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
L(+) AND DL - TARTARIC ACID
Explanation
Tartaric acid and its potassium, potassium-sodium and sodium
salts have been evaluated for acceptable daily intake by the Joint
FAO/WHO Expert Committee on Food Additives (see Annex I, Ref. Nos. 6,
7, 8 and 33) in 1961, 1963, 1964 and 1973.
The previous monographs have been expanded and are reproduced
below.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
L(+)-tartaric acid was reported to be inert in the human body
(Finkle, 1933).
When taken by mouth, only about 20% of ingested tartrate is
eliminated in the urine; the remainder is not absorbed as such since
it is destroyed in the intestinal tract by bacterial action (Underhill
et al., 1931; Finkle, 1933).
Contrary to the two above-mentioned studies a study has been
published where the percentages of both L(+) and D(-)-tartarte acids
eliminated in urine after intramuscular injection to one man were only
slightly greater than that after oral administration (Bauer and
Pearson, 1957).
The excretion of L(+)-tartaric acid in the urine after p.o.
administration was investigated in the rat, guinea-pig, dog and
rabbit. In the rat 68% (61-85) of a 400 mg/kg bw dose was recovered.
In the guinea-pig 13-27% of the dose was recovered from doses ranging
from 100 to 800 mg/kg bw. In the dog doses less than 600 mg/kg bw were
totally excreted in the urine (83-100%), but with higher doses
(600-1500 mg/kg) the recovery diminished to 50-60% and was associated
with slight renal changes. In the rabbit 90-99% of a dose of 50 mg/kg
bw was recovered. When the dose was raised to 100, 200 and 300 mg/kg
bw 21-23%, 15-26% and 2-3% were found in urine, respectively.
Histological studies revealed an increasing degree of kidney damage in
parallel with the decreasing excretion (Underhill et al., 1931).
Sodium tartrate in daily doses of up to 10 or even 20 g has been
used in medical practice as a laxative. It has been tested for this
action in a clinical study involving the application of daily doses of
10 g of sodium tartrate to 26 patients for an average of 11.8 doses,
giving laxative responses in 66% of the subjects. The only side-
effects noticed were nausea or vomiting (1.6%) and abdominal cramps
(2.1%) (Gold and Zahm, 1943). Following a single oral dose of
400 mg/kg monosodium (14C) L(+) tartrate to rats, 70% of the
radioactivity was excreted in urine, 16% in expired air and 14% in the
faeces within 48 hours. Most of the labelled material was excreted by
eight hours, the half-life for elimination from urine being 4.6 and
4.8 hours in male and female rats respectively. Comparison with
intravenous administration indicated that the portion of radioactivity
expired resulted from metabolism of the tartrate salt to 14Co2 by
the rat, about half of which occurred in the gut (HRC, 1975).
With monosodium (14C) L(+) tartrate given at a daily dose of
2.73 g/kg for seven consecutive days, the concentration of label in
blood and bone was maximal one hour after administration of the last
dose. Half-lives for elimination were 5.9 and nine days respectively
for blood and bone. By contrast, peak label concentrations in blood
and bone following the same dose of monosodiom (14C)DL(-) tartrate
occurred at three and 12 hours respectively while the half-lives were
6.5 and 2.5 days respectively for these organs. Labelled material in
bone was not associated with the mineralized fraction. Repeated doses
of 2.73 g/kg for seven days of monosodium (14C)DL(-) tartrate to rats
produced an increased kidney/body weight ratio compared to controls
while monosodium (14C)L(+)-tartrate produced no such change.
Autoradiographic studies demonstrated that after repeated oral
administration of monosodium (14C)DL-tartrate, radioactivity was
associated with the gastrointestinal tract, liver, kidneys and bone
during 24 hours; after 48 hours and eight days radioactivity was
associated only with bone and with granular deposits in the kidneys
(HRC, 1975).
TOXICOLOGICAL STUDIES
Reproductive and teratology studies
Teratology studies have been conducted in rats, mice, hamsters
and rabbits. Tartaric acid administered during the period of
organogenesis did not produce terata in either soft or skeletal
tissues of the highest dose tested which was hamsters, 225 mg/kg/day -
five days; rabbits, 215 mg/kg/day - 13 days; rats, 181 mg/kg/day - 10
days; mouse, 274 mg/kg/day - 10 days. Likewise no effects were noted
on nidation or on maternal or foetal survival rats (FDRL, 1973).
Acute toxicity
In the mouse, the LD50 of the sodium salt administered by mouth
was found to be 4360 mg/kg bw (Locke et al., 1942).
Tartaric acid administered by stomach tube in a dose of
5000 mg/kg was fatal to a dog (Sourkes and Koppanyi, 1950).
