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Toxicological information

Basic toxicokinetics

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Administrative data

basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference Type:
Intestinal Bacterial Metabolism of Rutin and its Relation to Mutagenesis
Kim D-H
Bibliographic source:
Arch.Pharm.Res. Vol. 19, No.1, pp. 41-45, 1996

Materials and methods

Objective of study:
Test guideline
no guideline followed
GLP compliance:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-oxo-4H-chromen-3-yl 6-O-(6-deoxy-alpha-L-mannopyranosyl)-beta-D-glucopyranoside
Test material form:
solid: particulate/powder

Test animals

other: SDD Wister
Details on test animals or test system and environmental conditions:
- Weight at study initiation: 230-300 g
- Diet: synthetic diet (44.1% wheat starch, 20% casein, 5% mineral mixture, 0.8% vitamin mixture and 0.1% choline chloride)
- Water: tap water ad libitum

Administration / exposure

Route of administration:
oral: feed
other: synthetic diet
Duration and frequency of treatment / exposure:
1 week
Doses / concentrationsopen allclose all
Dose / conc.:
25 mg/kg bw (total dose)
Dose / conc.:
50 mg/kg bw (total dose)
Dose / conc.:
100 mg/kg bw (total dose)
Dose / conc.:
150 mg/kg bw (total dose)
Dose / conc.:
250 mg/kg bw (total dose)
Dose / conc.:
500 mg/kg bw (total dose)
Dose / conc.:
1 000 mg/kg bw (total dose)
Dose / conc.:
1 250 mg/kg bw (total dose)
Dose / conc.:
1 500 mg/kg bw (total dose)
No. of animals per sex per dose / concentration:
Three to five rats were used for each group.
Control animals:
Details on study design:
Various concentrations of test item were orally administered to rats which were given the synthetic diet over a period of 1 week. The urine was collected at 24h intervals and analyzed by TLC.
On the other hand, Human intestinal bacteria were inoculated into 500 ml GAM broth containing 50mg test item, which was then incubated anaerobically at 37ºC for 5 days. 50 ml of the cultured broth was septically taken out at 12, 18, 24, 48, 72, 96 and 120h and extracted with EtOAc. This extract was assayed by TLC and Ames test (S.typhimurium TA98 and TA100).
Details on dosing and sampling:
- Tissues and body fluids sampled : urine
- Time and frequency of sampling: 24, 48 and 72h after administration of flavonoids.
- From how many animals: (samples pooled or not)
- Method type for identification: TLC)

Each urine was diluted 2-fold. Half of the urine was adjusted to pH2 with HCI and then extracted with ethylacetate. The other half of the urine was adjusted to 2N-HCI with 5N-HCI and the mixture was refluxed for 2hs at the boiling water bath. The resultant hydrolysate was then extracted with ethylacetate.

- Complete description: TLC (Developing solvents, CHCI3:MeOH=3 : 1).

Results and discussion

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
- Metabolites and mutagenicity on the urine of treated rats: From the urine of rats administered more than 1250 mg test item/kg body weight of rat, free quercetin was detected but the test item was not. If administered 150-1000 mg test item/kg rat, the free quercetin was not detected but by hydrolyzing the urine with 2N-HCI, the free quercetin was detected. However, in the case of administering less than 100 mg/kg, the hydrolysate of the urine was not detected and phenolic acid-like compounds were only detected.
The urine of rats administered more than 1250 mg/kg and the hydrolysate of the urine of rats adiminstered 150-1000 mg/kg were strongly mutagenic. However, the urine and its hydrolysate of rat treated with 100 mg/kg were not mutagenic.
- Metabolites of test item by human intestinal bacteria and theiir mutagenicity: The amount of quercetin was increased gradually with a corresponding decrease in the level of test item. Quercetin was increased for 12 h and then decreased gradually with a corresponding increase in the level of unidentified compounds. In the mutagenicity test, the revertants per plate of TA 98 were increased until 12 h and decreased thereafter. The sample cultured for 48hs was not mutagenic.
-Isolation and identification of the bacteria which degrade quercetin to phenolic acids: isolated the bacterium fissuring the Bringof quercetin or rutin from human feces was isolated (Q-05 Pediococcus species). Pediococcus Q-05 transformed quercetin to 3,4-dihydroxyphenylacetic acid.

Any other information on results incl. tables

Table 1. Antibacterial activity and mutagenesis of quercetin in  Salmonella/mammalian microsome assay.

CompoundConcentration (mg/ml)His+ revertant plateAntibacterial Activity (inhibition 100%)
DMSO 735100
1-Nitropyrene 318* 

Applicant's summary and conclusion

The test item, at concentrations higher than 100 mg/kg rat, was metabolised to quercetin, which is mutagenic according to Ames test in S. typhimurium TA98. After 12 hours quercetin was transformed to phenolic acids, which are not mutagenic by intestinal bacteria in human intestine.
Executive summary:

A study on relating the metabolism of the test item with mutagenicity was performed in rats. Three to five rats were used for each concentration group of 25, 50, 100, 150, 250, 500, 1000, 1250 or 1500 mg/kg of rat were orally administered. Urine samples were collected at 24, 48 and 72h after administration of the test item and analyzed by TLC. Also, human intestinal bacteria were inoculated into 500 ml GAM broth containing 50mg of test item and assayed according to Ames test. It was observed that Quercetin is mutagenic for TA98. In the case of rats, at  concentrations lower than 100 mg test item/kg, no test item or quercetin is absorbed, while at concentrations higher than 100 mg/kg, the presence of Quercetin (and mutagenicity) increases up to 12 hours, when it starts to  decrease as it is converted to phenolic acids, which are not mutagenic. These results suggest that the test item is metabolised by intestinal bacteria and transformed to the metabolite having novel biologial activity, such as from mutagenic to non-mutagenic by intestinal bacteria in human intestine.