Abstract:
Isoeugenol is one of several phenylpropenoid compounds that is used as a fragrance, food flavoring agent and in aquaculture as a fish anesthetic. Carcinogenicity testing in rats and mice by NTP resulted in clear evidence of carcinogenicity (hepatic adenomas/carcinomas) in male mice only. A nongenotoxic threshold mode of action (MOA) is postulated for isoeugenol and is discussed considering the IPCS MOA and Human Relevance Framework. The weight of evidence indicates that isoeugenol is not genotoxic and that the carcinogenic outcome in male mice relates directly to the metabolism of individual compounds. Benchmark Dose (BMD) modeling was conducted to determine a Point of Departure (POD) and potential threshold of carcinogenicity. The results of the BMD evaluation for isoeugenol resulted in an estimated POD for carcinogenicity in the male mouse of 8 mg/kg with a lower limit of 4 mg/kg, representing a POD for the determination of an acceptable daily intake. With application of uncertainty factors, an ADI of 40 μg/kg is calculated. This daily dose in humans would be protective of human health, including carcinogenicity. A corresponding maximum residual level (MRL) of 3200 μg/kg fish is also estimated based on this POD that considers the threshold MOA.
摘要:
异丁香酚是几种用作香料的苯基丙烯类化合物之一,食品调味剂和水产养殖中作为鱼类麻醉剂。通过NTP在大鼠和小鼠中的致癌性测试仅在雄性小鼠中产生了致癌性(肝腺瘤/癌)的明确证据。假定异丁香酚具有非遗传毒性阈值作用模式(MOA),并考虑到IPCSMOA和人类相关性框架进行了讨论。证据的权重表明异丁香酚不是遗传毒性的,并且在雄性小鼠中的致癌结果与单个化合物的代谢直接相关。进行基准剂量(BMD)建模以确定偏离点(POD)和潜在的致癌性阈值。异丁香酚的BMD评估结果导致雄性小鼠的致癌性POD估计为8mg/kg,下限为4mg/kg,代表用于确定可接受的每日摄入量的POD。随着不确定性因素的应用,计算的ADI为40μg/kg。这种每日剂量可以保护人类健康,包括致癌性。还基于考虑阈值MOA的该POD来估计3200μg/kg鱼的相应最大残留水平(MRL)。