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The mutagenic potential of the test article (grey granules, purity approx. 88 Fl.%, CASRN 496805-64-2, Lot: 1268147/1-1268154/1) was evaluated in the Bacterial Reverse Mutation Assay with S. typhimurium strains TA98, TA100, TA102, TA1535 and TA1537 in the presence and absence of metabolic activation (S9-mix: Aroclor 1254-induced rat liver).  This study was performed in compliance with OECD GLP (1997) and the German Chemical Law (1999). The study method was based on OECD 471 (1997), US EPA OPPTS 870.5100 (1998), and EEC Directive 92/69 L383A, B.14 (1992). Two independent mutagenicity studies were conducted (one plate incorporation test and one preincubation test. The test article was prepared in deionized water just prior to administration to the cells. In each mutagenicity assay, the test article was tested at up to 5000 ug/plate in each strain in the presence and absence of S9-mix. Strain-specific positive controls were tested in parallel. Each treatment was performed in triplicate. Toxicity (thinning of bacterial lawns and reduction in the number of colonies) was observed in all strains at 1600 or 5000 ug/plate in the presence or absence of S9-mix. No increase in the number of revertants in any strain at any dose in the presence or absence of S9-mix. All criteria for a valid assay were met as described in the protocol. Under the conditions of this study, the test article is not mutagenic in the Bacterial Reverse Mutation Assay in the presence or absence of metabolic activation.

 

The chromosome aberration potential of the test article (grey granules, purity approx. 88 Fl.%, CASRN 496805-64-2, Lot: 1268147/1-1268154/1) was evaluated in Chinese hamster lung (V79) cells in the presence and absence of metabolic activation (S9-mix: Aroclor 1254 induced rat liver). This study was performed in compliance with OECD GLP (1997) and the German Chemical Law (1999). The test method was based on OECD 473 (1997), US EPA OPPTS 870.5375 (1998), and EEC Directive 2000/32/EC, L136 B.10 (2000). The test material was prepared in cell culture medium (MEM) prior to administration. This assay was performed in two independent experiments. In the first assay, the cells were exposed to up to 1750 ug/mL test article for 3 hours in the presence and absence of metabolic activation with a 20 hour fixation time. In the second assay, the cells were exposed to up to 300 ug/mL test article for 20 hours in the absence of metabolic activation with a 20 hour fixation time. Since chromosomal aberration was observed in the first assay, the results from the second assay were not analyzed. Positive controls were tested in parallel. All dose levels were performed in duplicate. In the first assay, toxicity (decreased survival and mitotic index) was observed at concentrations greater than 250 ug/plate. There was no relevant increase in the number of polyploid cells as compared with the solvent controls. Moderate to distinct toxicity (mitotic index) was observed at clastogenic concentrations. Positive and solvent controls responded as predicted, indicating that the test was valid. The final report for this study concluded that the test article was clastogenic. However, since clastogenicity was only observed at toxic doses. According to current classification criteria, the test article is not clastogenic.

The chromosome aberration potential of the test article (grey granules, purity approx. 88 Fl.%, CASRN 496805-64-2, Lot: 1268147/1-1268154/1) was evaluated in the bone marrow of Sprague Dawley rats. This study was performed in compliance with OECD GLP (1997) and the German Chemical Law (2001). The test method was based on OECD 475 (1997), US EPA OPPTS 870.5385 (1998), and EEC Directive 2000/32, L136, B.12 (2000). T-7684 was prepared in deionized water (vehicle) just prior to dosing. Rats (5/sex/group) received two doses (separated by an interval of 24 hours) of 20 mg/kg cyclophosphamide (CP, positive control) or T-7684 at 0 (vehicle), 80, 250, or 800 mg/kg via oral gavage. Another group (5/sex) was similarly dosed with 800 mg/kg test article due to due clinical signs of toxicity that were observed in the first 800 mg/kg-treated group. Bone marrow was harvested at 24 hours after the second dose. Metaphases were examined for aberrations.  In the first 800 mg/kg-treated group, 2 females were found dead. Among animals treated at 800 mg/kg, the following clinical observations were noted: decreased motor activity, stilted gait, squatting posture, coat bristling, respiratory sounds, and blood-colored encrusted snout. These observations were noted in females starting at 24 hours after the first dose and in males starting at 24 hours after the second dose. The following macroscopic findings were observed among 800 mg/kg-treated animals: remarkably light spotted liver, flatulent stomach, and remarkable dark red-brown colored content of the gastrointestinal tract. No abnormal clinical observations or necropsy findings were noted in animals treated at 80 or 250 mg/kg. At 800 mg/kg, a reduced mitotic index (4.4%) was observed when compared to the negative controls (mitotic index 10.5%), indicating the presence of cytotoxicity. No polyploid metaphases or significant increase in the aberration rate excluding and including gaps was observed in any dose group. No significant increase in the number of aberrations was observed in any dose group. Marked increases in the number of chromosome aberrations were observed in positive control group animals, indicating that the test was valid. Based on the results of this test, the test article is not clastogenic.


Short description of key information:
In vitro genetic toxicity studies have been conducted on MV 31 K-Salt. The results of the studies are:

Bacterial Reverse Mutation Assay: Negative when tested according to OECD 471.

Chromosome Aberration Test: Negative when tested according to OECD 473.

An in vivo genetic toxicity study has been conducted on MV 31 K-Salt. The result of the study was:

Mammalian Bone Marrow Chromosome Aberration Test: Negative when tested according to OECD 475.

Endpoint Conclusion:

Justification for classification or non-classification

Criteria for classifying the test article as mutagenic are not met.