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Administrative data

Key value for chemical safety assessment

Additional information

Genetic toxicity in vitro

Several different in vitro tests have been undertaken and are available with reliable results.

In vitro gene mutation studies in bacteria:

Moriya et al, 1983, was selected as the key study for this endpoint. The study was conducted in a similar manner to the OECD 471 Guideline (Bacterial Reverse Mutation Assay) and was peer reviewed. It was allocated the reliability score of 2 due to omissions of reporting some parts of the methodologies. This study was conducted on both Salmonella typhimurium (TA1535, TA1537, TA1538, TA98 and TA100) and Echerichia coli (WP2), which gave a more reliable result. The registered substance was found to be mutgenic under the conditions of the test both with and without metabolic activation to both S. typhimurium and E. coli.

Brem et al (1974), Kerklan et al (1985), Zoetemelk et al (1987), Dunkel et al (1985), Carere & Morpurgo (1981) and Hemminki et al (1980) are presented as supporting information only. All supporting studies reported positive results under their respective test conditions.

in vitro gene mutation studies in mammalian cells:

Due to the variety of different test data available for this endpoint several key studies have been chosen to fully illustrate the mutagenic potential of the substance.

- DNA damage repair, unscheduled DNA synthesis and sister chromatid exchange studies:

As these tests examine very similar types of mutation reponses a single key study has been chosen to illustrate this. Smith-Oliver et al, 1986, was selected as the key study for these tests due to the reliability, depth of reporting and date of the study. The study was conducted in a similar manner to the OECD 482 Guideline (Genetic Toxicology: DNA Damage and Repair, Unscheduled DNA Synthesis in Mammalian Cells in vitro) and was peer reviewed. The study was allocated the reliability score of 2 due to incomplete reporting of test methodology. The DNA damage/repair study was conducted on Rat hepatocytes with a parallel study on Rat spermatocytes. The study reported a positive result under the conditions of the test with a dose-dependant increase in DNA repair in both spermatocytes and hepatocytes, and suggested that the conjugation of the registered substance to glutathione may be the first step in the production of genotoxic metabolites in hepatocytes and spermatocytes.

Sundheimer et al (1982) and Williams et al (1982) also examined DNA damage/repair on rat hepatocytes. Both studies reported positive results under their respective conditions. Geddes (1982) and Ellingham et al (1986) examined sister chromatid exchanges, both studies reported positive results under their respective test conditions. Sundheimer et al (1982), Williams et al (1982), Sundheimer et al (1982) and Williams et al (1982) are presented as supporting information only.

- Chromosome Aberration studies:

Ashita, 1989, was selected as the key study for this endpoint. The study was conducted in a similar manner to OECD 473 Guideline (in vitro mammalian chromosome aberration test) and was peer reviewed. The study was allocated the reliability score of 2 as the study was only conducted without metabolic activation. The study was conducted using Chinese Hamster Ovary (CHO) cells without metabolic activation and reported a positive result under the conditions of the test.

Ellinham et al, 1986, also examined the potential for chromosome aberrations caused by exposure to the registered susbtance, however none-standard cells were used and so this data is presented as supporting information only due to insufficient data to allow adequate comparisons with other test types. The study reported a positive response without metabolic activation.

- Mammalian gene mutation and lymphoma assays:

Due to the similarity of these test types a single key study has been selected to represent this data.

Tan & Hsie, 1981, was selected as the key study for this data as it was conducted in a similar manner to the OECD Guideline 476 (in vitro Mammalian Cell Gene Mutation Test) and was peer reviewed. The study was allocated the reliability score of 2 due to incomplete reporting of methodologies. The test was conducted on Chinese Hamster Ovary (CHO) cells examining the HGPRT locus. The study was conducted both with and without metabolic activation and reported a positive result in both metabolic conditions. The registered substance was also found to be cytogenic in both metabolic conditions.

Clive et al (1979), Crespi et al (1985) and Traul et al (1981) are presented as supporting information only. All studies reported postive results under the respective test conditions.

Genetic toxicity in vivo

The key study selected for in vivo genetic toxicity is Barnett et al, 1992. This study was conducted in a similar manner to the OECD 478 Guideline (Genetic Toxicology: Rodent Dominant Lethal Test) and was peer reviewed. The test organism was the mouse (Male DBA/2J and Female C57BL/6L strains) and dosing was via intraperitoneal injection. The registered substance was suspended in physiological saline at a nominal dose of 100mg/kg bw. A concurrent positive control (Procarbazine) was conducted to ensure validation of the results. The registered substance produced a negative result under the conditions of the test. The positive control substance produced a positive result proving the validity of the test methodology.

Teramoto et al (1980) is provided as supporting information only. This study was also conducted as a rodent dominant lethal test and produced a negative result.

Vogel & Chandler (1974) and White et al (1981) both produced positive results. Vogel and Chandler, 1974, was conducted on the fruit fly Drosophila menanogaster, while White et al, 1981, was conducted as an in vivo DNA damage/repair test on liver hepatic cells using mice dosed with radiolabelled registered substance. Due to the lack of information on these studies it was not possible to compare them properly against other results and methodologies to determine the reliability of the results. These studies are therefore only presented as supporting information.


Short description of key information:
Barnett et al, 1992, is selected as the key study for the genetic toxicity endpoint. Based upon the results of this rodent dominant lethal study the substance is not genotoxic to germ cells and therefore does not meet the criteria for classification.

Endpoint Conclusion: Adverse effect observed (positive)

Justification for classification or non-classification

The key information suggests that the registered substance is considered to be mutagenic. However, based upon the result of Barnett et al, 1992, the registered substance is not considered to be a genetic toxic substance to germ cells therefore the substance does not meet the criteria set out by 67/548/EEC for classification as a Catgeory 2 mutagen. The registered substance therefore meets the criteria for classification as Category 3 for genetic toxicity and should be labelled with Xn, R68 - Possible risk of irreversible effects, according to 67/548/EEC. As the registered substance is not considered to be genetically toxic to germ cells it does not meet the criteria for classification according to EC Regulation 1272/2008.