1.1.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 117-39-5
• Deleted CAS Reg. No.: 73123-10-1; 74893-81-5
• Chem. Abstr. Name: 2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyran-4-one
• IUPAC Systematic Name: 3,3′,4′,5,7-Pentahydroxyflavone
• Synonyms: CI 75670; CI Natural Yellow 10; 3,3′,4′,5,7-pentahydroxyflavone; 3,4′,5,5′,7-pentahydroxyflavone; 3,5,7,3′,4′-pentahydroxyflavone; quercetine

1.1.2. Structural and molecular formulae and relative molecular mass

1.1.3. Chemical and physical properties of the pure substance

• (a) Description: Pale-yellow needles (dihydrate) (Budavari, 1996)
• (b) Boiling-point: Sublimes (Lide, 1997)
• (c) Melting-point: 316.5°C (Lide, 1997)
• (d) Solubility: Slightly soluble in water and diethyl ether; soluble in ethanol and acetone (Lide, 1997)
• (e) Conversion factor: mg/m³ = 12.36 × ppm

3.1. Oral administration

Rat: Groups of 15 male and 15 female Fischer 344 rats, six weeks of age, were given quercetin (purity, 99%) in the diet at a concentration of 0.1% for 540 days. All of the treated animals survived. The incidence of tumours in the treated groups was not statistically different from that in controls (Takanashi et al., 1983). [The Working Group noted the small numbers of animals, which made the study inadequate for evaluation.]

Groups of 50 male and 50 female Fischer 344/DuCrj rats, six weeks of age, were fed quercetin (purity, at least 99.4%) in the diet at concentrations of 0 (control), 1.25 or 5% for 104 weeks and were maintained for a further eight weeks without quercetin. The high dose was the maximum tolerated. At the end of the 112-week study, the survival rates for males were 56, 66 and 68% and those for females were 66, 62 and 72% for the three groups, respectively. No statistically significant increase in incidence of tumours was seen, but males at the high dose showed a significant increase in the incidence of non-neoplastic hyperplastic polyps of the caecum, and one adenoma and two adenocarcinomas of the caecum were found in males at this dose and two adenomas of the colon occurred in females (Ito et al., 1989).

Groups of 70 male and 70 female Fischer 344/N rats, seven weeks of age, were given quercetin (purity, > 95%; ellagic acid was the predominant impurity at 1.1–2.6%) in the diet at concentrations of 0, 1000, 10 000 or 40 000 mg/kg (ppm) for 104 weeks. Ten animals per group were killed at 6 and 15 months. The high dose approached the maximum tolerated. Treatment did not affect the survival of either male or female rats, but the decreased body-weight gain of animals at the high dose was attributed to quercetin. As shown in Table 1, males at the high-dose had an increased incidence of renal tubular tumours (three adenomas and one adenocarcinoma) with none in control males, but the increase did not achieve statistical significance. After step-sectioning, a total of nine renal tubular tumours were found in these animals, and the increase was statistically significant. The severity of spontaneous progressive nephropathy was exacerbated in male rats by exposure to quercetin (Dunnick & Hailey, 1992; National Toxicology Program, 1992).

Table 1

Incidences of primary renal tubular adenomas or carcinomas in Fischer 344 rats exposed to quercetin.

3.2. Administration with known carcinogens

Many new studies have been conducted in which quercetin was tested in various initiation–promotion regimens with various carcinogens, with variable results. Both enhancing and inhibiting activity were found.

Mouse: In a study of skin carcinogenesis in groups of 30 CD-1 mice, prior treatment with quercetin had no effect on initiation of tumours by benzo[a]pyrene (Chang et al., 1985). Quercetin given by intramuscular injection or in the diet was reported to enhance the carcinogenicity of 3-methylcholanthrene in C57BL/6 mice by significantly shortening the latency of sarcomas at the site of intramuscular injection of 3-methylcholanthrene (Ishikawa et al., 1985). When quercetin was tested as a potential initiator in a two-stage model of mouse skin carcinogenesis with 12-O-tetradecanoylphorbol 13-acetate (TPA) as the promoting agent, local application twice a week for five weeks induced two skin tumours in 1/21 mice after 47 weeks of TPA treatment. No skin tumour was produced with quercetin alone or with dimethyl sulfoxide plus TPA (Sato et al., 1987).

