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Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-standard, published study.

Data source

Reference Type:
Lawrenz M, Mitchell HH & Ruth WA
Bibliographic source:

Materials and methods

Objective of study:
Test guideline
no guideline available
Principles of method if other than guideline:
Investigative study into the retention and toxicity of fluoride from calcium fluoride and cryolite (sodium hexafluoroaluminate)
GLP compliance:
: older study, pre-dates GLP

Test material

Constituent 1
Chemical structure
Reference substance name:
Calcium fluoride
EC Number:
EC Name:
Calcium fluoride
Cas Number:
Molecular formula:
calcium difluoride
Test material form:
not specified
Details on test material:
The cryolite (sodium hexafluoroaluminate) used in this experiment was a synthetic product marketed as an insecticide. It contained 43.7% fluorine and about 15% of non-cryolite material, including hydrated oxide of aluminum and compounds of sodium, calcium and silicon. The calcium fluoride was a chemically pure product.

Test animals

not specified
Details on test animals or test system and environmental conditions:
The cryolite (sodium hexafluoroaluminate) used in this experiment was a synthetic product marketed as an insecticide. It contained 43.7% fluorine and about 15% of non-cryolite material, including hydrated oxide of aluminum and compounds of sodium, calcium and silicon. The calcium fluoride was a chemically pure product.

Administration / exposure

Route of administration:
oral: drinking water
unchanged (no vehicle)
Details on exposure:
Each pair of rats received the same amount of food daily and the same amount of fluorine in the drinking water. The odd-numbered rats received water containing CaF2 and the even-numbered rats water containing cryolite.
Duration and frequency of treatment / exposure:
Daily for approximately 14 weeks. In order to avoid any possibility of the solid food depressing or obscuring the toxic effects of the test substances administered in the water, the consumption of the food and of the water was separated as much in time as possible. The rats were allowed to eat from 8 to 9.30 A.M. and during this time the water consumption was restricted to the 4 to 5 cc. of distilled water that was mixed with the food to prevent scattering. From 9.30 6 P.M. the rats had access to neither food nor water. At 6 P.M. they were given measured portions of the fluorine-containing water and after these were consumed they were given distilled water ad libitum until the following morning at 8 A.M.
Doses / concentrations
Doses / Concentrations:
Total fluoride intake was calculated to be equivalent to 0.75 mg/kg bw/d.
No. of animals per sex per dose / concentration:
12 per group
Control animals:
other: untreated rats were analysed for background fluoride levels
Positive control reference chemical:
Not applicable
Details on study design:
To permit an estimate of the initial fluorine content of the experimental rats, six rats of approximately the same weight range as the experimental rats were analyzed after removal of the contents of the alimentary canal. The entire carcasses of these rats were analyzed for fluorine by the technique used with the soft-tissue samples of the experimental rats.
Details on dosing and sampling:
After approximately 14 weeks of feeding, the rats were killed with ether and the digestive tracts removed, emptied, washed with distilled water and replaced. After determining the empty weights, the carcasses were autoclaved to facilitate the separation of the skeleton from the soft tissues. The latter were combined with water, finely ground and thoroughly mixed by hand. The bones, after removal of the teeth, were dried for 12 hours at 110°C,broken up and extracted with ether for 48 hours in a Soxhlet extractor. The extracted bone was then dried at 110°C for 20 minutes, weighed and finely ground in a hand mill. The teeth, after removal from the carcass, were washed first in water to remove all adhering tissue, and then in ether, after which they were dried at 110°C for 24 hours and weighed. The soft tissue, bones and teeth were analyzed separately for fluorine. Samples of soft tissue were weighed out, mixed with 15 cc. of a 10% solution of magnesium acetate and ashed for 12 to 16 hours at temperatures of 500-550°C. Samples of bone were ashed for 16 to 20 hours at 550°C,while the entire weight of teeth was ashed for 20 hours at 550 -600°C carefully ground in a mortar and re-ashed for 24 hours at the same temperature. The fluorine was isolated from the ash of all samples and analysed.
Not reported

Results and discussion

Preliminary studies:
Not applicable.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The quantities of fluorine retained during the experimental feeding period averaged 59.3% of the amount fed for the rats receiving the calcium fluoride supplement, and 59.2% for the rats receiving cryolite. The data do not reveal any appreciable difference between the rate of retention of fluorine from calcium fluoride and from cryolite.
Details on distribution in tissues:
Over 96% of the fluorine retained by the rats was deposited in the skeleton. The remainder of the recovered fluorine was deposited in about equal amounts in the teeth and in the soft tissues, 1.85 and 2.05%, respectively.
Details on excretion:
Not investigated.

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
Not relevant.

Any other information on results incl. tables

The fluorine in cryolite is no more toxic to growing rats nor is it retained in the body to a greater extent, than the fluorine in calcium fluoride when both are administered in aqueous solution at the rate of 0.58 mg per kilogram of body weight daily. The appearance of striations in the incisor teeth is equally rapid with both fluorine compounds. About 96% of the fluorine retained at an intake equivalent to 13 ppm of food consumed is deposited in the skeleton, and the remaining 4% is about equally divided between teeth and soft tissues.

Applicant's summary and conclusion

Fluoride retention was approximately 59% , with the large majority of the fluoride in the body present in the skeleton (~96%).
Executive summary:

In a study using 12 paired groups of albino rats, the authors administered fluoride in the form of calcium fluoride or cryolite in the drinking water for 14 weeks. Total fluoride intake (from the basal diet and drinking water) amounted to a dose leve of approximately 0.75 mg/kg bw/d. Bodyweight gain and food consumption were retarded in both dose groups. Clinical signs were limited to transient haematuria in both groups, and the appearance of dental striations in all animals from Week 8 -10. Analytical derminations at necropsy revealed fluoride retention of approximately 59%, and that the large majority of the fluoride in the body was present in the skeleton (~96%). No differences were apparent between the treated groups. The authors conclude that the effects of fluoride from these two insoluble salts are comparable.

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