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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    WORLD HEALTH ORGANIZATION





    SAFETY EVALUATION OF CERTAIN FOOD
    ADDITIVES AND CONTAMINANTS



    WHO FOOD ADDITIVES SERIES: 44





    Prepared by the Fifty-third meeting of the Joint FAO/WHO
    Expert Committee on Food Additives (JECFA)





    World Health Organization, Geneva, 2000
    IPCS - International Programme on Chemical Safety


    SODIUM SULFATE

    First draft prepared by Dr J.B. Greig

    Joint Food Safety & Standards Group, Department of Health, London,
    United Kingdom

    Explanation
    Biological data
         Renal clearance of the sulfate anion
         Toxicological studies
              Long-term studies
              Developmental toxicity
         Observations in humans
              General observations
              Occupational exposure
              Use of purgative preparations
                   Clinical trials
                   Case reports
    Comments
    Evaluation
    References

    1.  EXPLANATION

         Sodium sulfate has not been evaluated previously by the
    Committee. The sulfate anion was evaluated at the twenty-ninth meeting
    (Annex 1, reference 70), when an ADI 'not specified' was established,
    since sulfate is a natural constituent of food and is a product of
    sulfur metabolism in animals. Sodium sulfate was not specifically
    included in that ADI because no information was available to indicate
    that it was being manufactured or used as a food-grade material. It
    was evaluated at the present meeting at the request of the Codex
    Committee on Food Additives and Contaminants because it is being
    considered for inclusion in the draft General Standard for Food
    Additives.

         The Committee were unaware of any data on the dietary intake of
    sodium sulfate in human populations.

    2.  BIOLOGICAL DATA

    2.1  Renal clearance of the sulfate anion

         The renal clearance of the sulfate ion was measured in a
    cross-over clinical trial in six men and two women, aged 26-35,
    weighing 45-98 kg, and with an estimated body surface area of 1.4-2.2
    m2. On different, randomized study days at least four days apart,
    1-2 h after a light breakfast (hour 0), the subjects drank either 100
    ml water or a solution of 4.5 g sodium sulfate decahydrate in 100 ml

    water. This dose was repeated at hour 1, at which time the subjects
    emptied their bladders. Urine was then collected from hour 1 to hour
    3, and a blood sample was taken at hour 2.

         The serum concentration of sulfate at hour 2 and the 2-h urinary
    excretion of sulfate anion were both statistically significantly
    increased after the sulfate dose: mean  SD, 0.51  0.05 vs 0.41 
    0.04 mmol/L and 2.4  0.87 vs 1.6  0.46 mmol/L  73 m2 body surface
    area. The renal clearance of sulfate after the sulfate dose was
    greater than that after water, but the difference was not
    statistically significant. The authors also reported, with no details,
    that in a separate experiment, a 6-g oral dose of ascorbic acid had no
    effect on the urinary excretion of endogenous inorganic sulfate over
    12 h (Morris & Levy, 1983).

         In another randomized, cross-over clinical trial from the same
    laboratory, eight healthy men aged 23-26 and weighing 70-100 kg
    received 4.5 g of sodium sulfate as the decahydrate in water at 0, 2,
    4, and 6 h and 10 g activated charcoal suspended in water at hour 0,
    separately or in combination, after treatment with acetaminophen. When
    sodium sulfate was included in the treatment, the mean quantity of
    acetaminophen sulfate excreted in the urine increased but the
    difference from the treatment without sodium sulfate did not achieve
    statistical significance. The increase in the 24-h urinary excretion
    of sulfate anion was statistically significant, whether activated
    charcoal was included in the treatment or not (Galinsky & Levy, 1984).

    2.2  Toxicological studies

    2.2.1  Long-term studies

         Mice

         In a poorly reported study, 50 male and 50 female Swiss albino
    mice aged six weeks received 4-(hydroxymethyl)benzenediazonium sulfate
    by subcutaneous injection weekly for 26 weeks with 31 g of sodium
    sulfate dissolved in 0.01 ml of 0.9% saline. The mice were then kept
    for life. Tumours of the skin and subcutis were described as occurring
    at incidences similar to those of untreated laboratory historical
    controls; however, although tumours also developed in other tissues no
    similar statement was made (Toth, 1987).

    2.2.2  Developmental toxicity

         Mice

         As part of a study of the teratogenicity of morphine sulfate and
    other pharmacological agents, groups of pregnant CF-1 albino mice were
    injected subcutaneously on gestation day 8 or 9 with sodium sulfate at
    60 mg/kg bw given as 10 mg/ml in water. Examination of the excised

    fetuses revealed some statistically significant differences from
    saline-treated controls, but none of the measured parameters was
    consistently affected. Although skeletal abnormalities were observed
    in both groups, the difference seen from saline controls after dosing
    on day 9 of gestation was not significant, and the anomalies did not
    appear to involve fusions of the axial skeleton (Arcuri & Gautieri,
    1973).

