Hexafluorosilicic acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No studies with HFS acid are available. However a number of studies of various designs are available with the read-across substance NaF, including a key high quality two-generation study performed by the US FDA with NaF administered to rats in the drinking water at 100, 175 and 250 ppm. Mating, fertility and survival indices were not affected, and offspring viability also remained unaffected. Sodium fluoride caused an increase in the incidence of whitening of tooth enamel, in a dose-related manner from males and females in the 100, 175 and 250 ppm groups. There was an increase in the development of prominent growth lines in the upper incisors of F0 and F1 adult rats and F1 weanlings. The EU RAR for HF also considered the data available for the reproductive toxicity of NaF and concluded that the FDA study is key, for reasons of design, reporting and control of fluoride levels. The NOAEL for reproductive toxicity is 250 ppm NaF, which corresponds to ‘target’ NOAEL of at least 11.4 mg/kg bw.

 

Other supporting published studies reported effects of NaF on fertility in rats and mice, however their value and reliability is significantly compromised by the absence of any information on the fluoride levels in diet and/or drinking water.

Link to relevant study records

Reference

Endpoint:

two-generation reproductive toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

See attached read-across justification

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Other effects:

effects observed, treatment-related

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

No dose-related clinical effects were observed in either males or females.

There was a significant decrease in overall feed consumption by F0 males in the 250ppm group. Rats in the 175 and 250ppm groups drank significantly less than controls. This decreased consumption is attributed to decreased palatability. Weight gain of males and females showed a significant negative linear regression, however only the individual weight gain of the 250ppm males was statistically significantly less than controls.

Female mating indices were over 90% in all groups. Female fertility indices were decreased slightly in the 250 ppm group, but not significantly. Average time to mating was less in treated groups than in the controls but the differences were not dose related.

Mean water consumption per pregnant female was decreased in the 250ppm group during the entire period of gestation.
There were no effects on organ weights or organ to body weight ratios.
There was an increase in the development of prominent growth lines in the upper incisors of all rats that received 250ppm. Hyperkeratosis of hte limiting ridge of the stomach was diagnosed in a small number of rats from the 100, 175 and 250ppm groups.

Dose descriptor:

NOAEL

Effect level:

250 ppm (analytical)

Based on:

other: Sodium fluoride

Sex:

male/female

Basis for effect level:

other: No effects on reproduction were seen at the highest dose level

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

effects observed, treatment-related

No dose-related clinical effects were observed in either males or females.

Oveall mean feed consumption of F1 females showed a significant negative linear regression for days 0-70 although none of the values were significantly less than controls. F1 males in the treated groups ate less than the control group but the decreases were neither dose related nor significant. Rats in the 175 and 250ppm groups drank significantly less than controls. F1 males in the 100ppm group drank significantly less than the control group. This decreased consumption is attributed to decreased palatability.
Mating indices of females were over 90%. The fertility indices of the females in thhe 25 and 250ppm were slightly less than controls, but not significantly and probably due to random variation.
All the mating indices of the F1 males were less than those of the F0 males, but there was no dose-related decrease.
Mean fluid consumption per pregnant female was decreased in the 250ppm group during the entire period of gestation. Fluid consumption was significantly decreased in 17 5 ppm group females during the entire period of gestation.
Survival of F1 offspring to postnatal day 21 showed no dose-related effects. Growth and development were similar in all groups, and female and male runts were randomly distributed among the control and treatment groups.
There were no effects on organ weights or organ to body weight ratios.
There was an increase in the development of prominent growth lines in the upper incisors of all rats that received 250ppm. Hyperkeratosis of hte limiting ridge of the stomach was diagnosed in a small number of rats from the 250ppm group.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

250 ppm (analytical)

Based on:

other: Sodium fluoride

Sex:

male/female

Basis for effect level:

other: No effects on reproduction were seen at the highest dose level

Reproductive effects observed:

not specified

NaF consumption by F0 females ranged from 3.5-27.3 mg NaF/kg bw/d at 25 -250 ppm respectively, and consumption in F1 females was 3.8 -28.0 mg NaF/kg bw/d. Consumption in the F0 males was 2.8 to 23.1 mg NaF/kg/d, and in the F1 males was 3.0 -24.1 mg NaF/kg bw/d.

