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

Table 4.

Neurobehavioral effects of fluoride in experimental animals since 2016 (not included in the NTP report, 2016)

Species, strain, number of animals	Exposure duration, chemical form, route	Concentration in DW (mg/L)	F^– Doses^a (mg/kg/d)	NOAEL F^– (mg/L) (mg/kg/d)	LOAEL F^– (mg/L) (mg/kg/d)	Outcome (as stated by the authors)	Limitations	References
Developmental exposure
Rat, Sprague Dawley 40 F, 20 M (180–220g) 10 dams/dose	From pre-pregnancy until 2 months of delivery Sodium fluoride (DW)	NaF: 10, 50, 100 F^–: 4.52, 22.6, 45.2 Control group: tap water, < 1.0 mg/L F⁻	Dams^a: 0.23, 1.13, 2.26 Pups^a: 0.54, 2.71, 5.42	4.52 mg/L Corresponding to^a: Dams: 0.23 mg/kg/d Pups: 0.54 mg/kg/d	22.6 mg/L Corresponding to^a: Dams: 1.13 mg/kg/d Pups: 2.71 mg/kg/d	50 mg/L NaF and higher caused learning and memory impairments (MWM task, n = 5)	Control for litter effects: NR F^– concentration in food: NR MWM: age of pups NR; influence of activity level/motor deficits NR	Zhao et al. (2019)
Rat, Long–Evans hooded timed-pregnant dams	Start at GD 6 continued to PND 90 Sodium fluoride (DW)	2 DW control groups: low F^– diet (3.24 mg/kg F^–); standard diet (20.5 mg/kg F^–) Treatment: 10, 20 mg/L F^– with low F^– diet	0.08, 0.16^b,c	20 mg/L 0.16 mg/kg/d^b	–	Tests were performed at different ages according to guidelines Male pups were used for testing (n = 10–22) No exposure-related differences in motor, sensory, or learning and memory performance No influence on thyroid hormone parameters No exposure-related pathology in the heart, liver, kidney, testes, seminal vesicles, or epididymis Mild inflammation in the prostate gland at 20 mg/L F⁻ When examined as adults (> PND90), rats in the 20 ppm F⁻ dose group showed evidence of mild fluorosis Significantly elevated internal F^– burden in the weanling brain and femur	Number of dams per dose: NR 2 dose levels tested, no LOAEL	McPherson et al. (2018)
Rat, Wistar 90–120 days old 10/group	Dams: exposure from GD 0 until PND 21 Sodium fluoride (DW)	Fluoride treated groups: 5, 10 mg/L in filtered tap water; Control group: filtered tap water	0.27 and 0.54^b	–	5 mg/L (Long term memory retention) Corresponding to^b: 0.27 mg/kg/d	Tests: female offspring at PND 90 Inhibitory avoidance test: 5 mg/L F: latency did not differ from that of control at the short-term memory retention test, but was significantly shorter at the long- term memory retention test (p < 0.05) 10 mg/L F: latencies of rats were significantly shorter in both short- and long-term memory retention (p < 0.05)	Concentrations in DW: not clear whether NaF or F^–. Blinding: NR Conversion of DW concentration in doses: unclear F^– concentration in DW (control) and feed: NR Neurobehavioral tests: influence of activity level/motor deficits: NR 2 dose levels tested: no NOAEL	Bartos et al. (2018)
Rat, Sprague-Dawley 200 ± 20 g 10/group	From pregnancy until 6 months of delivery Sodium fluoride (DW)	NaF: 10, 50, 100 F^–: 4.52, 22.6, 45.2 Control: < 1.0 mg/L fluorine	Dams^a: 0.23, 1.13, 2.26 Pups^a: 0.54, 2.71, 5.42	4.52 mg/L Corresponding to^a: Dams: 0.23 mg/kg/d Pups: 0.54 mg/kg/d	22.6 mg/L Corresponding to^a: Dams: 1.13 mg/kg/d Pups: 2.71 mg/kg/d	MWM test: significant effects at 50 and 100 mg/L NaF on memory and learning (e.g. escape latency and the swimming distance) Comment: effects partly showed no dose and time dependence	Control for litter effects: NR F^– concentration in feed: NR Neurobehavioral tests: influence of activity level/motor deficits NR, age of animals NR	Chen et al. (2018)
