941).

         Rats were fed 0.75 g adipic acid per day for a period of four
    weeks. Three days after removal of adipic acid from the diet the rats
    were sacrificed. No residues of adipic acid were detected in body
    lipids or bound to body protein (Enders, 1941).

         Rats which had been maintained for 20-25 weeks on diets
    containing high levels of adipic acid (400 or 800 mg/day), and rats
    which had not previously received dietary adipic acid, were
    administered orally a total dose of 5.6 or 11.2 g of adipic acid, over
    a period of 14 days. There was no significant difference in the amount
    of unchanged adipic acid excreted in the urine of the test groups, nor
    was there any indication of excretion of oxalic or succinic acid in
    urine, above normal background levels (Lang and Bartsch, 1953).

         Fasted rats were administered by gavage, 0.25 g of adipic acid.
    After four hours the rats were sacrificed and liver glycogen
    determined. No significant glycogen synthesis occurred (Stohr, 1939).

         Fasted rats fed 250 mg 1-14C or 2-14C adipic acid. The carboxyl
    group was oxidized more rapidly than the second carbon. About 70% of
    the administered 14C was respired as CO2, during the 24 hour period
    following administration of the test compound. Analysis of the urine
    showed the presence of 14C labelled urea, glutamic acid, -ketoadipic
    acid, citric acid and unchanged adipic acid. Tissues from sacrificed
    rats contained little residual 14C. The 14C-glycogen was only
    isolated from the liver, when conditions were used that favoured
    glycogen formation. Adipic acid appears to be metabolized by
     oxidation in the same manner as other fatty acids (Russoff et al.,
    1960).

         Administration of 50 g of adipic acid or its sodium salt to human
    subjects, did not result in an increased excretion of urinary oxalic
    acid (Kabelitz, 1943).

    TOXICOLOGICAL STUDIES

    Acute toxicity

                                                                        

                             LD50            References
    Animal    Route     mg/kg body weight
                                                                        

    Mice M    p.o.          1 900            Horn et al. (1957)
    Mice -    i.v.            680            Horn et al. (1957)
    Rat M     i.p.            275            Horn et al. (1957)
    Rat M     p.o.            940            Litton Bioneties (1974)
    Rat -     p.o.          5 050            Younger Lab. (1975)
                                                                        

    Short-term toxicity

    Rat

         Groups each of 17-20 female rats were maintained for four weeks
    on diets containing adipic acid, at dose levels equivalent to 0, 10,
    20 or 40 mg/kg for 28 days. No adverse effect on growth was noted
    (Lang and Bartsch, 1953). Groups each of 18 male rats were maintained
    for five weeks on test diets, containing adipie acid, at dose levels
    equivalent to 0, 200, 400 or 800 mg/day. Growth was normal except in
    the high dose group in which there was a decreased growth rate (Lang
    and Bartsch, 1953).

         In another study groups of rats were maintained for 35 weeks on
    diets containing adipic acid so that daily dose was 0, 400 or 800 mg.
    During the first three weeks of the study, the animals in the high
    dose group, developed diarrhoea, and showed decreased growth rates.

    However recovery occurred at the end of this period, and by the end of
    the study, growth was similar in all groups. Pregnant females
    maintained in the high dose group produced normal litters and were
    able to suckle the offspring (Lang and Bartsch, 1953).

    Long-term toxicity

    Rat

         Groups each of 30 rats (Carworth Farm strain, 20 male, 10 female)
    were maintained on diets containing 0, 0.1, 1, 3, or 5% adipic acid,
    for a period of two years. Weight gains were normal for the .1 and 1%
    group, but significantly decreased for the 3 and 5% groups. Food
    consumption was normal in all groups except in the 5% group, where
    there was a consistent reduction in food intake. Survival of the test
    and control group animals was similar. At autopsy there were no
    significant differences in organ weight of test and control animals
    (kidney, spleen and heart of females, and brain, thyroid, lungs,
    heart, liver, spleen, kidneys, adrenals, and testis of males).
    Microscopic examination of the thyroid, lungs, heart, liver, spleen,
    kidneys, adrenals, stomach, small intestine, large intestine,
    pancreas, bone marrow, testes or ovaries, and uterus, did not show any
    compound related changes (Horn et al., 1957).

