Table 9.

In vivo reproductive and developmental toxicity studies published since 2006

Animals	Study design	Observations	Effect level	Reference
Pregnant Wistar rats	Preliminary study: Gavage; single doses of 0.0, 2.0, 2.5, 2.75, 3.0, 3.5 and 4.0 mg OTA/kg bw on one day in the period of GD 6–15. Sacrifice on GD 20 Main study: Gavage, single doses of 0.0 and 2.75 mg OTA/kg bw per day in the period of GD 6–15. Sacrifice on GD 20. N = 10 per group	Preliminary study: Doses of ≥ 3.0 mg/kg bw: pronounced maternal and developmental toxicity Doses of ≤ 2.0 mg/kg bw: no effects Main study: Dams: anorexia, polydipsia, polyuria, lacrimation, in particular when treated on GD6–8. Resorptions and post implantation loss when treated on GD6–7 Fetuses: Hydrocephaly, incomplete closure of skull and omphalocele, microphthalmia, enlarged renal pelvis and renal hypoplasia; malformed skulls, sternebrae, vertebrae, ribs, in particular in dams treated on GD6–7	2.75 mg OTA/kg bw per day (only one dose level tested)	Patil et al. (2006)
Male and female 45–49 days old Fischer rats	Diet, 0.0, 0.16, 0.4, 1.0 and 2.5 mg OTA/kg feed, corresponding to 0.0, 8.9, 21.7, 55.2 and 141.8 μg/kg bw per day(males) and 0.0, 11.9, 33.9, 73.3 and 167.0 μg/kg bw per day (females); From day 1–70 (F0 males and females pre‐mating, mating), from day 28–70 (F0 males, pregnant and non‐pregnant F0 females); From day 49–70 or PND1‐21 (F1 pups). N = 10 per group and sex	F0 males and females: mild increases in severity scores for tubular epithelial cell degeneration at 0.16 and 2.5 mg/kg in females and from 0.4 mg/kg onwards in males F0 males: ↓relative kidney weights at 1.0 and 2.5 mg/kg feed. At 2.5 mg/kg feed ↑ in albumin, sodium, total protein and bilirubin at 2.5 mg/kg feed F0 females: ↓relative kidney weights, bw, absolute ovary weight, cholesterol, RBC, haemoglobin, haematocrit, RDW, monocytes, neutrophils ↓ implantations at 2.5 mg/kg feed In F1 males from dams given 1.0 mg/kg feed ↓bw in on PND4, 7, 14, 21; In F1 females from dams given 1.0 mg/kg feed ↓ bw on PND4, 7; ↑ tubular degeneration in F1 males of dams given 0.16 mg/kg onward sand in F1 females from dams given 0.4 mg/kg onwards; In F1 males from dams given 1.0 mg/kg ↓relative kidney/liver weights, ↑ plasma cholesterol and in F1 males from dams given 0.4 mg/kg ↑ plasma phosphorous In F1 females from dams given 1.0 mg/kg ↓ relative liver weight, ↑ cholesterol and in F1 females from dams given 0.4 mg/kg onwards ↓ relative kidney weight	The authors set an LOAEL for ↓ body weight for female F0 rats at 167 μg/kg bw and a LOAEL for ↓ kidney weight in F0 males at 55.2 μg/kg bw per day and for F0 females at 167 μg/kg bw per day Authors set an LOAEL for ↓ bw for F1 males and females at 55 and 73.3μg/kg bw per day, respectively, was set and an LOAEL for ↓ relative kidney weight in F1 males at 55 μg/kg bw per day and for F1 females at 33.9 μg/kg bw per day	Bondy et al. (2018)
Pregnant rabbits	Diet, 0.0, 0.03, 0.06 mg OTA/kg bw for 15 days (GD 6–20); N = 5 per group	At 0.03 mg/kg bw: ↑ ALT, ↓ RBC, ↑MCV in dams, ↓fetus length and weight At 0.06 mg/kg bw: ↑ urea, AST, ALT; ↓ RBC, Hb, PCV; ↑MCV in dams, ↓ fetus length and weight At both doses, dams had mild to moderate degenerative changes (pyknosis, necrosis of glomeruli, congestion of tubular epithelial cells) in kidney, at high dose also accumulation of eosinophilic material. At high dose moderate degenerative changes in the liver (cellular shrinkage, widening of sinusoidal spaces, vacuolation). No effects on the intestine observed	0.03 mg/kg bw per day	Jan et al. (2017)
Young male inbred Swiss albino mice	Gavage, 0.0, 1.5, 3.0 mg/kg bw for 45 days. N = 10 per group	At 1.5 and 3.0 mg OTA/kg bw ↓ sperm count (−22% and ‐69%), sperm motility (−45% and −72%), sperm viability (−34% and‐59%) fertility rate (−50 and −77%)	1500 μg/kg bw per day	Chakraborty and Verma (2010a)
Groups of 12 mated female Crl:CD (SD) rats	Diet, 0.0, 012, 0.6, 3.0 mg/kg OTA from GD6‐21 (corresponding to 0.0, 8.0, 39.3, 203.6 μg/kg bw per day during gestation and 0.0, 16.1, 76.0 and 378.6 μg/kg bw per day during lactation period). Sacrifice of dams on PND 22. Offspring maintained until PND 77 (27 males and 10 females per group) without OTA. Interim sacrifice of offspring on PND 21 (10 males per group)	No effect on maternal parameters (behaviour, brain and kidney weight) At 3.0 mg/kg bw male and female offspring (F1) showed transient body weight decrease after weaning. Changes in hippocampal neurogenesis‐related parameters were seen in males at PND 21. Female and male offspring showed neuroprotective actions against OTA‐induced neurogenesis. All changes were reversed by PND77	Authors set the NOAEL for offspring neurogenesis at 0.6 mg OTA/kg feed, corresponding to 39.3–76.0 μg/kg bw per day	Tanaka et al. (2016)

ALT: alanine transaminase; AST: aspartate transaminase; F0: parent generation; F1: first filial generation; F2; second filial generation; GD: gestation day; Hb: haemoglobin; LOAEL: lowest observed adverse effect level; MCV: mean corpuscular volume; NOAEL: no observed adverse effect level; OTA: ochratoxin; PCV; packed cell volume; PND: post‐natal day; RBC: red blood cells; RDW: red cell distribution.