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EC number: -
CAS number: -
- Gene mutation in bacteria
To characterize the genotoxic potential of the test substance in
vitro, an Ames assay was conducted equivalent to OECD 471 with a
standard battery of Salmonella typhimurium tester strains including TA
98, TA 100, TA 102, TA 1535 and TA 1537 in concentrations ranging from
31.6 to 5000 µg/plate with and without metabolic activation in a plate
incorporation and a pre-incubation assay (pre-incubation for 30 min)
(Donath, 2011). The test substance did not exhibit biologically relevant
increases in revertant colony numbers of any tester strain either in the
absence or presence of metabolic activation. Further, no cytotoxicity
was observed. In conclusion, the test substance is considered as
non-mutagenic in the Ames test.
- Chromosome aberration in mammalian cells
Further, a recent GLP-guideline study according to OECD guideline
473 was performed to determine clastogenic properties of the test
substance (Oppong-Nketiah, 2012). Chinese hamster V79 cells were exposed
to the test substance with and without metabolic activation for 4 hours
in duplicates. For analyses, 100 metaphases per culture were scored. the
test substance induced cytotoxicity at 125 µg/mL without and at 600
µg/mL with metabolic activation which was determined by a reduced
mitotic index (125 µg/mL: 62%, 600 µg/mL:44% of controls, respectively).
Moreover, the aberration rate increased at the same concentrations
(without S9, 125 µg/mL: 2.5 vs 7% (excl. gaps); with S9, 600 µg/mL: 1
vs. 4% for controls and test plates, respectively (excl. gaps). As
cytotoxicity and clastogenicity occurred at the same concentrations, the
induction of chromosomal aberrations due to cytotoxicity cannot be
excluded. Further, false-positive results due to methodological reasons
cannot be obviated as control cells revealed a relatively high
aberration rate in the main experiment (controls: without S9: 4.5%
(incl. gaps) and 2.5% (excl. gaps); with S9: 4% (incl. gaps) and 1%
(excl. gaps)) which partially exceeded the amount of aberrant cells
exposed to the lowest dose concentrations applied (without S9: 31.3
µg/mL: 1.5% (incl. gaps) and 1% (excl. gaps), 62.5 µg/mL: 3.5% (incl.
gaps) and 1.5% (excl. gaps); with S9: 500 µg/mL: 2% (incl. gaps) and
1.5% (excl. gaps)). Thus, the results of the conducted mammalian
chromosome aberration test are inconclusive and are therefore not taken
into account for assessment.
-Genetic toxicity in vivo
Moreover, a mammalian erythrocyte micronucleus test according to
OECD guideline 474 was performed (Hofman-Hüther, 2012). 5 NMRI mice per
sex and dose group received a single intraperitoneal injection of 20, 50
and 100 mg/kg bw to cover a range from the maximum tolerable dose to
moderate systemic toxicity as determined in a previous range finding
study. Control animals received either 0.9% NaCl or 40 mg/kg bw
cyclophosphamide as negative or positive control substances,
respectively. Peripheral blood samples obtained from the tail vein were
collected 44 hours and 68 hours after test substance administration. For
evaluation, immature erythrocytes were labelled with anti-CD27
antibodies and were counted in a flow cytometer (10 000 immature
erythrocytes per animal). Further, the ratio between immature and mature
erythrocytes was calculated to detect toxic effects to the bone marrow.
Low- and mid-dose animals showed slight or moderate signs of systemic
toxicity whereas strong signs of toxicity were determined in all animals
of the high-dose group including reduced spontaneous activity,
constricted abdomen, piloerection (determined only in males),
bradykinesia, catalepsis, recumbency opisthotonos, half eyelid closure
and eye closure thereby proving systemic availability of the test
substance. Moreover, a slight decrease in the ratio of immature and
mature erythrocytes among the groups was determined which indicates
toxic effects on the bone marrow and therefore availability of the test
substance in the target tissue. Further, skin and urine of high-dose
animals were blue coloured attributable to the test item. Mean values of
micronuclei frequency were comparable among the different treatment
groups after 44 hours. In contrast, positive control animals showed a
statistically significant increase in the micronuclei frequency about 7-
and 9-fold in males and females, respectively, thereby validating the
study. In conclusion, the conducted mammalian micronucleus test did not
reveal an indication that the test substance induces cytogenetic damage
in vivo. Thus, the test substance did not show clastogenic properties in
the conducted micronucleus test in mice.
Taken all these data together, the test substance did not show
mutagenic properties in the bacterial reverse mutation test nor did it
induce cytogenetic damage in vivo. Therefore, the criteria for
classification according to GHS are not met.
The available data on
genetic toxicity do not meet the classification criteria according to
Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore
conclusive but not sufficient for classification.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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