Politano Valerie T, Lewis Elise M, Hoberman Alan M, Christian Mildred S, Diener Robert M, Api Anne Marie
Research Institute for Fragrance Materials, Inc, 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA.
Int J Toxicol. 2009 Mar-Apr;28(2):80-7. doi: 10.1177/1091581809333892.
Dihydromyrcenol, a widely used fragrance ingredient, was evaluated for developmental toxicity in pregnant Sprague-Dawley rats (25/group). Oral dosages of 0, 250, 500, or 1000 mg/kg/d in corn oil were administered on gestational days 7 to 17. Rats were observed for viability, clinical signs, body weights, and feed consumption. Caesarean sectioning and necropsy occurred on gestational day 21. Fetuses were weighed and examined for sex, gross external changes, and soft tissue or skeletal alterations. All rats survived until scheduled termination. No clinical signs were attributed to dihydromyrcenol. There were no gross tissue changes at necropsy. The 1000-mg/kg/d dosage group had reduced mean maternal body weight gains of 5% compared with controls, whereas absolute and relative feed consumption were significantly reduced during the dosage period. This threshold systemic maternal toxicity was associated with threshold developmental toxicity in the 1000-mg/kg/d dosage group. Fetal effects included a minimal approximately 3% reduction in fetal body weight; reversible variations in ossification, including retarded ossification of the metatarsal bones in the hindpaws; and an increase in supernumerary thoracic ribs with associated increases or decreases in thoracic and lumbar vertebrae, respectively. Based on these data, maternal and developmental no observable effect levels of 500 mg/kg/d and maternal and developmental no observable adverse effect levels of 1000 mg/kg/d were established for dihydromyrcenol. It was concluded that dihydromyrcenol is not a selective developmental toxicant in rats under the conditions of this study and that a margin of safety of 25 000 exists between reversible developmental delays in rats and the estimated daily human exposure level of 0.02 mg/kg/d.
二氢月桂烯醇是一种广泛使用的香料成分，对怀孕的斯普拉格 - 道利大鼠（每组25只）进行了发育毒性评估。在妊娠第7至17天，以玉米油为溶剂经口给予0、250、500或1000 mg/kg/d的剂量。观察大鼠的生存能力、临床体征、体重和饲料消耗量。在妊娠第21天进行剖腹产和尸检。对胎儿称重，并检查性别、大体外观变化以及软组织或骨骼改变。所有大鼠均存活至预定的处死时间。未观察到与二氢月桂烯醇相关的临床体征。尸检时未发现明显的组织变化。与对照组相比，1000 mg/kg/d剂量组的母体平均体重增加减少了5%，而在给药期间绝对饲料消耗量和相对饲料消耗量均显著降低。这种阈值全身性母体毒性与1000 mg/kg/d剂量组的阈值发育毒性相关。胎儿效应包括胎儿体重最小约3%的降低；骨化的可逆性变化，包括后爪跖骨骨化延迟；以及额外胸肋增加，分别伴有胸椎和腰椎数量的增加或减少。基于这些数据，确定二氢月桂烯醇的母体和发育无可见效应水平为500 mg/kg/d，母体和发育无可见不良反应水平为1000 mg/kg/d。得出的结论是，在本研究条件下，二氢月桂烯醇在大鼠中不是一种选择性发育毒物，并且在大鼠可逆性发育延迟与估计的人类每日暴露水平0.02 mg/kg/d之间存在25000的安全系数。
