Dihydrogen hexafluorozirconate(2-)

Endpoint summary

Description of key information

In rodents, repeated exposure to fluoride salts, such as sodium fluoride, causes alteration of teeth at daily doses of 4 mg NaF/kg bw/day or greater.  Higher repeated doses of 10 and 25 mg NaF/kg bw/day increase dental effects as well as cause toxic effects in bone and the stomach.  The severity of the toxic effects is related to increasing dose and duration of exposure.  In a life-time chronic exposure study in the rats, an extremely high concentration of 175 ppm sodium fluoride in drinking water was associated with an increased incidence of osteosclerosis in female rats and equivocal evidence of osteosarcoma in male rats. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

8.2 mg/kg bw/day

Study duration:

chronic

Species:

rat

Additional information

Subacute Toxicity:

A 28-day repeated oral toxicity study (Proctor & Gamble, Co., 1991) was conducted to characterize the systemic toxicity of sodium fluoride. Weanling male and female Sprague-Dawley rats were dosed by gavage at concentrations of 2.5, 25 or 250 ppm sodium fluoride. The NOEL was 25 ppm. The following effects were observed at 250 ppm; hematology - significant depression in mean cell volume of males and females and mean cell hemoglobin of males; clinical chemistry - significant decrease in total protein of males and females and significant increase in alanine aminotransferase, potassium and chloride of females only; several changes in the mineral analysis of teeth and bone; and increased absolute and relative stomach weights.

Subchronic Toxicity:

The U.S. National Toxicology Program (NTP, 1990) evaluated the toxicological effects of continuous exposure to 0, 30, 100 or 300 ppm sodium fluoride in drinking water on F344 male and female rats for a 6-month period. Sodium fluoride caused weight loss at 300 ppm, fluorosis of the teeth at 100 and 300 ppm, minimal hyperplasia of the gastric mucosa of the stomach at 100 and 300 ppm (however, one high dose rat of each sex had an ulcer), a dose-related increase in fluoride content of bone and urine with increasing fluoride concentration in the drinking water, and a significant increase in fluoride content in the plasma at 300 ppm. No significant signs of toxicity were observed at concentrations of 10 or 30 ppm.

The U.S. National Toxicology Program (NTP, 1990) evaluated the toxicological effects of continuous exposure to 0, 10, 50, 100, 200, 300 or 600 ppm sodium fluoride in drinking water of male and female B6C3F1 mice for a 6-month period. Sodium fluoride caused death in some animals at 600 ppm and in a single male animal at 300 ppm, weight loss at 200 to 600 ppm, fluorosis of the teeth at 100, 200, 300 and 600 ppm, acute nephrosis and/or lesions in the liver and myocardium in mice that died early, minimal alterations in bone growth/remodeling in the long bones at 50 to 600 ppm, a dose-related increase in fluoride content of bone and urine with increasing fluoride concentration in the drinking water, and a possible dose-related increase in fluoride content in the plasma. No signs of toxicity were observed at the low dose of 10 ppm sodium fluoride.

Chronic Toxicity

The U.S. National Toxicology Program (NTP, 1990) evaluated the toxicological and carcinogenic effects of continuous exposure to 0, 25, 100 or 175 ppm sodium fluoride in drinking water on male and female F344/N rats for a 2 -year period. Survival and weight gains of the male and female rats were not affected by fluoride treatment. Rats receiving sodium fluoride developed effects typical of dental fluorosis at 25, 100 and 175 ppm, and female rats had increased osteosclerosis at the high-dose of 175 ppm.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Key study. In the registration dossier for KF and NaF, a LOAEL of 10 mg/kg/by, based on NaF was selected from a chronic study as the relevant effect level. This is re-calculated to 8.2 mg/kg/day based on H2ZrF6, based on the fluoride content of both substances.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: stomach; other: bone

Justification for classification or non-classification

Based on the results described above, classification for repeated dose toxicity is not warranted.