Mouse, ICR 8–10 weeks old n = 60, number of animals/group unclear	Parents: one month and during gestation and lactation Offspring: until PND 90 Chemical form not reported (DW)	NaF (not clear): 50, 100 F^–: 22.6, 45.3 Control: 0 mg/L F^–(analytics not reported)	Dams^a: 2.0, 4.1 Pups^a: 4.1, 8.2	–	22.6 mg/L Dams^a: 2.0 mg/kg/d Pups^a: 4.1 mg/kg/d	MWM test (n = 6/group): 50 and 100 mg/L fluoride significantly prolonged the escape latency period. The number of crossings in a particular zone was decreased but not significantly	Characterization of test compound: NR Concentration in drinking water: not clear whether NaF or F^– was used. Randomization: NR Blinding: NR Control for litter effects: NR F^– concentration in DW (control) and feed: NR Neurobehavioral tests: influence of activity level/motor deficits: NR	Ge et al. (2018)
Mouse, Kunming 48 adults (24 M; 24 F; 20–25 g each), n = 6/group	Start at GD 0 throughout lactation Sodium fluoride (DW)	NaF: 25, 50, 100 F^–: 11.3, 22.6, 45.3		22.6 mg/L Corresponding to^a: Dams: 2.0 mg/kg/d	45.3 mg/L Corresponding to^a: Dams: 4.1 mg/kg/d	Neurobehavioral tests: offspring at PND 21 (n = 6) 100 ppm NaF: significantly enhanced number of total arm entries and working memory errors in the radial arm maze test compared to the control group. No difference was observed in open-field behaviors	Blinding: NR Control for litter effects: NR F^– concentration in DW (control) and feed: NR Neurobehavioral tests: influence of activity level/motor deficits: NR	Sun et al. (2018)
Mouse, ICR (25–30g) n/group unclear	from GD 7 to PND 21 Sodium fluoride (DW)?	NaF: 0, 25, 50, 100 F⁻: 0, 11.3, 22.6, 45.3 Control: analytics not reported	Dams: 0, 1.0, 2.0, 4.0	11.3 (learning and memory) Corresponding to^a: Dams: 1.0 mg/kg/d	22.6 (learning and memory) Corresponding to^a: Dams: 2.0 mg/kg/d	Neurobehavioral tests: offspring at PND 21 (n = 15) Open field test: number of entries into the center zone in 100 mg/L NaF group were significantly decreased No difference in the distance travelled and the time spent in center zone between control and F^– treatment groups was reported Eight-arm maze test: number of working memory errors, reference memory errors, and the total arm entries were significantly increased in 100 mg/L fluoride treatment group, but not on all training days. At 50 mg/L F^–: significant effects on working memory error and number of total arm entries only on day 7	Characterization of test compound: NR Randomization: NR Blinding: NR Control for litter effects: NR F^– concentration in DW (control) and feed: NR Neurobehavioral tests: influence of activity level/motor deficits: NR Effects were not observed on all training days	Wang et al. (2018)
Rat, Wistar Albino Timed pregnant rats aged 160–180 days 6/group	53 days; gestational and post gestational period Sodium fluoride (DW)	NaF: 20 mg/L; 20 mg/L + quercetin: 20 mg/kg/d by gavage F^–: 9.1 mg/L Control group: normal tap water	Dams^a: 0.46		9.1 mg/L Corresponding to^a: Dams: 0.46 mg/kg/d	Neurobehavioral tests: offspring at PND 14, 21, 30 Maze learning and open field: NaF treated pups showed significant (p < 0.05) decrease in learning ability, cognition, and increase in the latency period of goal achieving compared to the control Comment: preventive effect of quercetin was studied	NaF dose/concentration is unclear Blinding: NR Control for litter effects: NR Single dose tested F^– concentration in DW (control) and feed: NR Neurobehavioral tests: influence of activity level/motor deficits NR	Mesram et al. (2017)
Adult exposure