         Sodium sulfate was included in a test of a method for rapid
    assessment of teratogenicity. Pregnant ICR/SIM mice were given a
    saturated aqueous solution of sodium sulfate orally by gavage to
    deliver a dose of 2800 mg/kg bw per day on days 8-12 of gestation. No
    maternal deaths occurred and the average maternal weight gain during
    the treatment period was not significantly different from that of
    water-treated controls. Twenty-four litters were delivered alive, and
    none were resorbed. The mean numbers of neonates delivered alive and
    dead in each litter and the survival of neonates on day 3 were not
    statistically significantly different from those of controls. Neonatal
    body weights on days 1 and 3 and body-weight gain were recorded; only
    body weight on day 1 was statistically significantly greater than that
    of controls (Seidenberg et al., 1986).

    2.3  Observations in humans

    2.3.1  General observations

         Sodium sulfate decahydrate is listed in the  British
     Pharmacopoeia as having the action and use of a laxative, and it is
    recorded as complying with the requirements of the third edition of
    the  European  Pharmacopoeia (Department of Health, 1993, 1996).
    Sodium sulfate decahydrate and its anhydrous salt are listed in
     Martindale's  Pharmacopoeia, and the laxative use is noted; another
    medical use recorded is in the treatment of severe hypercalcaemia, in
    which it is given by slow intravenous administration of a 3.9% aqueous
    solution. It is also used as a diluent for food colours (Reynolds,
    1996).

    2.3.2  Occupational exposure

         A group of 119 workers in five sodium sulfate surface mines in
    Saskatchewan, Canada (selection criteria and response rate not
    stated) were studied. There was no control group. The workers were
    aged 17-58 years, and since the values for lung function were compared
    with those reported for men, it can be assumed that they were male.
    The concentrations of sodium sulfate dust in various work areas were
    reported to be 5, 40, and 150 mg/m3, but although some consideration
    was given to the extent and duration of exposure there was no
    stratification by integrated measures of exposure  time. Worker were
    classified as having had more ( n = 42) or less ( n = 77) than 10
    years of exposure. The workers were screened for lung disease,

    hypertension, oedema, calcium tetany, anaemia, dermatitis, perforation
    of the nasal septum, and frequent or persistent diarrhoea. Serum was
    analysed for calcium, sodium, and potassium cations, chloride and
    sulfate anions, and carbon dioxide. Urine was analysed for sulfate
    content. 

         The physical parameters measured, including serum sulfate,
    calcium, and serum electrolytes, were generally within the normal
    range of values. Erythema or hyperaemia of the nasal mucosa was seen
    in 24 subjects, and exposure to sodium sulfate dust was associated
    with nasal irritation followed by a runny nose. No obvious association
    with extent of exposure was seen for six workers who had below-normal
    values for lung function, and some of these workers were heavy
    smokers. There was no statistically significant difference between
    workers with more and those with less than 10 years of exposure with
    respect to lung function. The serum sulfate concentration of one
    worker was above the normal range. Urinary excretion of sulfate was
    0.90-4.9 g/L, and 30% of the workers excreted more than 3 g/L. Since
    there was no association with duration of exposure, the authors
    suggested that these high values could be attributed to recent
    exposure (Kelada & Euinton, 1978).

    2.3.3  Use of purgative preparations

    2.3.3.1  Clinical trials

         A prospective study was carried out on the basis of responses to
    a questionnaire about use at home of two bowel-cleansing preparations,
    sodium picosulfate and a polyethylene glycol preparation containing 40
    mmol/L of sodium sulfate. At follow-up after three months to detect
    any serious adverse effects, 165 patients (94% male) were recruited
    into the study, 82 of whom (mean age, 60 years; range, 22-86) had
    taken the polyethylene glycol preparation. Of these, eight had failed
    to take the full 4 L, 12 reported faecal incontinence, and 21 reported
    sleep disturbances. A statistically significant greater number of
    complaints from younger patients about taste disturbance, nausea,
    fullness, and cramp was not attributed specifically to either
    preparation (Heymann et al., 1996).

         In the study of the renal clearance of sodium sulfate described
    in section 2.1.1, administration of two doses of 4.5 g sodium sulfate
    decahydrate in 100 ml water at an interval of 1 h had no adverse
    effects except for occasional loose stools (Morris & Levy, 1983).
    Similarly, in another study from the same laboratory, only a few
    instances of loose stools were reported by persons who took four doses
    of an aqueous solution of 4.5 g sodium sulfate decahydrate (Galinsky &
    Levy, 1984).

