Table 1.

Experimental design and outcomes of the 37 studies selected for systematic review, after filtering to remove 7 studies in which estrus stage-dependent outcomes were analyzed without proper control of estrus cycle (see text). Studies are listed in the order presented in the text

Model	Exposure dose (mg/kg/day)	Lowest effective dose (mg/kg/day)*	Exposure window	Route**	OT***	Outcome assessment (age)	Outcome type	Reference
Rhesus macaque	0.4	0.4	E50-100	po to dams	--	E100	Histology, ERα, PR, Ki-67 immunohistochemistry, all genome gene expression	[54]
		0.4	E100-165			E165
White Leghorn hens	67, 134	134	E4	in ovo	--	P147	Histopathology, ERα expression	[55]
CD-1 mice	5	5	E9-E16	ip to dams	--	P14, P42	Expression and methylation of Hoxa10	[56]
Eker rats	50	50	P10-P12	sc	--	P12	Expression of 18 ERE genes	[57]
		50	P10-P12	sc	--	P480	Expression of 18 ERE genes
		--	P10-P12	sc	--	P90, P480	Tumor incidence, non-genomic ER signaling, activity of EZH2, histopathology
Eker rats	0.00005, 0.05, 50	--	P12	sc	--	P12	non-genomic ER signaling
Sprague-Dawley rats	0.00005, 0.01 0.05, 50	--	P12	sc	--	P12	non-genomic ER signaling
Sprague-Dawley rats	0.0004–0.05	--	P12	po	--	P12	non-genomic ER signaling
Sprague-Dawley rats	200, 400, 600	600	P1-P5	sc to dams	--	P6	CaBP-9k expression	[58]
Sprague-Dawley rats	5, 50, 400	5	E11-E20	sc to dams	--	E20	Transcriptome of uterus pooled with ovaries	[59]
Wistar-derived rats	0.05, 20	0.05	P1, P3, P5, P7	sc	--	P8	Hoxa10, Hoxa11 expression	[60]
	0.05, 20	0.05	P1, P3, P5, P7	sc	P80	P93 (after hormonal stimulation)	ERα, PR, Hoxa10, Hoxa11, SMRT, SPC-3 expression, DNA synthesis, Hoxa10 promoter methylation
Donryu rats	0.006, 6	--	E2-P21	po to dams	--	P14, 21, 28, 56	Uterus weight	[62]
		--				P10, 14, 21, 28	Uterus gland development, ERα immunohistochemistry
		--				~ P30-56	Cyclicity
		--				P77-450	Carcinogenicity after N-ethyl-N′-nitro-N-nitrosoguanidine intrauterine administration
Sprague-Dawley rats	200, 400, 600	600	E17-19	sc to dams	--	P5	CaBP-9k expression	[63]
Sprague-Dawley rats	600	600	P14-P16	sc to dams	--	P17	Transcriptome	[64]
CD-1 mice	0.5, 1, 5, 50, 200	0.5	E9-E16	ip to dams	--	P14, P42	Hoxa10 immunohistochemistry	[65]
Wistar-derived rats	0.05, 20	0.05	P1, P3, P5, P7	sc	--	> P80 at pregnancy	Reproductive performance, PR, ERα immunohistochemistry, and gene expression	[66]
Crj: CD (SD) IGS rats	0.0002, 0.002, 0.02, 0.2	0.02	E1-∞	po	--	>P70	Cyclicity of F1 and F2	[76]
		--					Fertility of F1, uterus weight, histology F1-F2
CD-1 mice	~ 0.003, 0.03, 0.3, 5, 50, 600	--	E1-∞	po	--	~ P56-112 (F1)	Cyclicity (for 3 weeks), fertility	[74]
		--				P21 (F1, F2)	Uterus weight, histopathology
Sprague-Dawley rats	~ 0.001, 0.02, 0.3, 5, 50, 500	500	E1-∞	po	--	~ P70-117	Fertility (F2)	[75]
		--				~ P70-117	Cyclicity (for 3 weeks, F1-F3), Fertility (F1)
		--				P21 (F1, F2)	Uterus weight
		500				F1-2 dams after weaning	Uterus weight
		--				F1-3 dams	Histopathology