Mouse, Kunming n = 60, 10/group	Three different exposure periods: 90, 120, 150 days Sodium fluoride (DW)	F^–: 68 mg/L Control: deionized water	6.1	68 mg/L (90 day exposure) Corresponding to^a: 6.1 mg/kg/d	68 mg/L (120 and 150 day exposure) Corresponding to^a: 6.1 mg/kg/d	8 /group were tested for a)Anxiety NaF for 90 days: no significant changes compared to the control group NaF for 120 days: significant alterations in all tests (p < 0.05) NaF for 150 days: elevated zero maze and emergence test were significantly altered (p < 0.05) b)Depression-like behavior: Changes were significantly elevated in mice exposed to 120 days compared to control (p < 0.05) No significant alterations were observed among 90 and 150 days treatment groups Comment: results are inconsistent with regard to exposure duration	Blinding: NR Single dose tested F^– concentration in feed: NR Neurobehavioral tests: influence of activity level/motor deficits: NR	Li et al. (2019)
Rat, Wistar, M age of 5 weeks (80–110 g) 10/group	4 weeks or 12 weeks Sodium fluoride (DW)	F^–b: 0, 60, 120	3.0, 6.0^a	60 mg/L (MWM) Corresponding to^a: 3.0 mg/kg/d (MWM)	120 mg/L (MWM) Corresponding to^a: 6.0 mg/kg/d 60 mg/L (open field test) Corresponding to^a: 3.0 mg/kg/d (MWM)	12 weeks of exposure, MWM at 120 mg/L: latency time was significantly longer than that of control group on the 1st and 2nd days of training sessions (p < 0.05), but not on 3rd to 5th day Open field test: number of instances of standing significantly decreased in all treated rats as compared to the control (p < 0.05). Numbers of crossing between center and surround zone significantly decreased in the high dose group. No differences for the distance moving in the center and the time spent in the center area among the different experimental groups Dental fluorosis was obvious in all treated rats Comment: results unclear: dependent on the training day	Concentration in DW is unclear: NaF or F^–. F^– concentration in DW (control) and feed: NR Neurobehavioral tests: influence of activity level/motor deficits NR	Yang et al. (2018)
Rat, Wistar, M 8/group	30 days Sodium fluoride Administration orally via intra-gastric tube		NaF^b: 5, 10, 20 F^–: 2.3, 4.5, 9.1 Control: water with low F^– level (< 0.027 mg/L)	9.1 mg /kg/d		Y-maze (working memory test): No significant difference in working memory was reported among groups There were significant increases in the degree of fluorosis during the treatment	Exposure route: not via DW F^– concentration in feed: NR 3 dose levels tested, no LOAEL	Pulungan et al. (2018)
Rat, Sprague-Dawley One-month old (100–120 g) 10/group	10 months Sodium fluoride (DW)	50 mg/L (DW); 50 mg/L fluoride (DW) + 50 mg vitamin E/kg/d by intragastric administration Untreated Control (< 0.5 mg/L F^–)	2.5		50 mg/L Corresponding to^a: 2.5 mg/kg/d	MWM: at 50 mg/L increased escape latency time, decreased number of crossings of the platform site, decreased time of staying on the site of the platform F^– concentration in feed: normal diet containing < 6 mg/kg fluoride Comment: preventive effects of vitamin E were examined	Characterization of the test compound: unclear whether NaF or F^-concentration in DW Single dose tested Neurobehavioral tests: influence of activity level/motor deficits NR	Dong et al. (2017)
Mouse, Swiss Albino, M One month old (30 ±5 g) 7/group	30 days Sodium fluoride (DW)	NaF: 120 mg/L; 120 mg/L + Curcumin or Resveratrol (30 mg/kg/d, orally) F^–: 54.4 mg/L Control: F^–free RO water (analytics not reported)	4.9		54.4 mg/ Corresponding to^a: 4.9 mg/kg/d	120 mg/L NaF: influence on learning and memory (MWM, CM test) Comment: preventive effect of curcumin and resveratrol was studied	Randomization: NR Blinding: NR Single dose tested F^– concentration in DW (control) and feed: NR Neurobehavioral tests: detailed description of the test was missing, influence of activity level/motor deficits NR	Sharma et al. (2018b)

