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. 2020 May 8;94(5):1375–1415. doi: 10.1007/s00204-020-02725-2

Table 2.

Selected high-quality developmental toxicity studies

Species, strain, number of animals	Exposure duration, chemical form, route	NaF concentration in DW (mg/L)	Doses (mg/kg/d)	NOAEL (mg/L) (mg/kg/d)	LOAEL (mg/L) (mg/kg/d)	Outcome (as stated by the authors)	Comments	References
Rat, CD, 26/group	GD 6 through 15 Investigations were done on GD 20 Sodium fluoride (DW)	< 0.6, 50, 150, 300	NaF^a: 0, 6.6, 18.3, 27.1	≥ 300 mg/L NaF 27 mg NaF/kg/d^a	–	Maternal exposure to NaF during organogenesis did not significantly affect the frequency of postimplantation loss, mean fetal body weight/litter, or external, visceral or skeletal malformations	NOAEL is the highest dose tested Drinking water: < 0.6 mg/L NaF Feed: 12.4 mg per kg fluoride	Heindel et al. (1996)
Rat, CD, 26/group		< 0.6, 50, 150, 300	Total F^– intake (water and feed)^a: 1, 4.0, 9.3, 13.2	13.2 mg F^– /kg/d^a	–			Heindel et al. (1996)
Rabbit, New Zealand White rabbits, 26/group	GD 6 through 19 Investigations were done on GD 30 Sodium fluoride (DW)	< 0.6, 100, 200, 400	NaF^a: 0, 10.3, 18.1, 29.2	≥ 400 mg/L NaF 29 mg NaF/kg/d^a	–	Maternal exposure to NaF during organogenesis did not significantly affect the frequency of postimplantation loss, mean fetal body weight/litter, or external, visceral or skeletal malformations	NOAEL is the highest dose tested Drinking water: < 0.6 mg/L NaF Feed: 15.6 mg per kg fluoride	Heindel et al. (1996)
Rabbit, New Zealand White rabbits, 26/group		< 0.6, 100, 200, 400	Total F^– intake (water and feed)^a: 0.8, 5.8, 8.8, 13.7	13.7 mg F^– /kg/d^a	–			Heindel et al. (1996)
Rat, CD, 35–37/group	GD 0 through GD 20 Investigations were done on GD 20 Sodium fluoride (DW)	0, 10, 25, 100, 175, 250	NaF^a: 0, 1.4, 3.9, 15.6, 24.7, 25.1	175 mg/L NaF 24.7 mg NaF/kg/d^a	250 mg/L 25.1 mg NaF/kg/d^a	Fetal growth, number of external anomalies in fetuses, development of specific bones, including sternebrae were not affected by NaF A significant increase in the average number of fetuses with three or more skeletal variations was observed in the 250 mg/L group The number of litters with fetuses with three or more skeletal variations was increased in the 250 mg/L group (not statistically significant)	Water consumption in the 175- and 250-mg/L groups was significantly less than that of the control females. The daily amount of NaF ingested was less than expected at the two higher dose levels Feed: 7.95 mg/kg fluoride Control: Aqua Cool Ultra Pure water	Collins et al. (1995)
Rat, CD, 35–37/group		0, 10, 25, 100, 175, 250	F^–^a: 0, 0.6, 1.8, 7.1, 11.2, 11.4	11.2 mg F^–/kg/d^a	11.4 mg F^– /kg/d^a			Collins et al. (1995)
Rat, CD, 48/sex/group	Continuously during three generations. F0 rats were treated for 10 weeks and mated within groups Investigations of F0, F1 and F2 fetuses were done on GD 20 Sodium fluoride (DW)	0, 25, 100, 175 or 250	NaF^a: 0, 3.4, 12.4–13.2, 18.8–19.3, 25.8–28.0	175 mg/L NaF 18.8–19.3 mg NaF/kg/d	250 mg/L NaF 25.8–28.0 mg NaF/kg/d	Sodium fluoride in drinking water at 175 mg/L produced no compound-related effects. Numbers of corpora lutea, implants, viable fetuses and fetal morphological development were similar in all groups. No dose-related anomalies in internal organs were observed in F2 fetuses Ossification of the hyoid bone of F2 fetuses was significantly decreased at 250 mg/L (considered as LOAEL)	Feed: 7.95 mg/kg fluoride Concentration of fluoride in the Pico system treated water: < 0.2 mg/L	Collins et al. (2001b)
Rat, CD, 48/sex/group		0, 25, 100, 175 or 250	F^–^a: 0, 1.5, 5.6–6.0, 8.5–8-7, 11.7–12.7	8.5–8.7 mg F^– /kg/d	11.7–12.7 mg F^– /kg/d			Collins et al. (2001b)

DW drinking water, GD gestation day, NaF sodium fluoride

^aAs reported by the authors of the study