Dressler W E, Re T E, Ackerman L J, Corbett J F
Clairol Research Laboratories, Stamford, CT 06922, USA.
Food Chem Toxicol. 1995 Aug;33(8):681-93. doi: 10.1016/0278-6915(95)00032-w.
N1(-)[tris(hydroxymethyl)]methyl-4-nitro-o-phenylenediamine was fed in the diet to groups of 30 male and 55 female Sprague-Dawley rats at levels of 0.2, 0.6 and 2.0% for up to 6 months. One mid-dose and two high-dose females developed palpable mammary masses that were subsequently diagnosed as mammary adenocarcinomas at a 13-wk interim kill involving 10 rats/sex/group. After 14 wk, 25 females per group with no apparent masses were mated in a reproduction/teratology study. Mammary tumours developed in a dose-related fashion both in the pregnant rats and in the remaining 20 females/group that continued on treatment for 6 months. On gestation day 20 (wk 17-18) the final incidences of mammary adenocarcinomas in the low-, mid- and high-dose mated dose groups were 20, 60 and 84%, respectively, while the corresponding incidences in the non-mated females at 6 months were 5, 40 and 85%. Most mammary tumours were encapsulated but, at 6 months, lung metastases were noted in four rats, and four females also had Zymbal's gland tumours. Non-neoplastic changes in male and female rats considered to be related to treatment included increases in thyroid follicular cell size accompanied by an accumulation of golden-brown pigment, multifocal hepatic necrosis with non-suppurative inflammation, and renal tubular pigmentation. Increases in foetal variations in the mid- and high-dose groups were considered to be related non-specifically to retarded growth. Malformations observed in the high-dose group were found primarily in single foetuses and were not considered to be treatment related. Although the mean numbers of micronucleated polychromatic erythrocytes in bone marrow obtained from high-dose treated females after 13 wk slightly exceeded historical negative control values, the data were not considered indicative of a genotoxic effect because of the absence of either a dose relationship or a substantive increase in the frequency of micronucleated cells.
将N1(-)[三（羟甲基）]甲基-4-硝基邻苯二胺以0.2%、0.6%和2.0%的水平添加到饮食中，分别喂养30只雄性和55只雌性斯普拉格-道利大鼠，持续6个月。在一项中期处死实验（每组10只大鼠/性别）中，13周时，1只中剂量和2只高剂量雌性大鼠出现可触及的乳腺肿块，随后被诊断为乳腺腺癌。14周后，在一项生殖/致畸研究中，将每组25只无明显肿块的雌性大鼠进行交配。在怀孕大鼠以及每组继续接受6个月治疗的其余20只雌性大鼠中，乳腺肿瘤均呈剂量相关方式发生。在妊娠第20天（第17 - 18周），低剂量、中剂量和高剂量交配组中乳腺腺癌的最终发生率分别为20%、60%和84%，而6个月时未交配雌性大鼠的相应发生率分别为5%、40%和85%。大多数乳腺肿瘤有包膜，但在6个月时，4只大鼠出现肺转移，4只雌性大鼠还患有齐默尔氏腺肿瘤。认为与治疗相关的雄性和雌性大鼠的非肿瘤性变化包括甲状腺滤泡细胞大小增加并伴有金棕色色素积累、多灶性肝坏死伴非化脓性炎症以及肾小管色素沉着。中剂量和高剂量组胎儿变异增加被认为与生长迟缓非特异性相关。高剂量组观察到的畸形主要出现在单个胎儿中，不认为与治疗有关。尽管13周后从高剂量处理的雌性大鼠获得的骨髓中微核多染红细胞的平均数量略超过历史阴性对照值，但由于缺乏剂量关系或微核细胞频率的实质性增加，这些数据不被认为表明有遗传毒性作用。