Species, strain, number of animals

Exposure duration, chemical form, route

Concentration in DW (mg/L)

F^– Doses^a (mg/kg/d)

NOAEL F^– (mg/L) (mg/kg/d)

LOAEL F^– (mg/L) (mg/kg/d)

Outcome (as stated by the authors)

Limitations

References

Developmental exposure

Rat, Sprague Dawley

40 F, 20 M (180–220g)

10 dams/dose

From pre-pregnancy until 2 months of delivery

Sodium fluoride (DW)

NaF: 10, 50, 100

F^–: 4.52, 22.6, 45.2

Control group: tap water, < 1.0 mg/L F⁻

Dams^a: 0.23, 1.13, 2.26

Pups^a: 0.54, 2.71, 5.42

4.52 mg/L

Corresponding to^a:

Dams: 0.23 mg/kg/d

Pups: 0.54 mg/kg/d

22.6 mg/L

Corresponding to^a:

Dams: 1.13 mg/kg/d

Pups: 2.71 mg/kg/d

50 mg/L NaF and higher caused learning and memory impairments (MWM task, n = 5)

Control for litter effects: NR

F^– concentration in food: NR

MWM: age of pups NR; influence of activity level/motor deficits NR

Zhao et al. (2019)

Rat, Long–Evans hooded timed-pregnant dams

Start at GD 6 continued to PND 90

Sodium fluoride (DW)

2 DW control groups: low F^– diet (3.24 mg/kg F^–); standard diet (20.5 mg/kg F^–)

Treatment: 10, 20 mg/L F^– with low F^– diet

0.08, 0.16^b,c

20 mg/L

0.16 mg/kg/d^b

–

Tests were performed at different ages according to guidelines

Male pups were used for testing (n = 10–22)

No exposure-related differences in motor, sensory, or learning and memory performance

No influence on thyroid hormone parameters

No exposure-related pathology in the heart, liver, kidney, testes, seminal vesicles, or epididymis

Mild inflammation in the prostate gland at

20 mg/L F⁻

When examined as adults (> PND90),

rats in the 20 ppm F⁻ dose group showed evidence of mild fluorosis

Significantly elevated internal F^– burden in the weanling brain and femur

Number of dams per dose: NR

2 dose levels tested, no LOAEL

McPherson et al. (2018)

Rat, Wistar

90–120 days old

10/group

Dams: exposure from GD 0 until PND 21

Sodium fluoride (DW)

Fluoride treated groups: 5, 10 mg/L in filtered tap water; Control group: filtered tap water

0.27 and 0.54^b

–

5 mg/L (Long term memory retention)

Corresponding to^b: 0.27 mg/kg/d

Tests: female offspring at PND 90

Inhibitory avoidance test: 5 mg/L F: latency did not differ from that of control at the short-term memory retention test, but was significantly shorter at the long- term memory retention test (p < 0.05)

10 mg/L F: latencies of rats were significantly shorter in both short- and long-term memory retention (p < 0.05)

Concentrations in DW: not clear whether NaF or F^–.

Blinding: NR

Conversion of DW concentration in doses: unclear

F^– concentration in DW (control) and feed: NR

Neurobehavioral tests: influence of activity level/motor deficits: NR

2 dose levels tested: no NOAEL

Bartos et al. (2018)

Rat, Sprague-Dawley

200 ± 20 g

10/group

From pregnancy until 6 months of delivery

Sodium fluoride (DW)

NaF: 10, 50, 100

F^–: 4.52, 22.6, 45.2

Control: < 1.0 mg/L fluorine

Dams^a: 0.23, 1.13, 2.26

Pups^a: 0.54, 2.71, 5.42

4.52 mg/L

Corresponding to^a: Dams: 0.23 mg/kg/d

Pups: 0.54 mg/kg/d

22.6 mg/L

Corresponding to^a: Dams: 1.13 mg/kg/d

Pups: 2.71 mg/kg/d

MWM test: significant effects at 50 and 100 mg/L NaF on memory and learning (e.g. escape latency and the swimming distance)

Comment: effects partly showed no dose and time dependence

Control for litter effects: NR

F^– concentration in feed: NR

Neurobehavioral tests: influence of activity level/motor deficits NR, age of animals NR

Chen et al. (2018)

Mouse, ICR

8–10 weeks old

n = 60,

number of animals/group unclear

Parents: one month and during gestation and lactation

Offspring: until PND 90

Chemical form not reported

(DW)

NaF (not clear): 50, 100

F^–: 22.6, 45.3

Control: 0 mg/L F^–(analytics not reported)

Dams^a: 2.0, 4.1

Pups^a: 4.1, 8.2

–

22.6 mg/L

Dams^a: 2.0 mg/kg/d

Pups^a: 4.1 mg/kg/d

MWM test (n = 6/group): 50 and 100 mg/L fluoride significantly prolonged the escape latency period. The number of crossings in a particular zone was decreased but not significantly

Characterization of test compound: NR

Concentration in drinking water: not clear whether NaF or F^– was used.

