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. 2020 May 13;18(5):e06113. doi: 10.2903/j.efsa.2020.6113

Table 2.

Repeated dose studies in mice published after 2006

Strain Dose and animals per group Duration/time of observation Main effects observed Effect level Reference
Inbred Swiss albino (♂) 0( a ), 1.5, 3 mg/kg bw per day (gavage, olive oil, 7 days/week) n = 10 45 days

  • Significant dose‐dependent increase in lipid peroxidation (TBARS), decrease in GSH and ascorbic acid, decreased activity of catalase, SOD, GPx, GSR, GST

 *LOAEL 1.5 mg/kg bw per day (based on renal non‐enzymatic and enzymatic antioxidants) Chakraborty and Verma (2010b)
C57BL/6J – p53 (p53 gene) proficient homozygous Gpt delta C57BL/6J – p53‐deficient homozygous Gpt delta (♂) 1 and 5 mg/kg bw per day (gavage, 0.1 M NaHCO3) n = not provided 4 weeks

  • Significant decreases in body weights and absolute and relative kidney weights (5 mg/kg bw)

  • Renal histopathological findings in OSOM: apoptosis, karyomegaly, vacuolisation of proximal tubule cells (1.5 mg/kg bw)

  • Significant increases in Spi−mutant frequencies in kidneys of p53‐deficient gpt delta mice (5 mg/kg bw)

 LOAEL* 1 mg/kg bw per day (based on renal histopathology) Hibi et al. (2013b)

C57BL/6 × FVB ‐ HO‐1+/+

C57BL/6 × FVB ‐ HO‐1−/− (♂, ♀)

 0, 2.5 mg/kg bw per day (i.p. 0.1 M NaHCO3 every 2nd day), n = not provided 20 days

  • Decreased survival rate in HO‐1−/−

  • Decreased body and relative kidney weight in HO‐1+/+ and HO‐1−/− (result presented combined for ♂ and ♀)

  • Increased serum creatinine in HO‐1+/+ and HO‐1−/− (result presented combined for ♂ and ♀)

 2.5 mg/kg bw every 2nd day, i.p. Loboda et al. (2017a)
C57BL/6 ‐ Nrf2+/+, C57BL/6 ‐ Nrf2−/− (♂, ♀) 0, 2.5 mg/kg bw per day (i.p., 0.1 M NaHCO3, every 2nd day), n=3‐5 20 days

  • Decreased body and relative kidney weight in Nrf2+/+and Nrf2−/− (result presented combined for ♂ and ♀)

  • Increased serum creatinine and Nrf2−/− (♂, ♀)

 2.5 mg/kg bw every 2nd day, i.p. Loboda et al. (2017b)

DNA; deoxyribonucleic acid; GPx: Glutathione peroxidase; GSH; glutathione; GSR: Glutathione reductase, i.p.: intraperitoneal; HO‐1: heme oxygenase 1, LOAEL; lowest observed adverse effect level; Nrf2: nuclear factor erythroid 2–related factor 2 (a protein that regulates expression of antioxidant proteins that protect against oxidative damage; n= number; RNA: ribonucleic acid; TBARS: thiobarbituric acid reactive substances; SOD: superoxide dismutase; spi− ‐ protein spitz precursor (a proto oncogene); wk: week.

*: NOAEL/LOAEL not explicitly reported but derived from data presented in study.

a

Untreated controls were maintained without any treatment.