    2.3.3.2  Case reports

         A 39-year-old woman who had attempted suicide by taking 40 g of
    barium carbonate was treated after gastric lavage with 60 g of sodium
    sulfate administered through a nasogastric tube and 2.5 g of magnesium
    sulfate intravenously. The subsequent development of progressive renal
    insufficiency was suggested to have been caused by precipitation of
    barium sulfate in the renal tubules (Phelan et al., 1984).

         A 45-year old woman with a history of coronary heart disease,
    thoracic aortic aneurysm, and multiple myocardial infarcts experienced
    exacerbation of her congestive heart failure after ingestion of a
    bowel preparation containing 240 g polyethylene glycol 3350, 23 g
    sodium sulfate, 6.7 g sodium bicarbonate, 5.9 g sodium chloride, and 3
    g potassium chloride reconstituted in 4 L of water and drunk at a rate
    of 240 ml every 10 min (Granberry et al., 1995).

         An 8.5-year-old girl with cystic fibrosis and associated
    disturbance of liver function became drowsy and had a hypoglycaemic
    convulsion after she ingested 1.2 L of a bowel-cleansing preparation
    based on polyethylene glycol 4000 and containing 40 mmol/L sodium
    sulfate over a period of 1 h (Shah et al., 1994).

    3.  COMMENTS

         The Committee considered that the results of the published
    studies in experimental animals do not raise concern about the
    toxicity of sodium sulfate. The compound has a laxative action, which
    is the basis for its clinical use. The minor adverse effects reported
    after use of ingested purgative preparations containing sodium sulfate
    may not be due to the sodium sulfate itself.

    4.  EVALUATION

         In the absence of any evidence of toxicity, the Committee
    allocated a temporary ADI 'not specified'1 in line with the
    principles established at its twenty-ninth meeting. The ADI was made
    temporary because no information was available on the functional
    effect and actual uses of sodium sulfate in foods. This information is
    required for evaluation in 2001.

                  

    1 ADI 'not specified' is a term applicable to a food component of
    very low toxicity which, on the basis of the available chemical,
    biological, toxicological, and other data, the total dietary intake of
    the substance arising from its use 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 those stated in the evaluation, the
    establishment of an ADI expressed in numerical form is deemed
    unnecessary.

    5.  REFERENCES

    Arcuri, P.A. & Gautieri, R.F. (1973) Morphine-induced fetal
    malformations. III. Possible mechanisms of action.  J. Pharm. Sci.,
    62, 1626-1634.

    Department of Health, Scottish Home & Health Department, Welsh Office
    & Department of Health and Social Security Northern Ireland (1993)
     British Pharmacopoeia, London, Her Majesty's Stationery Office

    Galinsky, R.E. & Levy, G. (1984) Evaluation of activated
    charcoal-sodium sulfate combination for inhibition of acetaminophen
    absorption and repletion of inorganic sulfate.  Clin. Toxicol., 22,
    21-30.

    Granberry, M.C., White, L.M. & Gardner, S.F. (1995) Exacerbation of
    congestive heart failure after administration of polyethylene
    glycol-electrolyte lavage solution.  Ann. Pharmacother., 29,
    1232-1235.

    Heymann, T.D., Chopra, K., Nunn, E., Coulter, L., Westaby, D. &
    Murray-Lyon, I.M. (1996) Bowel preparation at home: Prospective study
    of adverse effects in elderly people.  Br. Med. J., 313, 727-728.

    Kelada, F. & Euinton, L.E. (1978) Health effects of long-term exposure
    to sodium sulfate dust.  J. Occup. Med., 20, 812-814.

    Morris, M.E. & Levy, G. (1983) Serum concentration and renal excretion
    by normal adults of inorganic sulfate after acetaminophen, ascorbic
    acid, or sodium sulfate.  Clin. Pharmacol. Ther., 33, 529-536.

    Phelan, D.M., Hagley, S.R. & Guerin, M.D. (1984) Is hypokalaemia the
    cause of paralysis in barium poisoning?  Br. Med. J., 289, 882.

    Reynolds, J.E.F., ed. (1996)  Martindale--The Extra Pharmacopoeia,
    31st Ed., London, The Royal Pharmaceutical Society of Great Britain.

    Seidenberg, J.A., Anderson, D.G. & Becker, R.A. (1986) Validation of
    an in vivo developmental toxicity screen in the mouse.  Teratog.
     Carcinog. Mutag., 6, 361-374.

    Shah, A., Madge, S., Dinwiddie, R. & Habibi, P. (1994) Hypoglycaemia
    and Golytely in distal intestinal obstruction syndrome.  J. R. Soc.
     Med., 87, 109-110.

    Toth, B. (1987) Cancer induction by the sulfate form of
    4-(hydroxymethyl)benzene-diazonium ion of  Agaricus bisporus. 
     In vivo, 1, 39-42.
    


    See Also:
       Toxicological Abbreviations
       Sodium sulfate (ICSC)
       SODIUM SULFATE (JECFA Evaluation)
       Sodium sulfate (SIDS)