Table 1. Developmental DE-71 exposure studies of the thyroid hormone system and brain development in rats.

Exposure to DE-71	TH/TSH	Thyroid gland	Developmental neurotoxicity and hearing	Reference
Studies including only thyroid hormone system endpoints
0, 0.1, 1, 10 or 30 mg/kg/day to SD dams GD6-PND21 (wafer, oral) (n = 6–9)	Dam PD21 tT4 and fT4↓ up to ~50%, tT3↔, TSH↔ Pup PD21 tT4↓ up to 85%, fT4↓ up to 75%, tT3↔, TSH↔	-	-	[34] (Bansal et al., 2014)
0 or 18 mg/kg/day to SD dams GD6-LD18 (intragastric) (n = 3–7)	Dam LD19 tT4↓45%, tT3↔, TSH↔ Pup PND18 tT4↓75%, tT3↔, TSH↔	Dam thyroid gland weights were obtained but results not stated	-	[24] (Ellis-Hutchings et al., 2006)
0, 1.7, 10.2 or 30.6 mg/kg/day to LE dams from GD6-PND21 (oral gavage) (n = 7–9)	Male pup: PND4 tT4↓ up to 50%, tT3↔ PND21 tT4↓ up to 75%, tT3↔	-	-	[4] (Szabo et al., 2009)
0, 1, 10 or 30 mg/kg/day to LE dams GD6-PND21 (oral gavage) (n = unclear, maybe 38–48 dams per group for both GD20 and PND22)	Dam GD20: tT4↓ 48% in high dose, tT3↔ Dam PND22: tT4↓45%, tT3↔ Fetal GD20: tT4↓ (more than 15%, control group very close to LOQ) Pup PND4: tT4↓ up to 40%, tT3↔ Pup PND14: tT4↓ up to 66%, tT3↔	-	-	[35] (Zhou et al., 2002)
Studies also including developmental neurotoxicity endpoints
0, 0.3, 3.0 or 30 mg/kg/day to SD dams GD1-PND 21 (cookie, oral) (n = 20–22 litters, TH: n = 9–10, TSH: n = 20–22, thyroid histo n = 8–10)	Dam PND21: tT4 and tT3 ↓ (data not shown) Male pup PND21: tT4↓ up to ~95%, tT3↓ up to 40% Female pup PND21: tT4↓ up to ~90%, tT3↓ up to 40% Pup PND21, TSH↑ ~30% in high dose	Male pup PND21: increased epithelial cell height in high dose	Brain weight PND21, 50, 105, 250: ↔ except PND21 raw brain weight ↓ in low dose and relative brain weight ↑ in high dose PND21 (both sexes), Motor activity PND 16, 55, 110 and 230: ↔, except small changes in rearing PND110 Acoustic startle PND20 and 90: potentiation on PND90 indicating delayed effects on sensory reactivity Beam test PND 33, 60: ↔ Emergency latency PND35, 80: ↔ Morris Water Maze PND 235: ↔ Nicotine-induced activity PND450: ↔	[18] (Bowers et al., 2015)
0 or 30 mg/kg/day to Wistar rat pups PND5-22 (oral gavage) (Open field: n = 17, radial maze: n = 11, T4: n = 10)	Male pup PND 23: tT4↓ ~50% Female pup PND 23: tT4↓ ~50%	Male pup PND23: thyroid gland weight↔ Female pup PND23: thyroid gland weight↔	Brain weight PND23↔ Open field PND42 and 70: ↔ motor activity both sexes RAM PND100: reference memory deficit, females only	[19] (De-Miranda et al., 2016)
0, 1.7, 20.2 or 30.6 mg/kg/day to LE dams GD6-PND21 (oral gavage) (n > 15 per group, n = 8–13 in FOB, n = 7–8 open field, TSH n = 5–12)	Dams PND22: tT4↓ up to ~40%, tT3↔, TSH↑ ~130% in high dose Male pups PD4: tT4↓ 52% in high dose, TSH↔ Male pups PD7: tT4↓ 60% in high dose, TSH↔ Male pups PD14: tT4↓ up to 78%, TSH↔ Male pups PD21: tT4↓ up to 74%, TSH↔ Female pups PD4: tT4↓ 56% in high dose, TSH↔ Female pups PD7: tT4↓ 50% in high dose, TSH↔ Female pups PD14: tT4↓ up to 80%, TSH↔ Female pups PD21: tT4↓ up to 76%, TSH↔	-	FOB including open field PND24, 60 and 273: ↔, except significant interaction dose*age interaction from PD24-60, but no overall treatment effect on PND60 Motor activity in figure eight, PND 24 and 60: ↔ motor activity (motron) PND~110: ↔	[17] (Kodavanti et al., 2010)