Sprague-Dawley, Alderley Park (Wistar derived) rats	0.02, 0.1, 50	--	E6-E21	po to dams	--	P98	Uterus weight	[77]
		50					Cycle onset
Sprague-Dawley rats	231.8 at gestation, and 384.4 at lactation	--	E15-P10	po to dams	--	P77 at diestrus	Cyclicity (P48-P77), histology, uterus weight	[78]
Sprague-Dawley rats	0.0025, 0.008, 0.025, 0.08, 0.26, 0.84, 2.7, 100, 300	100	E6-P90	po	--	VO****+10 days, P69-90, P150-170	Cyclicity	[79]
		n/a				P21, P90 at estrus	Uterus weight
		0.008				P90	Histopathology
CD-1 mice	0.5, 10	0.5	E15-19	sc to dams	--	P63-77	Cyclicity	[80]
		--				P28, 56, 84, 112	Histopathology
Sprague-Dawley rats	4.35±1.85, 43.75±18.75	43.75±18.75	P1-P10	sc	--	P60-120	Cyclicity	[81]
ICR/Jcl mice	0.02, 0.2	0.02	E11-17	sc to dams	--	P26-56	Cyclicity	[82]
		--				P90-120	Fertility (pups number)
Crl:CD BR Sprague-Dawley rats	3.2, 32, or 320	--	E11-P20	po	--	P120-142	Cyclicity	[83]
Wistar rats	1.2	1.2	E6-P21	po to dams	--	P120, at estrus	Cyclicity, ERα immunohistochemistry, histopathology	[84]
Sprague-Dawley rats	~0.1, 1.2	--	E6-P21	po to dams	--	P1, 240, 360–480	Macroscopic abnormalities	[85]
		1.2				P120-138	Cyclicity
ICR/Jcl mice	10, 100	--	E10-E18	sc to dams	P30	P40	Histopathology	[86]
	~ 10, 100	~ 100	P1-P5	sc	P30	P40, P90	Histopathology
		~ 10			--	P61-P90	Cyclicity
		--				F1 dams after weaning (~13 week)	Uterus weight, histopathology
FVB mice	0.0005, 0.02, 0.05	0.0005	E11-E21	po to dams	--	VO***+30 days	Cyclicity	[87]
		0.0005				3, 6, 9 months	Fertility
Wistar-derived rats	0.0005, 0.05	0.0005	E9-P21	po to dams	--	P90, 360 in estrus	Histology, α SMA, vimentin, immunohistochemistry, proliferative, apoptotic activity	[88]
		n/a				P70-90, 340-360	Cycling
		0.0005			P360	P460	Histology, ERα, ERβ and PR immunohistochemistry, expression of IGF1, IGFR, p63
Sprague-Dawley rats	0.44±0.19, 4.35±1.85, 43.75±18.75	4.35±1.85	P1-P10	sc	--	P120-150	Fertility	[89]
CD-1 mice	0.000025, 0.00025, 0.025	0.000025	E8-P16	pump to dams	--	P60	Number of pups and pregnancies	[91]
Long-Evans rats	0.02, 0.2	--	E7-P18	po to dams	--	P23-143	Fertility and fecundity	[92]
Sprague-Dawley rats	0.1, 50	0.1	E6-E21	po to dams	--	P120 at estrus	Histopathology, ERα and ERβ immunohistochemistry	[93]
Balb-C mice	0.1, 1	0.1	E1-P7	sc to dams	--	P90	Histopathology, ectopic endometrium	[94]
Wistar rats	0.05, 20	0.05	P1, P3, P5, P7	sc	P80	P93	Vegf expression, endothelial proliferation	[96]
CD-1 mice	0.000025, 0.00025	0.000025	E9-P4	pump to dams	--	P90, at proestrus	ERα, PR expression, histopathology, DNA synthesis	[97]
CD-1 mice	0.0001, 0.001, 0.01, 0.1, 1	0.001	E9-E16	sc to dams	--	P540	Histopathology	[99]
Wistar rats	0.025, 0.25, 5, 50	--	E7-P22	po to dams		P16	Uterus weight	[112]
CD-1 mice	0.01, 0.1, 1	0.01	P1-P5	sc	--	P540	Histopathology	[126]

^*(n/c) – no conclusive results

^**ip – intraperitoneal injection, sc – subcutaneous injection, po – per oral administration, pump – osmotic pumps implanted subcutaneous

^***OT - Ovariectomy

^****VO – day of vaginal opening