Male and female Fischer 344 rats were fed diets containing 0, 1.0, 2.0, or 5.0% titanium dioxide (TiO2) coated mica for up to 130 wk. This dosage regimen produced no consistent or biologically important changes in survival, body weight gains, hematologic or clinical chemistry parameters or histopathology. Under the conditions of this 130 wk feeding study there was no evidence that TiO2-coated mica produced either toxicologic or carcinogenic effects at dietary concentrations as high as 5.0%. The results suggest that dietary exposure to TiO2-coated mica does not pose a significant human health hazard.
1,1'-Methylenebis[4-[(hydroxyimino)methyl]-pyridinium] (MMB4) dimethanesulfonate (DMS) is a bisquaternary pyridinium aldoxime that reactivates acetylcholinesterase inhibited by organophosphorus nerve agent. Time courses of MMB4 concentrations in plasma were characterized following 7-day repeated intramuscular (IM) administrations of MMB4 DMS to male and female Sprague-Dawley rats, New Zealand White rabbits, beagle dogs (single dose only), and rhesus monkeys at drug dose levels used in earlier toxicology studies. In general, there were no significant differences in MMB4 toxicokinetic (TK) parameters between males and females for all the species tested in these studies. After a single IM administration to rats, rabbits, dogs, and monkeys, MMB4 DMS was rapidly absorbed, resulting in average T max values ranging from 5 to 30 minutes. Although C max values did not increase dose proportionally, the overall exposure to MMB4 in these preclinical species, as indicated by area under the curve (AUC) extrapolated to the infinity (AUC∞) values, increased in an approximately dose-proportional manner. The MMB4 DMS was extensively absorbed into the systemic circulation after IM administration as demonstrated by greater than 80% absolute bioavailability values for rats, rabbits, and dogs. Repeated administrations of MMB4 DMS for 7 days did not overtly alter TK parameters for MMB4 in rats, rabbits, and monkeys (150 and 300 mg/kg/d dose groups only). However, C max and AUC values decreased in monkeys given 450 and 600 mg/kg IM doses of MMB4 DMS following repeated administrations for 7 days. Based on the TK results obtained from the current study and published investigations, it was found that the apparent volume of distribution and clearance values were similar among various preclinical species, except for the rat.
OPTISON (FS069), an ultrasonic diagnostic contrast agent, is a suspension of perfluoropropane (PFP)-filled album in microspheres of 2.0-4.5 microns average diameter and 5.0-8.O x 108 microspheresl ml. The following non clinical safety assessment studies in support of product regulatory submissions were conducted: genetic toxicology, single dose (rat, dog, monkey) and repeated (rat, dog) dose toxicology studies, hemodynamics, rabbit irritation, and in vitro blood compatibility. Dosages used throughout the studies were: 0.25, 5.0, 10, 20, or 25 ml/kg. OPTISON was nongenotoxic and nonirritant, and was compatible with human blood. It did not elicit adverse effects in single-dose studies at dosages of up to (and including) 20 ml/ kg. Initial studies conducted in rats and dogs with OPTISON repeated administration, 3 times per week for 3 weeks, showed no adverse effects in dogs to 20 ml/ kg and rats to 5 ml/kg. Mortality and adverse effects were noted in rats at dosages of 20 and 10 ml/ kg and were associated with acute pulmonary congestion. Subsequent repeated administrations for 29 and 31 consecutive days in rats and dogs, respectively, at 10 ml/kg, were not associated with adverse events, except for those which resulted from the anticipated immunogenic response to the IV administration of OPTISON human albumin-based microspheres. No changes in hemodynamic parameters attributable to OPTISON were reported at a dosage of 0.25 ml/ kg in dogs. It is, therefore, concluded that the intravenous administration of OPTISON, at dosages and dose regimens used in these studies, provides a large safety margin for the clinical efficacious dose for diagnostic ultrasound imaging.
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