Conclusions:

Read-across substance sodium fluoride administered in the drinking water for 10 weeks at dose levels up to 250ppm had no adverse effects on reproduction in rats.

Executive summary:

The effects of read-across substance sodium fluoride ingestion at 0, 25, 100, 175 or 250 ppm in drinking water was measured in rats over 3 generations.

Reproduction was not affected by NaF administration, and offspring viability also remained unaffected. The decreased fluid consumption noted in high dose groups was attributed to decreased palatability. Mating, fertility and survival indices were not affected. Sodium fluoride caused an increase in the incidence of whitening of tooth enamel, in a dose-related manner from males and females in the 100, 175 and 250 ppm groups. There was an increase in the development of prominant growth lines in the upper incisors of F0 and F1 adult rats and F1 weanlings. The reproductive NOAEL in rats was therefore 250 ppm.

Effect on fertility: via oral route

Dose descriptor:

NOAEL

11.4 mg/kg bw/day

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Published studies are available as supporting studies for fertility effects of sodium fluoride in rats and mice.

Araibi et al (1989) reported adverse effects on the fertility of male rats administered sodium fluoride in the diet exposed for 60 days at concentrations of 100 and 200 ppm. Exposure resulted in a reduction in successful matings and reduced litter size; findings were associated with a reduction in seminiferous tubule diameter and a thickened peritubular membrane. The numbers of tubules containing spermatozoa were decreased and serum testosterone levels were also reduced. Chinoy & Sequeira (1989) reported alterations in the histoarchitecture of the testes in mice gavaged with sodium fluoride at dose levels of 10 and 20 mg/kg bw/d for 30 days. Findings were characterised by severe disorganisation and denudation of germinal epithelial cells of the seminiferous tubules, absence of sperm from the tubular lumen, reduced in epithelial cell height, nuclear pyknosis, denudation of cells and absence of sperm occurred in the cauda epididymis. The effects seen after 30 days administration were reversible. Chinoy et al (1992) reported reduced fertility in male rats administered sodium fluoride by gavage at dose levels of 5 and 10 mg/kg bw for 30 days. Findings were accompanied by reduced sperm count and motility and various biochemical changes in the testes and epididymides (inhibited succinate dehydrogenase, adenosine triphosphatase).

The results of these studies are consistent, however their value and reliability is significantly compromised by the absence of any information on the fluoride levels in diet and/or drinking water. The actual levels of fluoride exposure cannot be accurately assessed. It is also notable that the findings of these published investigative studies of non-standard design contrast with the total absence of reproductive toxicity at comparable dose levels in the FDA studies reported below.

Messer et al (1973) investigated the reproductive toxicity of sodium fluoride in a two-generation study in which female mice were administered the test material in the drinking water at dose levels of 0, 50, 100 or 200 ppm. Female mice were fed a low fluoride diet (0.1-0.3 ppm fluoride). A progressive decline in litter production was seen in the control group. All females administered 200 ppm fluoride died over the study period; only a small number of litters were produced at the 100 ppm. It is suggested that a level of 50 ppm sodium fluoride (equivalent to approximately 7.5 mg/kg bw/day fluoride ion) is more adequate to maintain reproductive capacity in female mice. In a 3 -generation mouse study (Tao & Suttie, 1976), a first generation were exposed to 0 ppm and 2 ppm fluoride (as NaF) in a low fluoride diet, and mated with untreated males. Second and third generation females received 0, 2 and 100 ppm fluoride in the low fluoride diet. The low fluoride diet contained less than 0.5 ppm fluoride. No signs of fluoride toxicity were reported. No compound-related effects on reproduction were observed. The presence of a kidney infection may have affected the reliability of the study. The study is considered of limited value, however the authors suggest that the effects of fluoride seen in the study of Messer et al (1973) was due to the influence of fluoride on the absorption of iron from a low iron diet.

