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大鼠中混合生育酚磷酸酯的亚慢性经口毒性研究。

Subchronic oral toxicity study of mixed tocopheryl phosphates in rats.

作者信息

Gianello R, Hall W C, Kennepohl E, Libinaki R, Ogru E

机构信息

Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.

出版信息

Int J Toxicol. 2007 Sep-Oct;26(5):475-90. doi: 10.1080/10915810701620556.

Abstract

Rats were fed diets containing 0%, 1%, 3%, or 5% mixed tocopheryl phosphates for 90 days. No abnormal clinical signs related to treatment appeared. Some statistically significant changes in hematology and clinical chemistry parameters appeared, but the majority were not dose dependent, occurred in only one sex or group, and/or remained within the historical control range for this strain of rat. A statistically significant apparent reduction in blood protein was observed in animals treated with the tocopheryl phosphates, but further investigation showed that the test substance interfered with the protein assay. Repeat analysis using a method unaffected by plasma test substance levels showed no difference in plasma proteins among all groups. Gross necropsy revealed no abnormalities; reduced relative heart and epididymal weights were observed, but were not dose dependent and were considered incidental. Histopathological changes occurred only in the mesenteric lymph node and small intestine. Foreign material in a crystal-like form appeared in macrophages in both organs, and increased in a dose-related fashion. In the lymph node, sinus histiocytosis increased with dose, but the severity was similar between the control and low-dose groups. Foreign-body granulomatous inflammation, associated with Maltese cross birefringence of the crystals was seen in the mid- and high-dose animals, but not the low-dose group. Similarly, the small intestine showed increasing amounts of foreign material and inflammation in the mid- and high-dose but not in the 1% diet. The 1% diet (equivalent to 587 and 643 mg mixed tocopheryl phosphates/kg body weight/day for male and female rats, respectively) was considered the no observed adverse effect level.

摘要

给大鼠喂食含0%、1%、3%或5%混合生育酚磷酸酯的日粮,持续90天。未出现与处理相关的异常临床症状。血液学和临床化学参数出现了一些具有统计学意义的变化,但大多数变化不具有剂量依赖性,仅在一种性别或组中出现,和/或仍在该品系大鼠的历史对照范围内。在用生育酚磷酸酯处理的动物中观察到血液蛋白质有统计学意义的明显降低,但进一步研究表明,受试物质干扰了蛋白质测定。使用不受血浆受试物质水平影响的方法进行重复分析表明,所有组之间血浆蛋白质无差异。大体尸检未发现异常;观察到心脏和附睾相对重量减轻,但不具有剂量依赖性,被认为是偶然现象。组织病理学变化仅发生在肠系膜淋巴结和小肠。在这两个器官的巨噬细胞中出现了晶体样异物,并呈剂量相关增加。在淋巴结中,窦组织细胞增生随剂量增加,但对照组和低剂量组的严重程度相似。在中、高剂量动物中可见与晶体马耳他十字双折射相关的异物性肉芽肿性炎症,但低剂量组未见。同样,小肠在中、高剂量组中显示异物和炎症增加,但在1%日粮组中未出现。1%日粮(分别相当于雄性和雌性大鼠587和643毫克混合生育酚磷酸酯/千克体重/天)被认为是未观察到不良反应水平。

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