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Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

No data are available for the substance, however a number of studies (including high quality NTPA and FDA data) are available for NaF. The much greater water solubility of sodium fluoride (41300 mg/L) compared to calcium fluoride (15 mg/L) means that the bioavailability of fluoride from NaF is likely to be much greater than that of fluoride from CaF2 and therefore represents a worst case.

Published studies

Araibi et al (1989) report adverse effects on the fertility of male rats administered sodium fluoride in the diet 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) report 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 pkynosis, denudation of cells and absence of sperm occurred in the cauda epididymis. The effects seen after 30 days administration were reversible. Chinoyet al(1992) report 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.

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.

Messeret 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. 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.d fluoride) is required to maintain reproductive capacity in female mice. In a 3 -generation mouse study (Tao & Suttie, 1976), no effects of fluoride on reproduction were seen. The study is of limited value, however the authors suggest that the effects of fluoride seen in the study of Messeret 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 two-generation study (Sprandoet al, 1997). 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 (Sprandoet al, 1998). No effects on reproduction were seen at the highest dose level of 250 ppm in a guideline-comparable two-generation rat study (Collinset al, 2001). In a further FDA study designed primarily to assess the potential effects of fluoride on spermatogenesis (as indicated in various published studies), Sprandoet al(1996) demonstrated that injection of sodium fluoride into the rat testis was without effect on spermatogenesis.

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 concludes that the NOAEL for reproductive toxicity is 250 ppm NaF, which corresponds to approximately 10 mg/kg bw/d fluoride. The absence of any apparent effects on the reproductive organs in chronic toxicity and carcinogenicity studies is also notable.


Short description of key information:
No data are available for the substance, however a number of studies (including high quality FDA data) are available for NaF. Reliable data do not indicate any specific reproductive or developmental toxicity for inorganic fluoride compounds.

Effects on developmental toxicity

Description of key information
A number of studies (including high quality FDA data) are available for NaF. The much greater water solubility of sodium fluoride (41300 mg/L) compared to calcium fluoride (15 mg/L) means that the bioavailability of fluoride from NaF is likely to be much greater than that of fluoride from CaF2 and therefore represents a worst case.
Additional information

The developmental toxicity of calcium fluoride and sodium fluoride was investigated in the mouse. Pregnant female mice were administered the substances in the drinking water or by intraperitoneal injection during gestation. Treatment caused structural changes in the jaw and teeth of offspring, with retardation of skeletal calcification. Calcium fluoride was reported to be more toxic, possible due to the higher fluoride content; high doses of both substances caused resorption or foetal death (Fleming & Greenfield, 1954).

In a rat developmental toxicity study (NTP, 1994; Heindel et al, 1996), maternal toxicity (transiently reduced bodyweight gain) was apparent at the highest dose level of 300 ppm sodium fluoride (in drinking water), equivalent to 13 mg/kg bw/d fluoride. No evidence of developmental toxicity was seen at this dose level. No clear evidence of developmental toxicity was seen in an FDA rat study (Collins et al,1995) at dose levels of up to 250 ppm sodium fluoride in drinking water (equivalent to 12.3 mg/kg bw/d fluoride). Maternal toxicity in this study was limited to reduced food intake at the highest dose level. No evidence of developmental toxicity was seen in a rabbit study (NTP, 1993; Heindel et al, 1996) at dose levels of up to 400 ppm sodium fluoride (equivalent to 14 mg/kg bw/d fluoride from all sources).

Stratmann et al (1979a,b; 1981) studied the effects of calcium fluoride administration to mice by single intraperitoneal injection on Day 9 of gestation, by dietary administration throughout gestation or over several generations. Embryotoxic effects of calcium fluoride were noted in this study only at very high single intraperitoneal dose levels (1600 mg/kg bw or higher), very high dietary concentrations in the repeated dose phase (20.48g%) or in the generation study (10.24g% and higher). The authors note that the negative effects of the substance on embryogenesis are slight compared to other fluoride compounds and conclude that the substance shows no effects at dose levels relevant for caries prophylaxis and is 'absolutely safe'

Justification for classification or non-classification

Reliable data do not indicate any specific reproductive or developmental toxicity for inorganic fluoride compounds. No classification for reproductive toxicity is therefore proposed for calcium difluoride under the CLP Regulation (1272/2008/EC).