Inorganic nanoparticles provide the opportunity to localize bioactive agents to the target sites and protect them from degradation. In many cases, acute toxicities of inorganic nanoparticles used for delivery applications have been investigated. However, little information is available regarding the long-term toxicity of such materials. This review focuses on the importance of subchronic and chronic toxicity assessment of inorganic nanoparticles investigated for delivery applications. We have attempted to provide a comprehensive review of the available literature for chronic toxicity assessment of inorganic nanoparticles. Where possible correlations are made between particle composition, physiochemical properties, duration, frequency and route of administration, as well as the sex of animals, with tissue and blood toxicity, immunotoxicity and genotoxicity. A critical gap analysis is provided and important factors that need to be considered for long-term toxicology of inorganic nanoparticles are discussed.

Despite increasing reports of using silica nanoparticles (SNPs) for controlled drug delivery applications, their long-term toxicity profile following intravenous administration remains unexplored. Herein, we investigated the acute (10-day) and subchronic (60-day and 180-day) toxicity of nonporous SNPs of approximately 50 nm (Stöber SNPs50) and approximately 500 nm in diameter (Stöber SNPs500), and mesoporous SNPs of approximately 500 nm in diameter (MSNPs500) upon single-dose intravenous injection into male and female immune-competent inbred BALB/C mice. The Maximum Tolerated Dose (MTD) of the particles was determined 10 days post-injection. The MTD of SNPs was administered and toxicity evaluated over 60 and 180 days. Results demonstrate that Stöber SNPs50 exhibit systemic toxicity with MTD of 103 ± 11 mg.kg −1 for female and 100 ± 6 mg.kg −1 for male mice, respectively. Toxicity was alleviated by increasing the size of the particles (Stöber SNPs500). MTD values of 303 ± 4 mg.kg −1 for female and 300 ± 13 mg.kg −1 for male were observed for Stöber SNPs500. Mesoporous SNPs500 showed considerable systemic sex-related toxicity, with MTDs ranging from 40 ± 2 mg.kg −1 to 95 ± 2 mg.kg −1 for male and female mice, respectively. Studies of SNPs showed blood toxicity as a function of physiochemical properties such as significant differences in the mean corpuscular hemoglobin (MCHC) and platelet number at day 10 and white blood cell count at day 60. Histological examination also showed size-, porosity-and time-dependent tissue toxicity. Stöber

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