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 µg 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.