3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Expert statement

Adequacy of study:

supporting study

Data source

Reference

Reference Type:

other: expert statement

Title:

Unnamed

Report date:

2015

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one

EC Number:

241-753-7

EC Name:

3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one

Cas Number:

17772-51-9

Molecular formula:

C18H11NO3

IUPAC Name:

3-hydroxy-2-(3-hydroxyquinolin-2-yl)-1H-inden-1-one

Applicant's summary and conclusion

Executive summary:

Title:

Information/Assumptions regarding Toxicokinetics:

3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one; CAS 17772-51-9

Author:

Dr. Dieter Beyer

Bayer Pharma AG

GDD-GED-PSICO, Regulations

42096 Wuppertal

Germany

Completion Date:

2015-03-20

Sponsor:

LANXESS Deutschland GmbH

51369 Leverkusen

Germany

There are no experimental toxicokinetic data available for the substance and this statement is based on available data as physico-chemical data and toxicological data. This assumption follows the procedure indicated in the “Guidance on information requirements and chemical safety assessment chapter R.7c” of the ECHA guidance document (version 1.1, November 2012).

Available physico-chemical information taken into account:

Physical state:

The substance is a solid.

Particle size distribution:

According to OECD guideline 110, the particle size distribution of 3-Hydroxy-2-(3-hydroxy-2-quinolinyl)-1H-inden-1-one was determined by scanning electron microscopy method for the sieved fraction (< 100 µm, 7.40% of total sample) and presented on the basis of calculated mass fractions. The median diameter was 3.12 µm with the main fraction of 67.1% distributing in the range of 4 - 10 µm.

Structure:

3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one

Molecular weight:

289 g/mol

Water solubility:

Determined by the column elution method at 20 °C was <0.000026 g/L.

Log Pow:

4.8 at 25°C.

Vapor pressure:

The QSAR determination of the vapour pressure of 3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one using the model MPBPWIN included in the Estimation Program Interface (EPI) Suite v4.11 revealed a value of 3.45E-11 Pa at 25 °C.

Estimation of oral absorption:

Oral absorption is considered to be low, based on the physico-chemical data: molecular weight 289 g/mol, insoluble in water, log Pow above 4.

There is no evidence of absorption of 3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one in an acute oral study and in an oral 28 day study.

In an acute oral toxicity study no deaths, no clinical signs and no gross pathological findings were reported after dosing of 5 male and 5 female rats with 5000 mg/kg.

Oral administration of 3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one to Wistar rats at doses of 100, 300 and 1000 mg/kg/day for 28 days resulted in no changes of toxicological relevance. The orange discoloration of the feces noted in all treated groups represents a typical finding in gavage studies with colored substances or dyestuffs.

Although the slight increase in the incidence of dark yellow urine implies that a minimal absorption cannot be excluded, no discoloration was noted in any organ and there were no correlating macroscopical or microscopical findings.

Based on the results of this study, the no-observed-effect-level (NOEL) and no-observed-adverse-effect-level (NOAEL) were considered to be 1000 mg/kg body weight/day of 3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one, the highest dose tested.

Overall: oral absorption is assumed to be low based on physicochemical properties and oral toxicity experiments.

Estimation of dermal absorption:

Dermal absorption is likely to be low because it is a solid with a molecular mass above 100, insoluble in water and a log Pow value above 4.

There is no evidence of absorption of 3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one in acute dermal study. In this study 5 male and 5 female rats received a single semiocclusive dermal dose of 2000 mg/kg of the test item for 24 hours. Rats tolerated the dose without toxicologically relevant clinical signs, mortalities, toxicological effects on body weight development and gross pathological findings.

Overall: dermal absorption is assumed to be low based on physicochemical properties and acute dermal toxicity data.

Estimation of absorption via inhalation:

The calculated vapor pressure is anticipated to be low; 3.45E-11 Pa at 25 °C. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. The fraction of particles below 100 µm was reported to be only 7.4 % of total sample.

Consistent with the large, not inhalable, particle size of the compound, an acute inhalation toxicity study was aborted before any animal was exposed to the compound based on the low maximal technical producible concentration that could be achieved.

Overall: absorption by inhalation is assumed to be low based on physicochemical properties.

Overall estimation on absorption: absorption is anticipated to be similar and very low by oral, dermal and inhalation route.

Estimation of distribution:

Based on the high log Pow (4.8) and the insolubility in water it is not likely that the substance distributes into cells. This assumption is supported by the oral sub-acute toxicity study in which no relevant absorption or adverse effects were observed and the limit dose 1000 mg/kg/day.

Estimation of accumulation:

Poorly water soluble particles have the potential to accumulate in the lung. Based on the particle size distribution only 7.4% of the sample have a MMAD < 100 µm. Overall, the particle size distribution is not in favor of substantial accumulation.

Estimation of metabolism:

In vitro genotoxicity data do not indicate any genotoxic metabolites. The substance is negative in the absence and in the presence of S9 extracts (Ames test, in-vitro micronucleus test and gene mutation assay in mammalian cells (HPRT)).

Estimation of excretion:

Based on the low absorption potential of the compound excretion is anticipated mainly (exclusively) via the feces; this is supported by the sub-acute toxicity study.

Oral administration of 3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one to Wistar rats at doses of 100, 300 and 1000 mg/kg/day for 28 days resulted in no changes of toxicological relevance. The orange discoloration of the feces noted in all treated groups represents a typical finding in gavage studies with colored substances or dyestuffs.

Although the slight increase in the incidence of dark yellow urine implies that a minimal absorption cannot be excluded, no discoloration was noted in any organ and there were no correlating macroscopical or microscopical findings.