Oral toxicity of titanium dioxide P25 at repeated dose 28-day and 90-day in rats

Abstract

Background: Nanotechnology is indispensable to many different applications. Although nanoparticles have been widely used in, for example, cosmetics, sunscreen, food packaging, and medications, they may pose human safety risks associated with nanotoxicity. Thus, toxicity testing of nanoparticles is essential to assess the relative health risks associated with consumer exposure. Methods: In this study, we identified the NOAEL (no observed adverse effect level) of the agglomerated/aggregated TiO 2 P25 (approximately 180 nm) administered at repeated doses to Sprague-Dawley (SD) rats for 28 and 90 days. Ten of the 15 animals were necropsied for toxicity evaluation after the repeated-dose 90-day study, and the remaining five animals were allowed to recover for 28 days. The agglomerated/aggregated TiO 2 P25 dose levels used included 250 mg kg − 1 d − 1 (low), 500 mg kg − 1 d − 1 (medium), and 1000 mg kg − 1 d − 1 (high), and their effects were compared with those of the vehicle control. During the treatment period, the animals were observed for mortality, clinical signs (detailed daily and weekly clinical observations), functional observation battery, weekly body weight, and food and water consumption and were also subjected to ophthalmological examination and urinalysis. After termination of the repeated-dose 28-day, 90-day, and recovery studies, clinical pathology (hematology, blood coagulation time, and serum biochemistry), necropsy (organ weights and gross findings), and histopathological examinations were performed. Results: No systemic toxicological effects were associated with the agglomerated/aggregated TiO 2 P25 during the repeated-dose 28-day, 90-day, and recovery studies in SD rats. Therefore, the NOAEL of the agglomerated/aggregated TiO 2 P25 was identified as 1000 mg kg − 1 d − 1 , and the substance was not detected in the target organs. Conclusion: Subacute and subchronic oral administration of the agglomerated/aggregated TiO 2 P25 was unlikely to cause side effects or toxic reactions in rats.

Safety assessment of titanium dioxide (E171) as a food additive

“…In rats orally exposed to TiO 2 NPs < 30 nm, inconsistent and/or unexplained sex differences in some parameters were reported (e.g. hypobilirubinaemia in females (Chen et al (2015a); heart rate and blood pressure changes in females (Chen et al (2015b); leucocyte changes in females (Heo et al, 2020); higher absolute pituitary weights in males (Heo et al, 2020); lower blood insulin levels in females, lower C-peptide levels in males and differences in blood concentrations compared to controls in a glucose tolerance test in males (Chen et al, 2020b). The Panel considered that the TG changes reported in several studies were likely incidental study findings since the reductions were seen in only one sex and without a clear dose response (Chen et al, 2015b), lacked a clear dose response (Vasantharaja et al, 2015) or increased in a single dose study (Grissa et al, 2015) The Panel considered that the effects reported in mouse studies with TiO 2 NPs < 30 nm could be associated with accumulation of NPs in various tissues whereas inconsistent findings in rats were considered incidental.…”

“…In rats orally exposed to TiO 2 NPs < 30 nm, inconsistent and/or unexplained sex differences in some parameters were reported (e.g. hypobilirubinaemia in females (Chen et al., 2015a); heart rate and blood pressure changes in females (Chen et al., 2015b); leucocyte changes in females (Heo et al., 2020); higher absolute pituitary weights in males (Heo et al., 2020); lower blood insulin levels in females, lower C‐peptide levels in males and differences in blood concentrations compared to controls in a glucose tolerance test in males (Chen et al., 2020b).…”

“…descriptions of 'histopathological' lesions are unclear, some of the findings are not histopathological lesions, the number of lesions per organ and the number of animals with any lesions are not clearly stated), the Panel was not able to draw any conclusions. Heo et al (2020) (scoring 3 for NSC) performed a repeated-dose 28-day and a repeated-dose 90-day study in rats. TiO 2 NPs (21 nm) in sodium phosphate buffer were administered by gavage at 0, 250, 500 and 1,000 mg/kg bw per day.…”

“…Heo et al. (2020) (scoring 3 for NSC) performed a repeated‐dose 28‐day and a repeated‐dose 90‐day study in rats. TiO 2 NPs (21 nm) in sodium phosphate buffer were administered by gavage at 0, 250, 500 and 1,000 mg/kg bw per day.…”

“…(2015a); heart rate and blood pressure changes in females (Chen et al. (2015b); leucocyte changes in females (Heo et al., 2020); higher absolute pituitary weights in males (Heo et al., 2020); lower blood insulin levels in females, lower C‐peptide levels in males and differences in blood concentrations compared to controls in a glucose tolerance test in males (Chen et al., 2020b). The Panel considered that the TG changes reported in several studies were likely incidental study findings since the reductions were seen in only one sex and without a clear dose response (Chen et al., 2015bb), lacked a clear dose response (Vasantharaja et al., 2015) or increased in a single dose study (Grissa et al., 2015)…”