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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Adequacy of study:
supporting study

Data source

Reference
Reference Type:
publication
Title:
Comparative Toxicity of Fluorine Compounds
Author:
Smith MC & Leverton RM
Year:
1934
Bibliographic source:
Industrial & Engineering Chemistry July 1934. 791-797

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The authors investigated the comparitive toxicity of various forms of fluorine including calcium difluoride when administered to rats in the drinking water for 6 weeks. Investigations focussed on mortality, weight gain and dental effects.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Various fluorides, including calcium difluoride

Test animals

Species:
rat
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
The albino rats used were taken at 4 weeks of age from the stock colony and raised on Shierman's Diet B, composed of one-third whole milk powder, two-thirds ground whole Kansas red wheat, and salt equal to 2 per cent iii the weight of the wheat. Only male rats wcighiiig from 50-65 g at the time of weaniing were used.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Rats were administered various inorganic fluorides in the diet at equivalent cocnentrations for a 6-week exposure period. Sodium fluoride was incorporated into the diet at Ievels of 0.05% or multiples or fractions of this amount. All of the other compounds of fluorine were compared with sodium fluoride at the same percentage level of fluoride.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
6 weeks
Frequency of treatment:
Continuous / daily (dietary admixture)
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.00282, 0.00565, 0.0113, 0.0226, 0.0452, 0.226, 0.452, 0.9040, 1.3560, 1.8080, 3.6160 % fluorine equivalents
Basis:
nominal in diet
No. of animals per sex per dose:
1-40
Control animals:
yes, plain diet

Examinations

Observations and examinations performed and frequency:
Animals were observed for general health, growth and food consumption. The appearance of the teeth was recorded.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
dental fluorosis
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
Mortality:

Deaths occurred following the administration of fluoride in the form of calcium fluoride at concentrations of 3.6% within 3-4 weeks or at a lavel of 5.4% within 9-11 days. In contrast, mortaility was seen at levels of >0.0452% of more soluble salts.

Bodyweight effects:

Following the administration of calcium fluoride were only apparent at dose levels of 0.452%, equivalent to 475 mg/kg bw/d fluorine. The authors note that this level is approximately 20 times higher than the level of sodium fluoride causing similar effects and ten times higher than highest non-lethal concentration of sodium fluoride.

Effects on the teeth

Mild dental effects were noted with all sources of fluorine at comparable concentrations, however more severe effects were only seen at comparatively very high levels of calcium difluoride (20-40 times equivalent levels of sodium fluoride).

Effect levels

Dose descriptor:
NOAEL
Effect level:
0.226 other: %
Based on:
other: fluoride (as CaF2)
Sex:
male
Basis for effect level:
other: Bodyweight effects were seen at levels of 0.452% fluoride and higher

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Fluoride level

n

Weight gain (g)

Food intake (g)

0

40

158

466

0.00282

1

194

612

0.00565

1

176

560

0.0113

5

158

494

0.0226

8

152

462

0.0452

8

155

487

0.226

6

142

492

0.452

10

132

441

0.904

6

115

411

1.356

4

77

358

1.808

4

32

252

3.616

4

-

-

Applicant's summary and conclusion

Conclusions:
The results of the study indicate that the toxicity of calcium difluoride is markedly influenced by its low water solubiliy.
Executive summary:

The authors investigated the comparative toxicity of various forms of inorganic fluoride in a 6 -week feeding study in male rats. They noted that overt effects of calcium difluoride toxicity (bodyweight reduction, mortality) were seen only at very high concentrations compared to other, water-soluble fluorides. In contrast, mild dental effects were seen at comparable fluoride levels for all of the compounds investigated, however the more severe effects were only seen at much comparatively much higher concentrations of calcium difluoride. The results of the study therefore indicate that the toxicity of calcium difluoride is markedly influenced by its low water solubiliy.