Dietary administration of quercetin has been shown in some studies to inhibit tumours, including azoxymethane-induced colonic tumours in mice (Deschner et al., 1991) and skin tumour formation in three models of skin carcinogenesis in mice when administered by topical application (Nishino et al., 1984; Khan et al., 1988, Mukhtar et al., 1988).

Rat: In a model of pancreatic carcinogenesis with N-methyl-N-nitrosourea as the carcinogen, quercetin significantly enhanced focal acinar-cell hyperplasia in rats of each sex and produced a non-significant increase in the incidence of carcinomas in situ (Barotto et al., 1998).

Quercetin did not enhance the bladder tumour incidence induced in rats by N-nitrosobutyl-N-(4-hydroxybutyl)amine (Fukushima et al., 1983; Hirose et al., 1983), mammary gland, ear-duct and forestomach tumours induced in rats by 7,12-dimethylbenz[a]anthracene (DMBA) (Hirose et al., 1988) or intestinal carcinogenesis induced in rats by methylazoxymethanol acetate (Kato et al., 1984). In models of colon and mammary carcinogenesis, quercetin inhibited the development of aberrant crypt foci in rat colon (Matsukawa et al., 1997) and the incidence of DMBA- and N-methyl-N-nitrosourea-induced mammary cancer (Verma et al., 1988).

Hamster: Administration of 3% quercetin in the diet of male Syrian hamsters increased the mean number of renal tumour masses and the incidence of metastases after subcutaneous implants of oestradiol (Zhu & Liehr, 1994). Quercetin inhibited DMBA-induced buccal pouch carcinogenesis in hamsters (Balasubramanian & Govindasamy, 1996).

4.1.1. Humans

After oral administration of a single dose of 4 g quercetin to four male and two female volunteers, neither quercetin nor its conjugates was detected in the blood or urine during the first 24 h; 53% of the dose was recovered in the faeces within 72 h. After a single intravenous injection of 100 mg quercetin to six volunteers, the blood plasma levels declined biphasically, with half-lives of 8.8 min and 2.4 h; protein binding exceeded 98%. In the urine, 0.65% of the intravenous dose was excreted as unchanged quercetin and 7.4% as a conjugate within 9 h; no further excretion occurred up to 24 h (Gugler et al., 1975).

One male and one female volunteer were given a diet containing quercetin glucosides (64.2 mg expressed as the aglycone). The mean peak plasma concentration of quercetin was 196 ng/mL which was reached 2.9 h after ingestion. The time-course of the plasma concentration of quercetin was biphasic, with half-lives of 3.8 h for the distribution phase and 16.8 h for the elimination phase. Quercetin was still present in plasma 48 h after ingestion (Hollman et al., 1996). Similar findings were made for nine other human subjects (Hollman et al., 1997). The authors suggested that this slow elimination rate would lead to accumulation in plasma with repeated ingestion.

The metabolites of quercetin flavonols identified in urine samples collected from two male volunteers who consumed their habitual diets for three days were 3,4-dihydroxyphenylacetic acid, meta-hydroxyphenylacetic acid, and 4-hydroxy-3-methoxyphenylacetic acid (Gross et al., 1996).

4.1.2. Experimental systems

Autoradiographic analysis of a fasted rat 3 h after administration of a single oral dose of 2.3 mg/kg bw [4-¹⁴C]quercetin showed that although most of the radiolabel remained in the digestive tract it also occurred in blood, liver, kidney, lung and ribs. After oral administration of 630 mg/kg bw of the labelled compound to rats, 34% of the radiolabel excreted within 24 h, expressed as a proportion of the dose, was expired carbon dioxide, 12% in bile and 9% in urine; within 48 h, 45% was recovered in the faeces. Approximately 60% of the radiolabel in the faeces was identified as unmetabolized quercetin. Sulfate and glucuronide conjugates of quercetin and of an unidentified flavonoid were found in bile and urine. Incubation of [4-¹⁴C]quercetin with rat caecal and colon contents in vitro under conditions that were probably anaerobic resulted in the release of 6% of the radiolabel as carbon dioxide (Ueno et al., 1983).

