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

Table 1.

Repeated dose studies in rats published after 2006

Strain Dose and animals per group Duration/time of observation Main effects observed Effect level Reference
F344/N (♂) 0, 21, 70, 210 μg/kg bw per day (gavage, corn oil, 5 days/week)( a ), n = 5 14, 28, 90 days

  • Decreased relative kidney weight (90 day: 70, 210 μg/kg bw)

  • Renal histopathological changes involving S3 segment of proximal tubules in OSOM and medullary rays: single cell death, basophilia, karyomegaly (14 day: 210 μg/kg bw; 28 day and 90 day: 70, 210 μg/kg bw)

  • Increased BrdU labelling (28 day: 210 μg/kg bw; 90 day: 70, 210 μg/kg bw)

 NOAEL 21 μg/kg bw per day (5 days/week)( b ) (based on renal histopathology, gene expression, urinary KIM‐1 and urine biochemistry) Rached et al. (2007)

  • Increased mRNA expression of kidney injury marker genes (e.g. KIM‐1, lipocalin‐2, Timp‐1) (14 day: 210 μg/kg bw; 28 days and 90 days: 70, 210 μg/kg bw)

 Rached et al. (2008)

  • Increased urinary excretion of KIM‐1 (14 days and 28 days: 210 μg/kg bw; 90 days: 70, 210 μg/kg bw)

 Hoffmann et al. (2010)

  • Changes in urinary metabolome (14 days: 210 μg/kg bw; 28 days and 90 days: 70, 210 μg/kg bw)

 Sieber et al. (2009)

  • Altered expression of genes involved in cell cycle control and mitosis (14 days: 210 μg/kg bw; 90 days: 70, 210 μg/kg bw)

 Adler et al. (2009)
F344 gpt delta rats (♂, ♀) 0, 5 mg/kg diet corresponding to 0, 360 μg/kg bw (♂); 380 μg/kg bw (♀), n = 4–5 4, 13 weeks

  • Renal histopathological changes involving proximal tubule cells in OSOM: apoptosis, karyomegaly, vacuolisation (4 weeks and 13 weeks: ♂, ♀)

  • Site‐specific increase in Spi− but not gpt mutation frequencies indicative of deletion mutations in outer medulla (4 weeks: ♂; 13 weeks: n.d.; ♀: n.d.)

 5 mg/kg diet (corresponding to 360 μg/kg bw) (based on renal histopathology) Hibi et al. (2011)
4 weeks

  • Site‐specific changes in genes associated with cell cycle regulation, DNA damage and DNA repair in outer medulla (4 weeks: ♂; ♀: n.d.)

 Hibi et al. (2013a)
F344 gpt delta rats (♂) 0, 70, 210, 630 μg/kg bw (gavage, sodium bicarbonate, 7 days/weeks), n = 5 4 weeks

  • Decreased relative kidney weight (70, 210, 630 μg/kg bw)

  • DNA strand breaks (Comet assay) (70, 210, 630 μg/kg bw) and increase in γ‐H2AX (210, 630 μg/kg bw) in renal outer medulla

  • Changes in mRNA expression of homologous recombination repair and G2/M arrest‐related genes (70, 210, 630 μg/kg bw)

 LOAEL* 70 μg/kg bw per day (7 days/weeks) (based on kidney weight, DNA strand breaks) Kuroda et al. (2014)
F344 (♂) 0, 70, 210 μg/kg bw (gavage, corn oil, 5 days/weeks)( c ), n = 6 4, 13 weeks

  • Decreased kidney weight (13 weeks: 210 μg/kg bw)

  • Renal histopathological changes involving proximal tubule epithelium in OSOM: karyomegaly, cytoplasmic vacuolisation (13 weeks: 70, 210 μg/kg bw)

  • Increased protein expression of kidney injury markers (KIM‐1, clusterin) in OSOM (4 weeks: 210 μg/kg bw; 13 weeks: 70, 210 μg/kg bw)

  • Increased renal expression of PCNA indicative of cell proliferation (no quantitative data)

 LOAEL* 70 μg/kg bw per day (5 days/weeks)( d ) (based on renal histopathology) Qi et al. (2014a)
F344 (♂) 0, 70, 210 μg/kg bw (gavage, corn oil, 5 days/weeks)( c ), n = 6 2, 4, 13, 26 weeks

  • Decreased kidney weight (2 weeks: 70 μg/kg bw; 13 weeks: 70, 210 μg/kg bw; 26 weeks: 210 μg/kg bw)

  • Renal histopathological changes involving proximal tubular epithelial cells in OSOM: cytoplasmic vacuolisation and karyomegaly (13 weeks and 26 weeks: 70 and 210 μg/kg bw)

  • Changes in renal mRNA and miRNA expression profile (13 weeks: 70, 210 μg/kg bw; 2, 4, 26 weeks: n.d.)

 LOAEL* 70 μg/kg bw per day (5 days/week)( d ) (based on renal histopathology, renal/hepatic mRNA and miRNA expression and changes in gut microflora) Dai et al. (2014)

  • No apparent damage to liver but changes in hepatic mRNA and miRNA expression profile (13 weeks: 70, 210 μg/kg bw; 2, 4, 26 weeks: n.d.)

 Qi et al. (2014b)

  • Changes in gut microbiota based on 16S rRNA and shotgun sequencing of faecal samples (4 weeks: 70, 210 μg/kg bw; 2, 13, 26 weeks: n.d.)

