Developmental toxicity studies with 6 forms of titanium dioxide test materials (3 pigment-different grade & 3 nanoscale) demonstrate an absence of effects in orally-exposed rats

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.