Table 1 Overview of oral toxicokinetic and toxicodynamic studies in rodents
From: Critical review of the safety assessment of titanium dioxide additives in food
Study type | Oral dose | Particle structure (mean size) | Internal exposure | Main reported effects | Source |
|---|---|---|---|---|---|
Acute toxicity in mice | 5000 mg/kg | Structure not specified (25, 80 and 155 nm) | ~ 4 µg/g Ti in liver | Histopathologic findings in brain, liver and kidney | [42] |
Acute toxicity in rats | Up to 5000Â mg/kg | Coated rutile/anatase (73Â nm) | Not examined | None | [82] |
Bioavailability in rats | Up to 80 µg/kg | Radiolabeled anatase (50 nm) | Oral particle bioavailability of ~ 0.6% | None | [64] |
Bioavailability in rats | 5 mg/kg | Anatase and rutile (40 nm–5 µm) | None detected | None | [40] |
Toxicokinetics in rats | ~ 10 mg/kg/day for 5 days | Anatase and rutile (6–90 nm) | Oral particle bioavailability of ~ 0.02% | None | [67] |
Toxicokinetics in rats | Up to 2 mg/kg/day for 5 days | Anatase (20–60 nm) | Increased Ti concentrations in spleen and ovaries | Altered testosterone levels, histopathologic findings in thyroids | [68] |
Toxicokinetics in rats | Up to 30Â mg/kg/day for 7Â days | Anatase and rutile (primary sizes not specified) | None detected | None | [37] |
Toxicokinetics in rats | 12.5Â mg/kg/day for 10Â days | Rutile (500Â nm) | Detection of particles in GALT, lymph nodes and liver | None | [66] |
Subacute toxicity in mice | Up to 500Â mg/kg/day for 5Â days | Anatase/rutile (46Â nm) | Not examined | Histopathologic findings in gut mucosa | [134] |
Subacute toxicity in mice | Up to 100 mg/kg/day for 14 days | Anatase (20–50 nm) | Not examined | Histopathologic findings in liver | [83] |
Subacute toxicity in mice | 150Â mg/kg/day for 14Â days | Anatase (21Â nm) | Not examined | Histopathologic findings in liver | [84] |
Subacute toxicity in rats | 300 mg/kg/day for 14 days | Structure not specified (50–100 nm) | Not examined | Histopathologic findings in liver | [85] |
Subacute toxicity in rats | 24,000Â mg/kg/day for 28Â days | Rutile (173Â nm) | Detection of particles in GALT | None | [82] |
Subacute toxicity in rats | Up to 200Â mg/kg/day for 30Â days | Anatase (75Â nm) | Not examined | Histopathologic findings in liver | [88] |
Subchronic toxicity in mice | Up to 250Â mg/kg/day for 42Â days | Anatase (25Â nm) | Not examined | Increased sperm abnormalities | [86] |
Subchronic toxicity in mice | 64 mg/kg/day for 196 days | Anatase (18 and 120 nm) | ~ 0.15 µg/ml Ti in whole blood | Histopathologic findings in liver, kidney, spleen and pancreas | [65] |
Subchronic toxicity in rats | Up to 1000Â mg/kg/day for 90Â days | Coated rutile (145Â nm) | Detection of particles in GALT | None | [82] |
Subchronic toxicity in rats | Up to 1042Â mg/kg/day for 90Â days | Anatase/rutile (26Â nm) | Marginally higher Ti blood levels in males | None | [39] |
Subchronic toxicity in rats | Up to 50Â mg/kg/day for 30 and 90Â days | Anatase (24Â nm) | None | Altered serum enzyme levels | [87] |
Carcinogenicity in mice | Up to 8350Â mg/kg/day for 2Â years | Anatase (pigment-grade) | Not examined | Lower survival, hepatocellular carcinomas | [112] |
Carcinogenicity in rats | Up to 2900Â mg/kg/day for 2Â years | Anatase (pigment-grade) | Not examined | Hyperplastic bile ducts, thyroid carcinomas | [112] |
Reproductive toxicity in rats | Up to 1000 mg/kg/day in gestation | Anatase and/or rutile (43–213 nm) | Not examined | None | [114] |
Reproductive toxicity in rats | 100Â mg/kg/day in gestation | Anatase (10Â nm) | Increased Ti content in hippocampus | Impaired learning and memory | [116] |
Acute colitis model in mice | Up to 500 mg/kg/day for 7 days | Rutile (30–50 nm) | Not examined | Histopathologic findings in gut mucosa | [124] |
Colon cancer model in rats | Up to 10Â mg/kg/day for up to 100Â days | Anatase/rutile (22 and 118Â nm) | Detection of particles in GALT and liver | Histopathologic findings in gut mucosa | [135] |