 

FDA studies

The effects of sodium fluoride administration on spermatogenesis in rats were investigated in a supporting two-generation study (Sprando et al, 1997). Male and female rats received sodium fluoride in their drinking water at 0, 25, 100, 175 or 250 ppm. P generation rats were exposed for 10 weeks, then for 3 weeks during mating. Pregnant females (P) were exposed during gestation and lactation. F1 weanling males were exposed for 14 weeks. Dose-related effects were not observed within the P and F1 treatment groups in testis weights, prostate/seminal vesicle weights, non-reproductive organ weights, testicular spermatid counts, sperm production per gram of testis per day, sperm production per gram of testis, LH, FSH or serum testosterone concentrations. Histopathological changes in testicular tissues were not observed. In contrast to the previous studies, no effects were observed on reproductive organ weights, sperm parameters or biochemical parameters at dose levels of up to 250 ppm (drinking water). Additional detailed investigations by the same authors did not reveal any effects on spermatogenesis in F1 males (Sprando et al, 1998). A significant decrease in the absolute volume and volume percent of the lymphatic endothelium was observed in the 175 and 250ppm groups, and in the testicular capsule in the 100ppm group. The authors reported that the significance of this finding is not clear, and overall the results suggests that exposure to NaF does not adversely affect testis structure or spermatogenesis in the rat.

No effects on reproduction were seen at the highest dose level of 250 ppm in a key guideline-comparable two-generation rat study (Collins et al, 2001). The effects of NaF ingestion at 0, 25, 100, 175 or 250 ppm in drinking water was measured in rats over 3 generations. Reproduction was not affected by NaF administration, and offspring viability also remained unaffected. Decreased fluid consumption noted in high dose groups was attributed to decreased palatability. Mating, fertility and survival indices were not affected. Sodium fluoride caused an increase in the incidence of whitening of tooth enamel, in a dose-related manner from males and females in the 100, 175 and 250 ppm groups. There was an increase in the development of prominent growth lines in the upper incisors of F0 and F1 adult rats and F1 weanlings. The reproductive NOAEL in rats was therefore 250 ppm. In a further supporting FDA study designed primarily to assess the potential effects of fluoride on spermatogenesis (as indicated in various published studies), Sprando et al (1996) demonstrated that injection of sodium fluoride into the rat testis was without effect on spermatogenesis. The left testicle of rats was injected with sodium fluoride (0, 50, 175 and 250 ppm) to assess the effects of NaF on spermatogenesis. The only effects observed were signs of mechanical damage and occasional leucocyte infiltration which were related to the tissue damage caused by the injection, rather than fluoride exposure. The authors concluded that the rat is not adversely affected by direct exposure to fluoride at levels 200 times greater than those under normal conditions.

In contrast to the other studies which report effects of fluoride on male fertility and spermatogenesis, no effects were observed in the FDA studies following extensive investigation. The two-generation FDA study is of standard design and is comprehensively reported, and it is notable in these studies that the contribution of diet and drinking water to the total fluoride intake was assessed. The EU RAR for HF also considers the data available for the reproductive toxicity of NaF and concludes that the FDA studies are key, for reasons of design, reporting and control of fluoride levels. The EU RAR also concludes that the NOAEL for reproductive toxicity is 250 ppm NaF. The absence of any apparent effects on the reproductive organs in chronic toxicity and carcinogenicity studies is also notable.

Taking into account a daily water requirement of 20-30 mL/rat (Derelanko, The Toxicologist’s Pocket Handbook, Informa, 2008), the NOAEL of 250 ppm (250 mg/L) corresponds with 5- 7.5 mg/rat. Assuming a mean body weight of 250 g/rat, the NOAEL would be 20-30 mg/kg bw. Application of a conversion factor from source to target substance (see read-across justification) leads to ‘target’ NOAEL of at least 20 mg/kg bw x 0.57 = 11.4 mg/kg bw

Effects on developmental toxicity

Description of key information

No studies with HFS acid are available. However a number of studies of various designs are available with the read-across substance NaF, including high quality studies performed by the US NTP and FDA as weight-of-evidence. Two developmental toxicity studies were available in rats, leading to ‘target’ NOAEL of 10.3 mg/kg bw for maternal toxicity and 15.4 mg/kg bw for developmental toxicity in the first study and ‘target’ maternal/developmental NOAEL of 11.1 mg/kg bw (highest tested dose) in the second study. In the rabbit study, target NOAEL of 10.3 mg/kg bw for maternal toxicity and 16.5 mg/kg bw for developmental toxicity was obtained.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

See attached read-across justification

Reason / purpose for cross-reference:

read-across source

Species:

rat

Strain:

Sprague-Dawley

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
No maternal lethality occurred at any dose. Maternal wight gain was significantly reduced at 300ppm during the first 2 days of exposure (gestation days 6-8), and a trend toward decreased weight gain was noted for the treatment period as a whole. Maternal food intake was significantly decreased (compared to controls) in the 300ppm group between gestation days 8-10. Water consumption was significantly decreased during exposure in the 300ppm group. No other differences were noted. At necropsy there were no effects on kidney or liver weights.