Randomization: NR

Blinding: NR

Control for litter effects: NR

F^– concentration in DW (control) and feed: NR

Neurobehavioral tests: influence of activity level/motor deficits: NR

Ge et al. (2018)

Mouse, Kunming 48 adults (24 M;

24 F; 20–25 g each),

n = 6/group

Start at GD 0 throughout lactation

Sodium fluoride (DW)

NaF: 25, 50, 100

F^–: 11.3, 22.6, 45.3

22.6 mg/L

Corresponding to^a:

Dams: 2.0 mg/kg/d

45.3 mg/L

Corresponding to^a:

Dams: 4.1 mg/kg/d

Neurobehavioral tests: offspring at PND 21 (n = 6)

100 ppm NaF: significantly enhanced number of total arm entries and working memory errors in the radial arm maze test compared to the control group. No difference was observed in open-field behaviors

Blinding: NR

Control for litter effects: NR

F^– concentration in DW (control) and feed: NR

Neurobehavioral tests: influence of activity level/motor deficits: NR

Sun et al. (2018)

Mouse, ICR

(25–30g)

n/group unclear

from GD 7 to PND 21

Sodium fluoride (DW)?

NaF: 0, 25, 50, 100

F⁻: 0, 11.3, 22.6, 45.3

Control: analytics not reported

Dams: 0, 1.0, 2.0, 4.0

11.3 (learning and memory)

Corresponding to^a:

Dams: 1.0 mg/kg/d

22.6 (learning and memory)

Corresponding to^a: Dams: 2.0 mg/kg/d

Neurobehavioral tests: offspring at PND 21

(n = 15)

Open field test: number of entries into the center zone in 100 mg/L NaF group were significantly decreased

No difference in the distance travelled and the time spent in center zone between control and F^– treatment groups was reported

Eight-arm maze test: number of working memory errors, reference memory errors, and the total arm entries were significantly increased in 100 mg/L fluoride treatment group, but not on all training days. At 50 mg/L F^–: significant effects on working memory error and number of total arm entries only on day 7

Characterization of test compound: NR

Randomization: NR

Blinding: NR

Control for litter effects: NR

F^– concentration in DW (control) and feed: NR

Neurobehavioral tests: influence of activity level/motor deficits: NR

Effects were not observed on all training days

Wang et al. (2018)

Rat, Wistar Albino Timed pregnant rats aged 160–180 days

6/group

53 days; gestational and post gestational period

Sodium fluoride (DW)

NaF: 20 mg/L; 20 mg/L + quercetin: 20 mg/kg/d by gavage

F^–: 9.1 mg/L

Control group: normal tap water

Dams^a: 0.46

9.1 mg/L

Corresponding to^a: Dams: 0.46 mg/kg/d

Neurobehavioral tests: offspring at PND 14, 21, 30

Maze learning and open field:

NaF treated pups showed significant (p < 0.05) decrease in learning ability, cognition, and increase in the latency period of goal achieving compared to the control

Comment: preventive effect of quercetin was studied

NaF dose/concentration is unclear

Blinding: NR

Control for litter effects: NR

Single dose tested

F^– concentration in DW (control) and feed: NR

Neurobehavioral tests: influence of activity level/motor deficits NR

Mesram et al. (2017)

Adult exposure

Mouse, Kunming

n = 60,

10/group

Three different exposure periods: 90, 120, 150 days

Sodium fluoride (DW)

F^–: 68 mg/L

Control: deionized water

6.1

68 mg/L (90 day exposure) Corresponding to^a: 6.1 mg/kg/d

68 mg/L (120 and 150 day exposure)

Corresponding to^a: 6.1 mg/kg/d

8 /group were tested for

a)Anxiety

NaF for 90 days: no significant changes compared to the control group

NaF for 120 days: significant alterations in all tests (p < 0.05)

NaF for 150 days: elevated zero maze and emergence test were significantly altered (p < 0.05)

b)Depression-like behavior:

Changes were significantly elevated in mice exposed to 120 days compared to control (p < 0.05)

No significant alterations were observed among 90 and 150 days treatment groups

Comment: results are inconsistent with regard to exposure duration

Blinding: NR

Single dose tested

F^– concentration in feed: NR

Neurobehavioral tests: influence of activity level/motor deficits: NR

Li et al. (2019)

Rat, Wistar, M age of 5 weeks (80–110 g)

10/group

4 weeks or 12 weeks

Sodium fluoride (DW)

F^–b: 0, 60, 120

3.0, 6.0^a

60 mg/L (MWM) Corresponding to^a: 3.0 mg/kg/d (MWM)

120 mg/L (MWM) Corresponding to^a: 6.0 mg/kg/d

60 mg/L (open field test) Corresponding to^a: 3.0 mg/kg/d (MWM)

12 weeks of exposure, MWM at 120 mg/L: latency time was significantly longer than that of control group on the 1st and 2nd days of training sessions (p < 0.05), but not on 3rd to 5th day

Open field test: number of instances of standing significantly decreased in all treated rats as compared to the control (p < 0.05). Numbers of crossing between center and surround zone significantly decreased in the high dose group. No differences for the distance moving in the center and the time spent in the center area among the different experimental groups

Dental fluorosis was obvious in all treated rats

Comment: results unclear: dependent on the training day

Concentration in DW is unclear: NaF or F^–.

