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Due to finalization of the ICH S3A Q&A focusing on microsampling, application of microsampling technique to regular non-clinical animal studies is expected for non-clinical safety assessment of pharmaceuticals. In Europe, microsampling from the tail vein or saphenous vein has often been used, whereas sampling from the jugular vein is thought to be more common for non-clinical studies in Japan. Therefore, we assessed the toxicological effects of serial microsampling from the jugular vein of SD rats in a common 28-day study at 4 independent organizations. Fifty microliter sampling was performed at 6 timepoints on day 1 to 2 and 7 timepoints on day 27 to 28 and its toxicological influences on body weight, food consumption, hematological and clinical chemistry parameters, and organ weights (on day 29 for 3 and day 28 for 1 organizations) were evaluated. The serial microsampling was shown to have no or minimal influences on the assessed parameters. The observed statistical differences for the 18 parameters were sporadic and did not appear to be systemically associated with microsampling. However, the sporadic changes were more often observed in females (14/18 parameters) than in males (6/18), suggesting the possibility that female rats were more susceptible to treatment-based influences. The current results indicate that serial 50 μL sampling from the jugular vein of SD rats had no or very slight toxicological effects, suggesting that this microsampling condition is applicable for toxicokinetic evaluation of non-clinical rat toxicity studies.

Aryl-substituted α,β-difluoroallyl alcohols 1 were readily hydrolyzed in the presence of a catalytic amount of montmorillonite K 10 (clay) in hexane at reflux temperature for 1 h to give the corresponding (Z)-α-fluoro-β-aryl-substituted acrylaldehydes 2 in good yields.

2,3,3-Trifluoro-1-propenyl p -chlorobenzenesulfonate ( 1 ), readily available from 2,2,3,3-tetrafluoropropanol, reacted smoothly with various Grignard reagents at 50 °C to afford the corresponding (Z)-α,β-difluoroallyl alcohols 2 in moderate to excellent yields. These alcohols were smoothly hydrolyzed in the presence of a catalytic amount of montmorillonite K10 (Clay) to provide (Z)-α-fluoro-α,β-unsaturated aldehydes 3 in good yields.

During mechanical alloying, MA, using a high energy planetary ball mill of Al-12at.%Ti-X (X=Cr, Fe, Ni, Cu) mixed powders, aluminum rich Al-(10 ∼ 15.8)at.%Ti-(3.4∼26.3)at.%X supersaturated solid solution with small grain sizes of 4 ∼ 6 nm are obtained. Increase in the concentration of the 3rd element Cr, Fe, Ni, promotes amorphization of the aluminum rich supersaturated solid solution by MA, though no amorphous phase is formed in Al-13.1 at.%Ti mechanically alloyed powder. On the other hand, dissolution of about 12at.%Cu in Al-11 1at.%Ti supersaturated solid solution causes no amorphization during MA. The results obtained suggest that a critical value of the total elastic lattice strain, about 2% due to the largely, reduced lattice parameter in nanosize crystals is the most important factor for the amorphization of Al-rich supersaturated solid solutions.

2,3,3-Trifluoro-1-propenyl p -chlorobenzenesulfonate ( 1 ), readily available from 2,2,3,3-tetrafluoropropanol, reacted smoothly with various Grignard reagents at 50 °C to afford the corresponding (Z)-α,β-difluoroallyl alcohols 2 in moderate to excellent yields. These alcohols were smoothly hydrolyzed in the presence of a catalytic amount of montmorillonite K10 (Clay) to provide (Z)-α-fluoro-α,β-unsaturated aldehydes 3 in good yields.

Aryl-substituted α,β-difluoroallyl alcohols 1 were readily hydrolyzed in the presence of a catalytic amount of montmorillonite K 10 (clay) in hexane at reflux temperature for 1 h to give the corresponding (Z)-α-fluoro-β-aryl-substituted acrylaldehydes 2 in good yields.