Potassium hydrogendifluoride

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Dose descriptor:

NOAEL

10 mg/kg bw/day

Additional information

Published studies

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. 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.

FDA studies

The effects of sodium fluoride administration on spermatogenesis in rats were investigated in a two-generation study (Sprando et 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 (Sprando et al, 1998). No effects on reproduction were seen at the highest dose level of 250 ppm in a guideline-comparable two-generation rat study (Collins et al, 2001). In a further 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.

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 studies with potassium hydrogen difluoride 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 FDA.

Effects on developmental toxicity

Description of key information

No studies with potassium bifluoride 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.

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

14 mg/kg bw/day

Additional information

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).

Toxicity to reproduction: other studies

Additional information

The substance will form HF under physiological conditions, with subsequent dissociation to the constituent (hydrogen, potassium and fluoride) ions.T he toxicologically relevant component of the substance is considered to be fluoride, and systemic toxicity following repeated oral and inhalation exposure may result from fluoride. Reliable studies do not indicate any developmental toxicity or reproductive toxicity of fluoride

Justification for classification or non-classification

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