Three out of seven male rabbits died following oral
administration of disodium tartrate in an average dose of 5290 mg/kg;
while six male rabbits survived an average oral dose of 3680 mg/kg
(Locke et al., 1942). Renal damage has been observed only after the
intravenous administration of tartaric acid in doses of 0.2-0.3 g in
rabbits and rats (Bodansky et al., 1942; Gold and Zahm, 1943).
A fatal case of tubular nephropathy in man following accidental
ingestion of 30 g tartaric acid has been reported (Robertson and
Lönnell, 1968).
Short-term studies
Cat
Sodium tartrate was injected subcutaneously three times a week
for a total of 45 doses to two, one, two and two cats in doses of 0,
50, 75 and 100 mg/kg, respectively. The weights of the kidneys were
essentially the same for the treated and the control groups, and the
kidneys appeared similar on gross examination. The kidneys of four
animals were examined histologically. The sections of the two control
animals were normal, while those of the two animals on the 100 mg/kg
dose level showed considerable tubular degeneration (Gold and Zahm,
1943).
Dog
Tartaric acid was administered in daily oral doses of 990 mg/kg
bw to each of four dogs for 90-114 days. Casts appeared in the urine
of three dogs; the blood chemistry remained normal except in one dog
in which azotaemia developed with death in 90 days. Weight changes
varied from a weight gain of 30% to a loss of 32% (Krop and Gold,
1945).
Rabbit
Three rabbits survived 17 consecutive daily feedings of disodium
tartrate in an average dosage of 1150 mg/kg; whereas, average dosages
of 3680 mg/kg killed three out of six rabbits in six to 19 consecutive
daily feedings (Locke et al., 1942).
A study in which 15 male New Zealand rabbits were fed 7.7% sodium
tartrate in the diet for 22 weeks produced no evidence of toxicity
either in terms of body and organ weight (testes and thyroid) changes
or pathology (Packman et al., 1963).
Long-term studies
Rat
Groups of 24 rats (12 of each sex) were fed diets containing
0.1%, 0.5%, 0.8% and 1.2% of tartaric acid for a period of two years.
A group of 48 rats served as controls. No significant toxic effects
were observed in any of the groups as determined by growth rate (for
the first year), mortality throughout the experiment, and gross and
microscopic findings at the end of the two-year period. An
exceptionally thorough microscopic pathological examination was
carried out (Fitzhugh and Nelson, 1947).
Groups of 35 male and 35 female Sprague-Dawley rats were
administered diets containing 0, 2.56, 4.22, 6.02 or 7.68% monosodium
L(+) tartrate for 104 weeks. A dosage related reduction in body weight
gain, food intake and efficiency of food utilization recorded in
treated rats during the first 26 weeks of treatment. Thereafter, rats
receiving 2.56% had body weight gains and food intake values similar
to those of controls. Other treated rats continued to show body weight
gains and food intake values which were lower than those of the
controls. A treatment related reduction in mortality incidence was
recorded which was probably associated with the reduced food intake.
Urinalysis, haematology, blood chemistry and organ weight data
revealed no adverse reactions to treatment with monosodium L(+)
tartrate. Histopathology revealed no evidence of treatment related
change, and in particular, there was no indication of an untoward
effect on the spontaneous tumour profile of the rat (HRC, 1976).
REFERENCES
Bauer, C. W. and Pearson, R. W. (1957) J. Amer. Pharm. Ass.
Sci. Ed., 46, 575-578
Bodansky, O., Gold, H. and Zahm, W. (1942) J. Amer. Pharm. Ass.
Sci. Ed., 31, 1
Finkle, P. (1933) J. Biol. Chem., 100, 349
Fitzhugh, O. G. and Nelson, A. A. (1947) J. Amer. Pharm. Ass.
Sci. Ed., 36, 217
Gold, R. and Zahm, W. (1943) J. Amer. Pharm. Ass. Sci. Ed., 32,
173
Krop, S. and Gold, H. (1945) J. Amer. Pharm. Ass. Sci. Ed., 34, 86
Locke, A., Locke, R. B., Schlesinger, H. and Carr, H. (1942)
J. Amer. Pharm. Ass. Sci. Ed., 31, 12
Packman, E. W., Abbott, D. D. and Harrisson, J. W. E. (1963)
Toxicol. and Appl. Pharmacol., 5, 163-167
Robertson, B. and Lönnell, L. (1968) Act. path. microb. Scand.,
74, 305-310
Sourkes, T. L. and Koppanyi, T. (1950) J. Amer. Pharm. Ass.
Sci. Ed., 39, 275
Underhill, F. P., Leonard, C. S., Gross, E.G. and Joleski, T. C.
(1931) J. Pharmacol. Exp. Ther., 43, 359
Unpublished reports (1973) Food and Drug Research Laboratories Inc.
Unpublished report (1975) Huntingdon Research Centre
Unpublished report (1976) Huntingdon Research Centre
See Also:
Toxicological Abbreviations