    Special studies

    Teratological studies

    Mice

         Groups of 20-24 mated female albino CD-1 mice were dosed with
    adipic acid daily from day 6 through day 15 of gestation. The dose
    levels used were 0, 2.6, 12.0, 56.0 and 263.0 mg/kg body weight. Body
    weights were recorded on days 0, 6, 11, 15 and 17 of gestatton. On day
    17 all dams were subjected to Caesarian section, and the numbers of
    implantation sites, resorption sites and live and dead foetuses
    recorded. The urogenital tract of each dam was examined. The body
    weight of live pups was recorded. All foetuses were examined
    externally, and one-third of each litter was examined for soft-tissue
    abnormalities and the remaining two-thirds for skeletal abnormalities.
    No compound related embryotoxic or teratogenic effects were observed
    (Food and Drug Research Labs., Inc., 1973).

    Rats

         Groups of 20-24 mated female albino rats (Wistar derived stock)
    were dosed daily with adipic acid at dose levels 0, 2.9, 13.0, 62.0
    and 288 mg/kg body weight, from day 6 through day 15 of gestation.
    Body weights were recorded on days 0, 6, 11, 15 and 20 of gestation.
    On day 20 all dams were subjected to Caesarian section, and the

    numbers of implantation sites, resorption sites and live and dead
    foetuses recorded. The urogenital tract of each dam was examined. The
    body weight of live pups was recorded. All females were examined
    externally, and one-third of each litter was examined for soft-tissue
    abnormalities and the remaining two-thirds for skeletal abnormalities.
    No compound related embryotoxic or teratogenic effects were observed
    (Food and Drug Research Labs., Inc., 1973).

    Hamsters

         Groups of 21-24 mated female golden hamsters were dosed daily
    with adipic acid at dose levels of 0, 2.0, 9.5, 44.0 and 205 mg/kg
    body weight from day 6 through 10 of gestation. Body weights were
    recorded on days 0, 8, 10 and 14 of gestation. On day 14 all dams were
    subjected to Caesarian section, and the number of implantation sites,
    resorption sites and live and dead foetuses recorded. The urogenital
    tract of each dam was examined. The body weight of live pups was
    recorded. All foetuses were examined externally, and one-third of each
    litter was examined for soft-tissue abnormalities and the remaining
    two-thirds for skeletal abnormalities. No compound related embryotoxic
    or teratogenic effects were observed (Food and Drug Research Labs.,
    Inc., 1973).

    Rabbits

         Groups each of 10-14 mated female rabbits (Dutch-belted) were
    dosed daily with adipic acid at dose levels 0, 2.5, 12.0, 54.0 and
    250 mg/kg body weight, from day 6 through day 18 of pregnancy. Body
    weights were recorded on days 0, 6, 12, 18 and 29 gestation. On day 29
    all dams were subjected to Caesarian section and the numbers of
    corpora lutea, implantation sites, resorption sites and live and dead
    foetuses recorded. The urogenital tract of each dam was examined.

         All foetuses were examined externally. The body weight of live
    pups was recorded. All foetuses were maintained in an incubator for 24
    hours, for the evaluation of neonatal survival. All surviving pups
    were sacrificed, examined for visceral abnormalities, and then for
    skeletal abnormalities. No compound related embryotoxic or teratogenic
    effect were observed (Food and Drug Research Labs., Inc., 1974).

    Mutagenicity studies

    Host mediated assay

    Acute study

         Adipic acid was administered orally to male mice (ICR random-
    bred) approximately 12 weeks old at three dose levels: 100, 2500 or
    5000 mg/kg. Positive controls and negative vehicle controls were

    included in the study. Salmonella TA-150, G-46 or Saccharamyces
    D3 were injected i.p. 30 minutes after administration of the test
    compound. Three hours after the injection, each animal was killed,
    their peritoneal cavities were asceptically exposed and washed with 2
    ml of sterile saline. As much fluid as possible was removed from the
    cavity. The peritoneal washings were diluted and plated in accordance
    with generally accepted procedures. The mutation frequency of bacteria
    and the yeast mitotic recombinants (recombinant frequency), for each
    of the samples was determined. There was no significant increase in
    mutant frequencies at the dose levels tested with Salmonella TA-1530
    and G-46. Tests with Sacchromyces D3 produced a dose-response
    effect on recombinant frequency (Litton Bionetics, 1974).