 Guo et al. (2014)
Wistar (♂) 0, 1, 4 mg/kg bw (gavage, corn oil, daily), n = 6 7 days

  • Decreased body weight, increased relative kidney and liver weight (1, 4 mg/kg bw)

  • Increase in AST, ALP, LDH, total protein, albumin, glucose, BUN and serum creatinine (1, 4 mg/kg bw)

  • Renal histopathological changes: denaturalisation and necrosis in the epithelial cells of renal tubules in cortex and outer medulla (1, 4 mg/kg bw)

  • Increased expression of kidney injury marker genes (1, 4 mg/kg bw)

  • Minor effects on markers of oxidative stress (ROS, SOD) (1, 4 mg/kg bw)

 LOAEL* 1 mg/kg bw per day (7 days/week) (based on organ and body weight, renal histopathology, blood biochemistry) Zhu et al. (2016a)
Wistar (♂) 0, 289 μg/kg bw (gavage, 0.1 M NaHCO3; every 2nd day)( e ), n = 8 90 days

  • Slight increase in ALT and decrease in serum albumin

  • No histopathological changes in liver (kidney not examined)

 289 μg/kg bw every 2nd day( e ) Gagliano et al. (2006)
Wistar (♂) 0, 50, 125, 250, 500 μg/kg bw (gavage, 51 mM NaHCO3, every 2nd day)( f ), n = 4 10 days

  • Renal histopathological changes involving S3 segments, predominantly in the medullary rays: single cell damage, desquamation of the luminal membrane and whole cells, thinning of epithelium, accumulation of the cell debris in the tubule lumen) (≥ 50 μg/kg bw)

  • Increased renal expression of OAT1, OAT2 and OAT3 (≥ 50 μg/kg bw)

 LOAEL * 50 μg/kg bw every 2nd day( g ) (based on renal histopathology) Zlender et al. (2009)
F344/NSIc (♂) 0( h ), 210 μg/kg bw (gavage, 0.1 M NaHCO3, daily), n = 10 28 days

  • Renal histopathological changes involving proximal tubular cells in OSOM: karyomegaly

  • Increase in Ki‐67 immunoreactive cells in OSOM

  • Altered expression of cell cycle‐related genes

 210 μg/kg bw per day (based on renal histopathology) Taniai et al. (2012a)

  • Alterations in gene expression in kidney

 Taniai et al. (2012b)
F344/NSlc (♂) 0( h ), 210 μg/kg bw (gavage, 0.1 M NaHCO3; 7 days/week), n = 15–16 28 days

  • Decreased body weight, decreased absolute and relative kidney weight,

  • Renal histopathological changes in OSOM: karyomegaly

  • Increased PCNA immunostaining

  • Altered gene expression in kidney

 210 μg/kg bw per day (7 days/weekweek) (based on renal histopathology) Taniai et al. (2014)
F344/IcoCrl (♂,♀) 0, 210, 500 μg/kg bw (gavage, 0.1 M NaHCO3, 7 days/week), n = 6 7, 21 days

  • Decreased body weight (21 days: 500 μg/kg bw♂), decreased absolute kidney weight (21 days: ♂, ♀; not reported at which dose)

  • Renal histopathological changes: degeneration, necrosis, karyomegaly of proximal tubule cells (7 days: 500 μg (kg bw ♂, ♀, 210 μg/kg bw n.d.; 21 days: 210, 500 μg/kg bw ♂, ♀)

 LOAEL* 210 μg/kg bw per day (based on renal histopathology) Pastor et al. (2018)

  • No effect on GST activity, GSH/GSSG ratio, SOD activity

  • No evidence for DNA SBs based on Comet assay

 Enciso et al. (2018)

ALT: alanine aminotransferase; AST: aspartate aminotransferase; BrdU: bromo‐desoxy‐uridine; BUN: blood urea nitrogen; clusterin: protein associated with clearance of cellular debris and apoptosis; DNA: deoxyribonucleic acid; γ‐H2AX: H2A histone family member X phosphorylated on Ser 139, marker for DNA damage; G2/M arrest: gap2/mitotic arrest; Gpt: Glutamic‐pyruvic transaminase gene; GSH; glutathione; GSH/GSSG ratio: ratio of reduced GSH to oxidised GSH (GSSG); GST: glutathione S‐transferase; 8‐OH‐dG: 8‐hydroxy‐deoxyguanine; Ki‐67: marker protein for proliferation; KIM‐1; Kidney injury molecule‐1; LDH: lactate dehydrogenase; LOAEL: lowest observed adverse effect level; LOEL: lowest observed effect level; MDA: malondialdehyde; miRNA: micro RNA; mRNA: messenger RNA; n: number; n.d.: not determined; NOAEL; no observed adverse effect level; OAT; organic anion transporter; OSOM: outer stripe of the outer medulla; OTA: ochratoxin; PCNA: proliferating cell nuclear antigen ROS: reactive oxygen species; S3 segment: Straight segments of the proximal tubule that descend into the outer medulla; SOD: superoxide dismutase; spi− – protein spitz precursor (a proto oncogene); TIMP‐1: tissue inhibitor of metalloproteinase‐1 (a protein); wk: week.

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

a

Equivalent to 0, 15, 50, 150 μg/kg bw per day.

b

Equivalent to 15 μg/kg bw per day.

c

Equivalent to 0, 50, 150 μg/kg bw per day.

d

Equivalent to 50 μg/kg bw per day.

e

Equivalent to 145 μg/kg bw per day.

f

Equivalent to 25, 62.5, 125, 250 μg/kg bw per day.

g

Equivalent to 25 μg/kg bw per day.

h

Untreated control animals were maintained on the basal diet and tap water without any treatment during the experimental period.