INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
WORLD HEALTH ORGANIZATION
TOXICOLOGICAL EVALUATION OF SOME
FOOD COLOURS, EMULSIFIERS, STABILIZERS,
ANTI-CAKING AGENTS AND CERTAIN
OTHER SUBSTANCES
FAO Nutrition Meetings Report Series
No. 46A WHO/FOOD ADD/70.36
The content of this document is the result of the deliberations of the
Joint FAO/WHO Expert Committee on Food Additives which met in Rome,
27 May - 4 June 19691
Food and Agriculture Organization of the United Nations
World Health Organization
1 Thirteenth report of the Joint FAO/WHO Expert Committee on Food
Additives, FAO Nutrition Meetings Report Series, in press;
Wld Hlth Org. techn. Rep. Ser., in press.
QUERCETIN AND QUERCITRON
Biological Data
Biochemical aspects
Twelve hours after oral administration of C14-labelled quercetin to
rats, 44 per cent. of the radioactivity was still found in the
intestinal tract and 15.1 per cent. was recovered in respiratory
carbon dioxide. Small amounts were found in the blood and kidney and
an appreciable amount in the lungs and in the wall of the
gastro-intestinal tract. No other organs contained detectable amounts
of radioactivity. The urine contained about 4 per cent. of the
administered activity (Petrakis et al., 1959).
In the urine radioactive phloroglucinolearboxylic acid, phloroglucinol
and protocatechuic acid could be identified in ether extracts of
lyophilized stomach and its contents. A fourth radioactive compound
not identified and a radioactive "quercetin-like" compound were also
noted. It was not unchanged quercetin. Incubation of quercetin with a
porcine gastric mucin gave the same results (Kallianos at al., 1959).
Following intraperitoneal injection of labelled quercetin, then
probably vanillic acid was found in the urine. Quercetin may possibly
be degraded in the rat by at least two metabolic pathways, but it was
found that Protocatechuic acid, phloroglucinolcarboxylic acid and
phloroglucinol were artefacts arising during the chemical extraction
procedures (Petrakis et al., 1959; Masri et al., 1959).
After oral administration of quercetin to rabbits, the following
substances were found in urine: 3,4-dihydroxyphenylacetic acid,
3-hydroxyphenylacetic acid and its glucuronide and
3-methoxy-4-hydroxyphenylacetic acid (Murray et al., 1954; Booth et
al., 1956). Protocatechuic acid has been found in rat kidney after
administration of the colour (Douglass & Hogan, 1958).
Quercetin and other flavonoids are inhibitors of catechol-0-methyl
transferase. This would account, at least in part, for raised amounts
of 3, 4-dihydroxyphenylacetic acid in the urine.
Acute toxicity
Animal Route LD50 Reference
per kg body-weight
rabbit i.v. 100 mg* (quercetin) 7
rabbit i.v. 270 mg* (quercitron) 7
given in two doses
* No toxic signs were seen.
Short-term studies
Rat. When 20 or 100 mg of commercial quercetin was given by stomach
tube to rats as a suspension, either in a single dose or in four daily
doses of 5 mg or 25 mg respectively, 50 per cent. of the animals
developed cataracts within ten weeks. No bilateral cataracts were
observed. Chromatographically pure quercetin did not cause cataracts
under similar conditions (Nakagawa et al, 1961).
Long-term studies
Rat. Seven groups of 10 weanling rats, 5 of each sex, were placed on
the following diets, 0, 0.25, 0.5 and 1.0 per cent. of quercetin or
quercitron, for 410 days. No evidence of abnormalities or injury as
judged by growth, food consumption, blood composition, organ weights
and histopathological examination could be found (Ambrose et al.,
1952).
Comments
The production of cataracts in rats with commercial quercetin was not
observed with the chromatographically pure compound and, consequently,
may be attributable to impurities. However, information on the
occurrence of toxic impurities in commercial samples of quercetin and
quercitron is required. The metabolic fate of this colour needs
elucidation. Adequate long-term studies in a rodent species and a
two-year study in a non-rodent mammalian species are required.
EVALUATION
Not possible on the data available.
REFERENCES
Ambrose, A. M., Robbins, D. J. & De Eds, F. (1952) J. Amer. Pharm.
Ass., 41, 119
Booth, A. N., Murray, C. W., Jones, F. T. & De Eds, F. (1956)
J. Biol. Chem., 223, 251
Douglass, C.D & Hogan, R. (1958) J. Biol. Chem., 230, 625
Kallianos, A. G., Petrakis, P. L., Shetlar, M. R. & Wender, S. H.
(1959) Arch. Biochem., 81, 430
Masri, M. S., Booth, A.N. & De Eds, F. (1959) Arch. Biochem., 85,
284
Murray, C. W., Booth, A. N., De Eds, F. & Jones., F. T. (1954)
J. Amer. Pharm. Ass., 43, 361
Nakagawa, Y., Shetlar, M. R. & Wender, S. H. (1961) Proc. Soc. exp.
Biol., 108, 401
Petrakis, P. L., Kallianos, A. G., Wender, S. H. & Shetlar, M. R.
(1959) Arch. Biochem., 85, 264