Dose descriptor:

NOAEL

Remarks:

maternal toxicity

Effect level:

150 ppm (nominal)

Based on:

other: Sodium fluoride

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
NaF exposure did not significantly affect the frequency of post-implantation loss, mean fetal body weight per litter, or external, visceral, or skeletal malformations.

Dose descriptor:

NOAEL

Remarks:

developmental

Effect level:

300 ppm (nominal)

Based on:

other: sodium fluoride

Sex:

male/female

Basis for effect level:

other: developmental toxicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Control water fluoride levels were <0.6 ppm NaF.

Food contained an average of 12.4 ppm F (11.6 -13.4 ppm F).

The calculated doses from drinking water were 7, 18 and 27 mg NaF/kg bw/d (3, 8 and 12 mg F/kg bw/d) for the low, intermediate and high-dose groups respectively. Intake from food added approximately 2 mg NaF/kg bw/d (1 mg F/kg bw/d) to the intake for each group.

Determination of serum fluoride levels in the 10 animals per group terminated on 16 revealed mean levels of 0.007 ± 0.002, 0.035 ± 0.040, 0.039 ± 0.039, and 0.187 ± 0.076F at the end of the exposure period.

Conclusions:

Read-across substance sodium fluoride in drinking water was not maternally toxic up to doses of 300ppm, although decreased water consumption was seen as a result of poor palatability at this dose. There was no evidence of developmental toxicity in this study.

Executive summary:

Pregnant Sprague-Dawley CD rats were exposed to read-across substance sodium fluoride in their drinking water at concentrations of 0, 50, 150 or 300 ppm daily between gestation days 6 and 15. Maternal weight gain was significantly reduced at 300 ppm during the first two days of exposure (days 6 to 16). Maternal water consumption (grams/kg/day) during exposure was significantly decreased in the animals exposed to 300ppm NaF. Post-exposure water consumption was normal in these animals indicating the probability of decreased palatability of the 300ppm solution. Necropsy of the maternal animals revealed no effects on kidney or liver weights. NaF exposure did not significantly affect the frequency of post-implantation loss, mean fetal body weight per litter, or external, visceral, or skeletal malformations.

This study established a NOAEL for maternal toxicity of 150 ppm (18 mg NaF/kg bw/d) and a NOAEL of 300 ppm for developmental toxicity (27 mg NaF/kg bw/d) administered in drinking water to pregnant CD rats during organogenesis.

Reference 2

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

See attached read-across justification

Reason / purpose for cross-reference:

read-across source

Species:

rat

Strain:

Sprague-Dawley

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
There was no dose-related behavioural changes or clinical signs. Water consumption was significantly reduced at 175 and 200pm, and feed consumption was significantly reduced at 250 ppm, body weights reflected feed consumption trends; significant decreases in body weight gain were seen in 250ppm females on days 0-3 and 6-9, and overall on days 0-20. The mean number of implants per litter was significantly reduced in the 250 ppm was significantly decreased, however findings correspond with a lower number of corpora lutea in this group.

Dose descriptor:

NOAEL

Remarks:

maternal toxicity

Effect level:

175 ppm (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Remarks:

developmental toxicity

Effect level:

250 ppm (nominal)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
A significant increase was seen in the average number of foetuses with 3 or more skeletal variations in the 250ppm group, and the numbers of litters with foetuses with 3 or more skeletal variations was also increased in this group but not significantly so.

Dose descriptor:

NOAEL

Remarks:

teratogenicity

Effect level:

250 ppm (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: teratogenicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Water consumption by females was lower at dose levels of 175 and 200 ppm. This resulted in a lower than expected NaF consumption. Pregnancy rate was over 90% in all groups. A significantly lower number of corpora lutea was seen in the dams of the 250 ppm group. Implantation efficiency (% corpora lutea that implanted) was more than 90% in all groups except the 25 ppm group, although the small decrease was not significant. The occurrence of in utero deaths was similar in the control and treated groups. The mean number of male foetuses per litter was significantly decreased in the 175 ppm group compared to the control, but was not dose related therefore considered to be random.