After oral administration of 0.5 g/kg bw quercetin to rabbits, the main urinary metabolites were 3,4-dihydroxyphenylacetic acid, 3-methoxy-4-hydroxyphenylacetic acid and 3-hydroxyphenylacetic acid (Booth et al., 1956).

Quercetin was rapidly metabolized by O-methylation in male Syrian hamsters (Harlan Sprague-Dawley) two to four months of age given an intraperitoneal injection of 50 or 500 mg/kg bw quercetin mixed in 50% glycerol:water. The major metabolite of quercetin in the ether extract of urine was identified as 3′-O-methylquercetin. A major portion of the 3′-O-methylquercetin eliminated in urine was conjugated by glucuronidation or sulfation. Only 2% of the total flavonoid content of the extract was unmetabolized quercetin. The rates of O-methylation of quercetin in vitro catalysed by porcine liver catechol-O-methyltransferase or cytosolic fractions of Syrian hamster kidney were about three orders of magnitude higher than the rates for endogenous catechols, such as catechol oestrogens and catecholamines (Zhu et al., 1994).

4.2.1. Humans

No data were available to the Working Group.

4.2.2. Experimental systems

The acute oral and subcutaneous LD₅₀ values of quercetin in the mouse are 160 and 100 mg/kg bw (Sullivan et al., 1951). Rabbits were unaffected by intravenous administration of 100 mg/kg bw or by diets containing 1% quercetin for 410 days (Ambrose et al., 1952).

Male and female Fischer 344 rats were given a diet containing 0, 1.25 or 5% quercetin for 104 weeks and then a normal diet for a further eight weeks (see section 3 for details), with average intakes for males and females, respectively, of 427 and 497 mg/kg bw per day for those consuming the 1.25% quercetin diet and 1926 and 2372 mg/kg bw per day for rats consuming the 5% diet. With 5% quercetin, the body weights of males and females at the high dose were decreased throughout the study. There were no treatment-ascribed effects on clinical signs, deaths or the results of urinalysis or haematology. Decreases in serum glucose concentration and increases in some relative organ weights were observed at the high dose, the latter being attributed to growth retardation. A higher incidence of hyperplastic polyps of the caecum was observed at the high dose in comparison with controls. No significant increase in adverse changes was observed in other organs (Ito et al., 1989).

Male and female Fischer 344 rats, seven weeks of age, were given quercetin in the diet at concentrations of 0, 1000, 10 000 or 40 000 mg/kg of diet (ppm) for two years (to provide estimated doses of approximately 40, 410 and 1900 mg/kg bw per day during the second year). Rats were necropsied after 6 and 15 months of treatment for interim evaluations. The body weights of animals at the high dose were reduced relative to those of controls during the last year of the study. The only treatment-related toxic lesions were detected microscopically at the 6- and 15-month evaluations and consisted of pigmentation of the superficial epithelium of the glandular stomach and the distal segments of the small intestine, the latter also being seen at two years. The authors noted that quercetin is a yellow compound, and adsorption of this chemical or a metabolite was probably the cause of the tissue pigmentation. After two years of quercetin administration, the incidence of hyperplasia of the renal tubular epithelium was increased, with mild exacerbation of chronic nephropathy in male rats (see section 3 for neoplastic effects). Male rats also had dose-related increases in the incidence of renal pelvic epithelial hyperplasia and of parathyroid gland hyperplasia, which are commonly observed in male rats with advanced nephropathy (Dunnick & Hailey, 1992).

Quercetin inhibits Na⁺-K⁺ ATPase in both plasma and mitochondrial membranes (Lang & Racker, 1974; Suolinna et al., 1975). Inhibition of glucose oxidation in neutrophils via the hexose monophosphate pathway and inhibition of uptake of 2-deoxyglucose were also reported (Long et al., 1981). Quercetin inhibited glycolysis in Erhlich ascites tumour cells, due probably to a lowering of the intracellular pH by inhibition of lactate efflux (Belt et al., 1979). Administration of 5–20 µg/mL quercetin caused pronounced inhibition of the growth of several cell lines (Suolinna et al., 1975). Liposome-encapsulated quercetin inhibited DNA synthesis in Ehrlich ascites tumour cells (Podhajcer et al., 1980).

