Fluorine

Endpoint summary

Description of key information

Effects of repeated fluoride exposure in experimental animals were seen on the teeth, bones, respiratory tract and kidney.

Evidence from epidemiological studies in humans also indicates that prolonged exposure to fluoride causes dental and skeletal effects.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

0.72 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Proprietary study conducted according to GLP, and comparable to current guidelines.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Fluorine reacts instantly and violently with moisture under formation of hydrogen fluoride. Hydrogen fluoride will further react to fluoride.

The toxicologically relevant component of the substance is therefore considered to be fluoride, and systemic toxicity following repeated inhalation and oral exposure may result from fluoride. Read-across is therefore proposed to other soluble fluoride salts, which demonstrate the critical effect to be skeletal fluorosis. Dermal absorption of fluoride is not predicted under normal conditions of use.

Repeated dose oral toxicity

Comprehensive repeated dose toxicity studies by oral route are available for sodium fluoride. In a 6-month oral (drinking water) rat study, the effects of exposure to NaF were limited to reduced weight gain, dental fluorosis, thickening and ulceration of the gastric mucosa at the highest dose level of 300 ppm; gastric effects were also seen at 100 ppm. The fluoride content of plasma, bone and teeth increased with dose levels (NTP 1990). The NOEL for this study was 30 ppm, however these local effects are considered not to be relevant for the risk assessment. Therefore 100 ppm of NaF in the drinking water (5.2 and 6.4 mg/kg bw for male and female rats, respectively) was considered a NOAEL in this 6-month rat study.

In a 6-month oral mouse study, mortality attributable to acute nephrosis was seen at the highest dose level of 600 ppm (NTP 1990). Skeletal effects were seen in males at 50 ppm and in both sexes at the higher dose levels. Therefore the LOAEL was determined to be 50 ppm (5.1 mg/kg bw).

Repeated dose dermal toxicity

No studies are available. The effects of dermal exposure will be dominated by local irritation/corrosion. There is no evidence of significant dermal absorption of fluorine under exposure conditions where the integrity of the skin barrier is maintained. Testing for repeated dose dermal toxicity can therefore be waived on scientific grounds and for reasons of animal welfare.

Repeated exposure inhalation toxicity

In a published study (Sadilova 1974), female rats were exposed to 1 mg/m3 HF 6 hours/day for 1 month. Effects were noted on the teeth, bones and respiratory tract.

Two studies were conducted over longer exposure periods. In a range-finding study, groups of five male and five female Fischer-344 rats were exposed to measured concentrations of HF at 0 (air), 1, 10, 25, 65, or 100 ppm for 6 h/d, 5 d/wk for 14 d; survivors were sacrificed 2 d later (Placke et al., 1990). No deaths occurred in females inhaling 1 ppm or 10 ppm. Exposures at 25 ppm and above resulted in death in all females, with deaths beginning on the eighth, third, and second day of exposure at the 25-, 65-, and 100-ppm concentrations, respectively. No deaths occurred in males inhaling 1, 10, or 25 ppm; exposures at 65 ppm and 100 ppm resulted in death in all males, with deaths beginning on the third and second day at the 65-ppm and 100-ppm concentrations, respectively. No deaths occurred during the first day of exposure at any concentration. In the group exposed at 1 ppm, no effects other than a slight increase in lung-to-body weight ratio occurred. There were no clinical signs of toxicity in either gender at 1 and 10 ppm. There were no effects observed at 1 ppm except for a slight increase in absolute and relative lung weights in females and in absolute and relative heart weights in males. At 10 ppm and above, body weight and organ weight (liver, heart, kidney, and lungs) changes occurred in one or both genders. Clinical signs of nasal and ocular mucosal irritation occurred in the 25-, 65-, and 100-ppm groups. Dermal crust formation, ocular opacity, and tremors were also observed.

In a subchronic study (Placke et al., 1991), groups of 10 male and 10 female rats were exposed to concentrations of HF at 0.1, 1.0, or 10 ppm, administered as described above, for 91 d. Animals were observed for clinical signs, weighed, and subjected to hematology and blood chemistry examinations; tissues were examined microscopically. Five males and one female in the group exposed at 10 ppm died. Clinical signs included red-colored discharge from the eyes and nose, ruffled fur, alopecia, and hunched posture. Body weights were depressed, major organ weights were increased, and some blood parameters were changed compared with the control group. Dental malocclusions were observed in 11 animals. No deaths occurred at the two lower exposure concentrations.

Justification for classification or non-classification

Classification for repeated dose toxicity is not proposed.