Warheit D B, Boatman R, Brown S C
Chemours Company, Wilmington, DE, USA.
Boatman Toxicology Consulting LLC, USA.
Regul Toxicol Pharmacol. 2015 Dec;73(3):887-96. doi: 10.1016/j.yrtph.2015.09.032. Epub 2015 Oct 21.
Six different commercial forms and sizes of titanium dioxide particles were tested in separate developmental toxicity assays. The three pigment-grade (pg) or 3 ultrafine (uf)/nanoscale (anatase and/or rutile) titanium dioxide (TiO2) particle-types were evaluated for potential maternal and developmental toxicity in pregnant rats by two different laboratories. All studies were conducted according to OECD Guideline 414 (Prenatal Developmental Toxicity Study). In addition, all test materials were robustly characterized. The BET surface areas of the pg and uf samples ranged from 7 to 17 m(2)/g and 50-82 m(2)/g respectively (see Table 1). The test substances were formulated in sterile water. In all of the studies, the formulations were administered by oral gavage to time-mated rats daily beginning around the time of implantation and continuing until the day prior to expected parturition. In 3 of the studies (uf-1, uf-3, & pg-1), the formulations were administered to Crl:CD(SD) rats beginning on gestation day (GD) 6 through GD 20. In 3 additional studies (uf-2, and pg-2, pg-3 TiO2 particles), the formulations were administered to Wistar rats beginning on GD 5 through 19. The dose levels used in all studies were 0, 100, 300, or 1000 mg/kg/day; control group animals were administered the vehicle. During the in-life portions of the studies, body weights, food consumption, and clinical observations before and after dosing were collected on a daily basis. All dams were euthanized just prior to expected parturition (GD 21 for Crl:CD(SD) rats and GD 20 for Wistar rats). The gross necropsies included an examination and description of uterine contents including counts of corpora lutea, implantation sites, resorptions, and live and dead fetuses. All live fetuses were sexed, weighed, and examined externally and euthanized. Following euthanasia, fresh visceral and head examinations were performed on selected fetuses. The fetal carcasses were then processed and examined for skeletal alterations. There was no evidence of maternal or developmental toxicity at any dose level tested in any of the six studies. Based on these results, the no-observed-adverse-effect level (NOAEL) for titanium dioxide was 1000 mg/kg/day, the highest administered dose, in both the Sprague-Dawley (Crl:CD(SD) and Wistar rat strains.
在单独的发育毒性试验中测试了六种不同商业形式和尺寸的二氧化钛颗粒。三个颜料级（pg）或3种超细（uf）/纳米级（锐钛矿和/或金红石）二氧化钛（TiO2）颗粒类型由两个不同实验室评估对怀孕大鼠的潜在母体和发育毒性。所有研究均按照经合组织准则414（产前发育毒性研究）进行。此外，对所有测试材料进行了全面表征。pg和uf样品的BET表面积分别为7至17 m²/g和50 - 82 m²/g（见表1）。测试物质用无菌水配制。在所有研究中，从植入前后开始每天经口灌胃给予配制剂给经定时交配的大鼠，持续至预期分娩前一天。在3项研究（uf - 1、uf - 3和pg - 1）中，从妊娠第6天（GD）至GD 20给Crl:CD(SD)大鼠给予配制剂。在另外3项研究（uf - 2以及pg - 2、pg - 3二氧化钛颗粒）中，从GD 5至19给Wistar大鼠给予配制剂。所有研究中使用的剂量水平为0、100、300或1000 mg/kg/天；对照组动物给予赋形剂。在研究的活体部分期间，每天收集给药前后的体重、食物消耗量和临床观察结果。所有母鼠在预期分娩前（Crl:CD(SD)大鼠为GD 21，Wistar大鼠为GD 20）实施安乐死。大体尸检包括对子宫内容物的检查和描述，包括黄体计数、植入部位、吸收情况以及活胎和死胎。对所有活胎进行性别鉴定、称重、外部检查并实施安乐死。安乐死后，对选定的胎儿进行新鲜内脏和头部检查。然后对胎儿尸体进行处理并检查骨骼改变。在六项研究中的任何一项中，在任何测试剂量水平下均未发现母体或发育毒性的证据。基于这些结果，二氧化钛的未观察到有害作用水平（NOAEL）在斯普拉格 - 道利（Crl:CD(SD)和Wistar大鼠品系中均为1000 mg/kg/天，即最高给药剂量。