Foetal growth was not affected by NaF, even in the high dose groups with dams exhibiting reduced food and water consumption. Male control foetuses weighed 4.0 g, and crown-rump length was 4.1cm; male foetuses from treated groups weighed 3.9 -4.1g and crown-rump length was 4.0 -4.1cm. Female control foetuses weighed 3.8g and crown-rump length was 4.0 cm; female foetuses from treated groups weighed 3.7 -3.8g and crown-rump length was 3.9 -4.0cm.

Conclusions:

No evidence of developmental toxicity was seen in this study.

Executive summary:

The developmental toxicity of read-across substance sodium fluoride was determined in rats. Mated females were exposed to sodium fluoride in the drinking water at concentrations of 0, 25, 100, 175 and 250 ppm on gestation days 0 -20. Caesarean sections were performed on gestation day 20 and foetuses were examined. Sodium fluoride was not teratogenic at any dose tested. There was no effect on the development of specific bones including sternebrae. Foetal growth was not affected by sodium fluoride, even in dams exhibiting significantly decreased food and water consumption (250ppm; decreased feed and water consumption, 175ppm decreased water consumption). A significant increase was seen in the average number of foetuses with three or more skeletal variations in the 250 ppm group, however the number of affected litters was not significantly increased. There was no dose related effect on sodium fluoride on the incidence of soft tissue variations.

Reference 3

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

See attached read-across justification

Reason / purpose for cross-reference:

read-across source

Species:

rabbit

Strain:

New Zealand White

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
No maternal toxicity occurred. Pregnancy rates were 84%, 87%, 78%, and 83% in the control to high exposure groups, respectively. Maternal body weight change for the animals receiving 400 ppm NaF was significantly lower than that of control animals for the period from gestation day 6 to 8 (14 grams average weight gain for controls vs. 112 grams weight loss for the 400 ppm group); this difference probably resulted from significantly decreased food and water consumption during the same period. Maternal body weight change was significantly increased from gestation day 10 to 12 (22 grams average weight gain for controls vs. 71 grams weight gain for the 400 ppm group), but did not differ among groups for the treatment period as a whole, indicating that animals in the 400 ppm group recovered from the weight change effects observed during the first few days of exposure to NaF in the drinking water. Maternal water consumption (g/kg/day) during exposure was significantly decreased in the animals exposed to 400 ppm NaF. Post-exposure water consumption was normal in these animals indicating the probability of dereased palatability of the 400 ppm solution. Maternal food consumption was decreased compared to control during the first four days of treatment (g/day on gestation day 6 to 8 and 8 to 10; g/kg/day on gestation day 6 to 8), but was normal thereafter. No clear clinical signs of toxicity were observed. Necropsy of the maternal animals revealed no effects on kidney or liver weights.

Dose descriptor:

NOAEL

Remarks:

maternal toxicity

Effect level:

200 ppm (nominal)

Based on:

other: Sodium fluoride

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Exposure did not affect the frequency of post-implantation loss, mean foetal body weight per litter, or external, visceral, or skeletal malformations.

Dose descriptor:

NOAEL

Remarks:

developmental toxicity

Effect level:

400 ppm (nominal)

Based on:

other: Sodium fluoride

Sex:

female

Basis for effect level:

other: developmental toxicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Drinking water contained less than 0.6 ppm of sodium fluoride (the detectable limit). Water intake provided approximately 84%, 91 % and 95% of the total F consumed for the low through high concentration groups in this study. Determination of serum fluoride levels, in 7-8 pregnant animals per group, revealed levels of 0.06 ± 0.04, 0.24 ± 0.10, 0.39 ± 0.14, and 0.70 ± 0.33 ppm at the end of the exposure period for the control through high dose groups, respectively.

Conclusions:

There was evidence of minimal maternal toxicity but no evidence of developmental toxicity with levels of read-across substance sodium fluoride in drinking water as high as 400 ppm (resulting in an average exposure of 29 mg/kg bw/d) although the palatabillity of a 400 ppm sodium fluoride solution apparently reduced water consumption.