    Subacute study

         Adipic acid was administered orally to male mice (ICR random-
    bred) approximately 12 weeks old at three dose levels: 100, 2500 or
    5000 mg/kg/day for five consecutive days. Thirty minutes after the
    last dosing the animals were inoculated with the test organisms, and
    treated in the same fashion as those in the acute study. There was no
    significant increase in mutant frequencies with Salmonella TA-1530
    and G-46, nor significant recombinant count increase with the
    Saccharomyces.

    In vitro study

         Cultures of S. typhimurin (G-46 and TA-1530) were plated on
    appropriate media and adipic acid added to the plate. Serial dilutions
    of the cultures were made and the number of mutant colonies observed.
    Cultures of strain D3 Saccharomyces cells were shaken with adipic
    acid and plated, and the frequency of mutant colonies observed.
    Positive controls and negative vehicle controls were included in the
    study. There were no compound-related effects (Litton Bionetics,
    1974).

    In vivo cytogenetics

         For the acute study, adipic acid was administered
    intragastrically to groups each of 15 rats, at dose levels 0, 3.75,
    37.5 or 375 mg/kg. For the subacute study the dose levels of adiplc
    acid were 3.75, 37.5 or 375 mg/kg/day for five consecutive days.
    Negative and positive controls were included in the study; chromosomal
    abberations in the bone marrow cells of each group was evaluated. No
    detectable significant abberation of the bone marrow metaphase
    chromosomes was observed (Litton Bionetics, 1974).

    In vitro cytogenetics

         Human embryonic lung cultures (WI-38) were grown in the presence
    of adipic acid (2, 20 or 200 mcg/ml) as well as positive and negative
    control compounds. There was no significant abberatlon in the anaphase
    chromosomes that could be attributed to the presence of the test
    compound (Litton Bionetics, 1974).

    Dominant lethal studies

         Adipic acid was administered orally to groups each of 10 male
    rats at dose levels of 3.75, 37.5, 375 mg/kg body weight (one dose per
    the acute study) and in the subacute study 3.75, 37.5, 375 mg/kg body
    weight (one dose/day for five days). A negative control group received
    saline solution and a positive control group triethylene melamine
    (i.p.) 0.3 mg/kg. The males were sequentially mated with two females
    per week for eight weeks (seven weeks in the subacute study). The
    females were sacrificed 14 days after mating, and the uterus examined
    for corpora lutea early foetal deaths, late foetal deaths and total
    implantations for uterine horn. In the acute study a significant
    decrease in the average number of implantations at weeks 1 and 4, and
    corpora lutea at weeks 4 and 7 was observed in the intermediate dose
    level. Significant increases in pre-implantation losses were observed
    at week 1 for both the low and intermediate dose. In the subacute
    study only minor differences were observed between negative control
    and experimental groups (Litton Bionetics, 1974).

    REFERENCES

    Enders, A. (1941) Arch. Exptl. Pathol. Pharmocol., 197, 706-709

    Flaschentrager, B. (1926) Z. Physiol. Chem., 159, 297-308

    Food and Drug Research Labs., Inc. (1973) Report FDA 71-50 (Adipic
    Acid). Unpublished data submitted to USFDA

    Food and Drug Research Labs., Inc. (1974) Report 71-20 (Adipic Acid).
    Unpublished data submitted to USFDA

    Horn, H. J., Holland, E.G. and Hazleton, L. W. (1957) J. Agr. Food
    Chem., 5, 759-762

    Kabelitz, G. (1943) Klinische Wochemschrift, 22, 439-441

    Lang, K. and Bartsch, A. R. (1953) Biochemische Zeitschrift, 323,
    462-468

    Litton Bionetics (1974) LBI Project No. 2446. Unpublished data
    submitted to USFDA

    Russoff, I. I., Baldwin, R. R., Dominques, F. J., Monder, C., Ohan, W.
    J. and Thiessen, R., jr (1960) Tox. and Appl. Pharmacol., 2,
    316-330

    Stohr, R. (1939) Klinische Wochenschrift, 17, 1663-1664

    Younger Lab. (1975) Unpublished data submitted to Monsanto Company


    See Also:
       Toxicological Abbreviations
       Adipic acid (ICSC)
       Adipic acid (FAO Nutrition Meetings Report Series 40abc)
       ADIPIC ACID (JECFA Evaluation)
       Adipic Acid (SIDS)