0, 40, 60 mg/kg/day to Wistar dams GD7-PD16 (oral gavage) (n = 19–21)	Dam GD15 tT4↓ up to 60%, tT3↓ up to 25%, TSH↔ Pup PD8-PD27 tT4↓ ~60% all doses, PD16 tT3↓ ~25% all doses, PD27 tT3↓~15% all doses	Dam PD27 thyroid gland weight↔ Female pup PD16 thyroid weight↔ Male pup PD27 thyroid weight↔ Male PD16 histology: no changes in follicular epithelium, follicular morphology, stroma or c-cells but increased minimal vacuolation of follicular colloid in high dose	Motor activity PD21 and PD79: ↔ Morris water maze at 4.5–6 months of age: ↔ Hearing function at 7.5–8 months: ↔	This study
For comparison: studies with exposure to TPO-inhibitors in same or similar studies
0, 0.8, 1.6 or 2.4 mg/kg/day PTU to Wistar dams GD7-PD17 (oral gavage) (n = 18–21)	Dam GD15: tT4↓ with up to ~60% Pup PND16: tT4↓ with up to ~85%	Pups PND16: thyroid gland weight↑ Pup histology PND16: marked changes with hyperplasia and hypertrophy of epithelial cells, papillary projections into lumen and reduced lumen size	Motor activity: PND 14↓, PND17↔, PND23↑, 16 weeks: ↑ Morris water maze, weeks 8–9: ↔ RAM, males 5–6 months: ↓ learning and memory Hearing, adult offspring: ↓	[10] (Axelstad et al., 2008)
0 or 30 mg/kg/day PTU to Wistar rat pups PND5-22 (oral gavage) (Open field: n = 17, radial maze: n = 11, T4: n = 10)	Male pup PND 23: tT4↓ >95% Female pup PND 23: tT4↓ >95%	PND23: thyroid gland weight↑, both sexes	Brain weight, relative PND23: ↑, both sexes Open field PND42 and 70: ↑motor activity, both sexes RAM PND100: working and reference memory learning deficits, both sexes	[19] (De-Miranda et al., 2016)
0, 8 mg/kg/day MMI, 16 mg/kg/day MMI, 25 or 50 mg/kg/day amitrole SD dams GD7-PD22 (oral gavage) (n = 12). Effects are similar in both MMI and amitrole unless otherwise stated.	Dam GD15: tT4↓ up to ~60%, tT3↓23% in high dose amitrole, TSH↑ up to ~800% Dam PD22: tT4↓ up to ~60% in MMI and 90% in amitrole, tT3↑30% in low dose MMI, TSH↑ up to ~800% Male pup PD16: tT4↓ up to ~80–90% in high dose, tT3↓25–35% in high dose, TSH↑330–425% in high dose Female pup PD17: tT4↓ up to ~80–90% in high dose, tT3↓25–30% in high dose, TSH↑250–360% in high dose	Dam PD22: thyroid gland weight ↑ Male pup PD16: thyroid gland weight↑ Female pup PD17: thyroid gland weight↑ Male pup PD16 histology (n = 4): hyperplasia/hypertrophy, irregular follicles, reduced lumen size and colloid depletion	Motor activity, offspring PND21:↑	[6] (Ramhøj et al., 2022)

Abbreviations: f: free, LD: lactation day, LE: Long-Evans, MMI: Methimazole, PND: postnatal day, PD: pup day, PTU: propylthiouracil, RAM: radial arm maze, SD: Sprague-Dawley, T4: thyroxine, T3: 3,3´,5-tri-iodothyronine, TH: thyroid hormones, t: total, TSH: thyroid stimulating hormone

All doses given in mg/kg bodyweight/day.