Executive summary:

Pregnant New Zealand White rabbits were exposed to read-across substance sodium fluoride in their drinking water at concentrations of 0, 100, 200 or 400 ppm daily between gestation days 6 and 19. There was evidence of minimal maternal toxicity but no definitive evidence of developmental toxicity with levels of sodium fluoride in drinking water as high as 400ppm (resulting in an average exposure of 29 mg/kg bw/d) although the palatabillity of a 400 ppm sodium fluoride solution apparently reduced water consumption. This study established a NOAEL for maternal toxicity at 200 ppm NaF in drinking water (approximately 18 mg/kg bw/d) and a NOAEL for developmental toxicity of 400ppm NaF in drinking water (approximately 29 mg/kg bw/d) administered to pregnant NZW rabbits during organogenesis.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

11.1 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

high quality

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

In a rat developmental toxicity study (NTP, 1994; Heindel et al, 1996), pregnant Sprague-Dawley CD rats were exposed to NaF in their drinking water at concentrations of 0, 50, 150 or 300 ppm daily between gestation days 6 and 15. Maternal toxicity (transiently reduced bodyweight gain) was apparent at the highest dose level of 300 ppm sodium fluoride (in drinking water). No evidence of developmental toxicity was seen at this dose level. This study established a NOAEL for maternal toxicity of 150 ppm (18 mg NaF/kg bw/d) and a NOAEL of 300 ppm for developmental toxicity (27 mg NaF/kg bw/d) administered in drinking water to pregnant CD rats during organogenesis. This leads to target NOAEL of 18 mg/kg w/d x 0.57 =10.3 mg/kg bw for maternal toxicity and 27 mg/kg bw/d x 0.57 = 15.4 mg/kg bw for developmental toxicity.

No clear evidence of developmental toxicity was seen in an FDA rat study (Collins et al, 1995). Mated females were exposed to NaF in the drinking water at concentrations of 0, 25, 100, 175 and 250 ppm on gestation days 0 -20. Sodium fluoride was not teratogenic at any dose tested. There was no effect on the development of specific bones including sternebrae. Foetal growth was not affected by sodium fluoride, even in dams exhibiting significantly decreased food and water consumption (250 ppm; decreased feed and water consumption, 175 ppm decreased water consumption). A significant increase was seen in the average number of foetuses with three or more skeletal variations in the 250 ppm group, however the number of affected litters was not significantly increased. There was no dose related effect on sodium fluoride on the incidence of soft tissue variations. Maternal toxicity in this study was limited to reduced food intake at the highest dose level. Taking into account a daily water requirement of 20-30 mL/rat (Derelanko, The Toxicologist’s Pocket Handbook, Informa, 2008), the NOAEL of 250 ppm (250 mg/L) corresponds with 5.-7.5 mg/rat. Assuming a mean body weight of 450 g/pregnant rat, the NOAEL would be 11.1-16.7 mg/kg bw. Application of a conversion factor from source to target substance (see read-across justification) leads to ‘target’ NOAEL of at least 11.1 mg/kg bw x 0.57 = 6.3 mg/kg bw.

 

No evidence of developmental toxicity was seen in a rabbit study (NTP, 1993; Heindel et al, 1996). Pregnant New Zealand White rabbits were exposed to sodium fluoride in their drinking water at concentrations of 0, 100, 200 or 400 ppm daily between gestation days 6 and 19. There was evidence of minimal maternal toxicity but no definitive evidence of developmental toxicity with levels of sodium fluoride in drinking water as high as 400ppm (resulting in an average exposure of 29 mg/kg bw/d) although the palatabillity of a 400 ppm sodium fluoride solution apparently reduced water consumption. This study established a NOAEL for maternal toxicity at 200 ppm NaF in drinking water (approximately 18 mg/kg bw/d) and a NOAEL for developmental toxicity of 400ppm NaF in drinking water (approximately 29 mg/kg bw/d) administered to pregnant NZW rabbits during organogenesis. This leads to target NOAEL of 18 mg/kg w/d x 0.57 =10.3 mg/kg bw for maternal toxicity and 29 mg/kg bw/d x 0.57 = 16.5 mg/kg bw for developmental toxicity.

Justification for classification or non-classification

Reliable studies do not indicate any developmental toxicity or reproductive toxicity of fluoride. No classification is therefore proposed.