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Well conducted studies using OECD guidelines provided negative results for three (3) of the four (4) studies with the exception of the chromosome aberration study conducted in HPBL cells which gave an equivocal result. Because of the equivocal result the study was repeated with CHO cells which gave a clearly negative result.
These results provide evidence that the registration substance does not produce in vitro genotoxicity.
Data tables in attached file ( AD63KG 704 BTL_Tables-ONLY.PDF_.
A well conducted, mammalian in vitro gene mutation assay was conducted according to OECD guideline 476 of 21 July 1997. All validation criteria were met, and positive and vehicle controls were comparable to historical records at this testing facility. Therefore, the negative result obtained with the conditions of this assay were met, and EXP1200078 is considered to be negative in the mammalian in vitro gene mutation assay.
Content of PDF attachment.
EXP1200078 was negative for the induction of structural and numerical chromosome aberrations in CHO cells in both the non-activated and the S9-activated test systems.
Attached data tables:
SUMMARY (COMBINED DATA)
It can not be determined if EXP1200078 is capable of causing structural alterations to structural chromosomes using HPBL as the target in an in vitro experimental system.
A well conducted study (OECD 474) in rats examining the production of bone marrow micronuclei resulted in negative findings at a dose of 2000 mg/kg. These results demonstrate that the registration substance does not produce genotoxicity using an in vivo protocol.
Evaluation of Test Results
Once the criteria for a valid assay were met, the results were evaluated. Test substance was considered to be positive if it induced a significant increase in mnPCE frequency (p£0.05) at any dose level or sampling time compared to the concurrent vehicle control. The test substance was considered to be negative if no significant increase in mnPCE frequency was observed (p > 0.05) compared to the concurrent vehicle control. Other criteria may have been used in reaching a conclusion about the study results (e.g., magnitude of any increase, dose-dependency, comparison to historical control values, biological significance, etc.). In such cases, the Study Director used sound scientific judgment and clearly reported and described any such considerations.
Definitive Micronucleus Assay
No mortality occurred during the course of the definitive assay. All rats appeared normal throughout the observation period. Clinical signs are presented inTable 1.
Bone Marrow Analysis
No appreciable reductions in the PCEs/EC ratio in the test substance group compared to the vehicle control group were observed indicating the test did not induce cytotoxicity.
No statistically significant increase in the incidence of mnPCEs in the test-substance treated group was observed relative to the negative control group (p > 0.05, Kastenbaum-Bowman tables). The positive control induced a statistically significant increase in the incidence of mnPCEs (p < 0.05, Kastenbaum-Bowman tables). The number of mnPCEs in the vehicle control groups did not exceed the historical control range.
The incidence of mnPCEs per 10,000 PCEs scored (2000 PCEs/animal) and the proportion of polychromatic erythrocytes per total erythrocytes are summarized and presented for each treatment group by sacrifice time inTable 2. Individual animal data is presented inTable 3.
Based upon this, all criteria for a valid test were met as specified in the protocol. The Common Technical Document (CTD) Summary Table is included inAppendix IV.
A well conducted guideline study to examine in vivo mutagenesis (chromosome aberration) of EXP1200078 at the MTD (2000 mg/kg) did not result in any mutagenic response. The test substance, EXP1200078,was evaluated for its clastogenic activity and/or disruption of the mitotic apparatus by detecting micronuclei in polychromatic erythrocyte (PCE) cells in rat bone marrow.
No adverse effects were found at the dose of 2000 mg/kg in this in vivo genetic toxicity assay.
The registration substance did not produce adverse effects in well conducted in vitro and in vivo genetic toxicity studies.
Therefore, in accordance to Regulation (EC) No 1272/2008 it is concluded that the registration substance does not merit any classification related to the genotoxicity endpoint.
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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