F^– concentration in DW (control) and feed: NR

Neurobehavioral tests: influence of activity level/motor deficits NR

Yang et al. (2018)

Rat, Wistar, M

8/group

30 days

Sodium fluoride

Administration

orally via

intra-gastric tube

NaF^b: 5, 10, 20

F^–: 2.3, 4.5, 9.1

Control: water with low F^– level (< 0.027 mg/L)

9.1 mg /kg/d

Y-maze (working memory test):

No significant difference in working memory was reported among groups

There were significant increases in the degree of fluorosis during the treatment

Exposure route: not via DW

F^– concentration in feed: NR

3 dose levels tested, no LOAEL

Pulungan et al. (2018)

Rat, Sprague-Dawley

One-month old (100–120 g)

10/group

10 months

Sodium fluoride (DW)

50 mg/L (DW);

50 mg/L fluoride (DW) + 50 mg vitamin E/kg/d by intragastric administration

Untreated

Control (< 0.5 mg/L F^–)

2.5

50 mg/L

Corresponding to^a: 2.5 mg/kg/d

MWM: at 50 mg/L increased escape latency time, decreased number of crossings of the platform site, decreased time of staying on the site of the platform

F^– concentration in feed: normal diet containing < 6 mg/kg fluoride

Comment: preventive effects of vitamin E were examined

Characterization of the test compound: unclear whether NaF or F^-concentration in DW

Single dose tested

Neurobehavioral tests: influence of activity level/motor deficits NR

Dong et al. (2017)

Mouse, Swiss Albino, M

One month old (30 ±5 g)

7/group

30 days

Sodium fluoride (DW)

NaF: 120 mg/L; 120 mg/L + Curcumin or Resveratrol (30 mg/kg/d, orally)

F^–: 54.4 mg/L

Control: F^–free RO water (analytics not reported)

4.9

54.4 mg/ Corresponding to^a: 4.9 mg/kg/d

120 mg/L NaF: influence on learning and memory (MWM, CM test)

Comment: preventive effect of curcumin and resveratrol was studied

Randomization: NR

Blinding: NR

Single dose tested

F^– concentration in DW (control) and feed: NR

Neurobehavioral tests: detailed description of the test was missing, influence of activity level/motor deficits NR

Sharma et al. (2018b)

Search criteria were: PubMed database for animal studies published between January 2005 and February 2019 with the key words in the title/abstract including ‘fluoride’, ‘sodium fluoride’ and ‘neurotoxicity’ and/or ‘developmental toxicity’ and/or ‘brain’. In addition to the PubMed search, the reference lists of included studies, records that do not contain original data (i.e., reviews, editorials, or commentaries), and the Fluoride Action Network website (https://fluoridealert.org/studies/brain02/) were checked for further studies. Publications where the full text was not available in English or not published in a journal (master thesis, dissertations etc.) were excluded

CM classic maze, DW drinking water, F female, GD gestation day, M male, MWM morris water maze, NR not reported, PND postnatal day

^aConversion of F^–concentration in drinking water into daily doses was performed by application of default conversion factors derived by EFSA (EFSA 2012). For chronic studies, a default factor of 0.05 for rats and 0.09 for mice should be used, e.g., 1 mg/L in water is equivalent to a dose of 0.05 and 0.09 mg/kg bw per day in rats and mice, respectively. For subchronic studies, a default factor of 0.09 for rats and 0.15 for mice should be used. For subacute studies, a default factor of 0.12 for rats and 0.18 for mice should be used. In case the authors only reported F^– concentration in drinking water, conversion factors of 0.05/0.09 (rats/mice) were used for adult animals/the parental generation and conversion factors of 0.12/0.18 (rats/mice) for the pups or short-term exposure of young animals

^bAs indicated by the authors

^cValues obtained by applying default conversion factors of EFSA (EFSA 2012): dams (conversion factor of 0.05): 0.5, 1 mg/kg/d; pups (conversion factor of 0.12): 1.2, 2.4 mg/kg/d