2,6-二甲基苯胺限度问题求助

兰陵-萧

雷诺嗪缓释片原研在TGA的申报资料中提到2,6-二甲基苯胺的日接受剂量为20.4μg/g~110μg/g，请问有没有哪位大神知道上述限度值的来源，或者说这个数据是如何推导出来的？NTP上找不到对应的数据

兰陵-萧

以下为资料的原话：
The sponsor also commissioned two nonclinical risk assessments on DMA relative to potential exposure from ranolazine under the conditions of use. Both assessors referred to methodologies advocated in the ICH guideline.21 The updated guideline permits the use of compound-specific assessments (compared with. TTC-based acceptable intake of 1.5 μg/day) when sufficient carcinogenicity data exists, such that a compound-specific acceptable intake can be extrapolated from measures of carcinogenic potency. Information on the carcinogenicity of DMA is available from a 2 year dietary study in rats (NTP, 1990)
and is the only source of data on carcinogenic potency.
The first nonclinical assessor referred to a follow-up report to the NTP report where carcinogenic potential (TD50) was set at 20.4 mg/kg. By linear extrapolation the acceptable lifetime daily intake was calculated as 0.41 μg/kg/day (24.5 μg/day for 60 kg adult or 20.4 μg/day for 50 kg adult). The amount of DMA detected in 750 mg ranolazine tablets after 24 months storage (1.6 μg/tablet or 3.2 μg/day based on average batch values outlined above in Table 7) were at least 6.4 fold lower than the extrapolated acceptable lifetime daily intake of 20.4 μg/day (for 50 kg adult at the MRHD). The assessor indicated that this was an acceptable safety factor but recommended that the shelf life of Ranexa be no more than 24 months to ensure ranolazine degradation was minimal.
The second nonclinical assessor evaluated risk assessments conducted by other regulatory bodies where acceptable daily levels of DMA ranged between 20.4 μg/day to 110 μg/day (for 50 kg adult). The most conservative approach gave acceptable daily levels of 29 μg/day (20.4 μg/day for 50 kg adult) and was the same as that outlined by the first……

wenzhao10

谢谢分享。。