Quercetin inhibited ethoxyresofurin O-deethylation by liver microsomes prepared from β-naphthoflavone-treated Long Evans rats, by 15% at a concentration of 10 nmol/L to 80% at 250 nmol/L (Sousa & Marletta, 1985); and it had a similar effect in microsomes prepared from 3-methylcholanthrene-treated Sprague-Dawley rats, causing 50% inhibition at a concentration of 15 µmol/L (Moon et al., 1998). Quercetin also inhibited ethoxyresorufin O-deethylase activity in human microsomes, causing 50% inhibition at 12 ± 6 µmol/L (Siess et al., 1995). Quercetin also inhibited para-nitroanisole demethylation and benzo[a]pyrene hydroxylation reactions of β-naphthoflavone-treated Long Evans rat microsomes, by 26% at a concentration of 0.25 µmol/L, 78% at 5 µmol/L, 32% at 0.1 µmol/L and 95% at 500 µmol/L (Sousa & Marletta, 1985). Hydroxylation of benzo[a]pyrene by a sample of human liver microsomes was also inhibited by quercetin, by 14% at a concentration of 0.005 mmol/L and 81% at 1 mmol/L (Buening et al., 1981). Quercetin was a potent uncoupler of P450 reactions, acting by dissociation of the reduced P450–oxygen complex, and increased the rate of hydrogen peroxide formation by almost twofold (Sousa & Marletta, 1985).

In liver nuclei isolated from male Sprague-Dawley rats, quercetin caused a concentration-dependent increase in DNA damage and lipid peroxidation and a concentration-dependent decrease in nuclear glutathione content and glutathione S-transferase activity (Sahu & Washington, 1991; Sahu & Gary, 1996).

Quercetin was reported to have 1% of the oestrogenic activity of oestradiol in HeLa cells transfected with the human oestrogen receptor and the pERE-TK-CAT reporter plasmid (Santti et al., 1997).

4.3.1. Humans

No data were available to the Working Group.

4.3.2. Experimental systems

Groups of 8–12 pregnant rats received 0, 2, 20, 200 or 2000 mg/kg bw quercetin on day 9 or on days 6–15 of gestation by oral gavage. No overt signs of toxicity were observed in the dams at any dose. Quercetin did not affect embryonic viability or morphology but fetal growth retardation was seen after exposure to 200 or 2000 mg/kg bw on day 9 and to 2 or 2000 mg/kg bw on days 9–15 (Wilhite, 1982).

4.4.1. Humans

No data were available to the Working Group.

4.4.2. Experimental systems (see Table 2 for references)

Table 2

Genetic and related effects of quercetin.

Quercetin induced DNA damage and SOS repair in bacterial cells. It did not induce differential toxicity in DNA repair-deficient strains of Samonella. It was mutagenic in several strains of Salmonella typhimurium and Escherichia coli in the absence of exogenous metabolic activation. In single studies, quercetin induced gene conversion but not gene mutation in Saccharomyces cerevisiae and induced sex-linked recessive lethal mutation in Drosophila melanogaster. In vitro, it caused DNA unwinding in rat liver nuclei and induced DNA single-strand breaks in mouse lymphoma L5178Y cells, but it did not induce unscheduled DNA synthesis in rat hepatocytes. Quercetin consistently induced gene mutation at the tk locus in mammalian cells in vitro, but hprt locus mutants were induced in only one of four studies. Sister chromatid exchange was induced in three of four studies in Chinese hamster cells in vitro, and chromosomal aberrations were induced in several Chinese hamster cell lines and in a human cell line in vitro. It induced cell transformation in mammalian cells. It induced sister chromatid exchange, micronuclei and chromosomal aberrations in human lymphocytes in vitro with and without exogenous metabolic activation. Urine and faecal extracts of rats treated with quercetin were mutagenic to Salmonella typhimurium TA98. Micronuclei were not induced by quercetin administered in vivo, either in bone-marrow cells of mice in four studies, in peripheral blood cells of mice in one study or in bone-marrow cells of rats in one study. Chromosomal aberrations were not induced in bone-marrow cells of rats treated in vivo in one study. Dominant lethal effects were not induced in either male mice or male rats in a single study.