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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-standard, published, investigatiev study

Data source

Reference
Reference Type:
publication
Title:
CHANGES IN THE TEETH AND JAWS OF NEONATAL WEBSTER MICE AFTER ADMINISTRATION OF NaP AND CaF2 TO THE FEMALE PARENT DURING GESTATION
Author:
Fleming HS & Greenfield VS
Year:
1954
Bibliographic source:
J. Dent. Res 33 (6) 780-788

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Assessmnet of developmental toxicity, with a focus on the teeth and jaw
GLP compliance:
no
Remarks:
: older, literature study, pre-dates GLP
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Reagent grade calcium fluoride and sdoium fluoride

Test animals

Species:
mouse
Strain:
Swiss Webster
Details on test animals and environmental conditions:
Constant temperature of 75 F.

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
The study was conducted on 245 pregnancies in which the animals received fluorides (eighty mice receiving NaF via drinking water, fifty mice
receiving CaF2 via drinking water, sixty mie6 receiving NaF via injection, fifty-five mice receiving CaF2 via injection) and on twenty-five additional
pregnancies that served as controls.

NaF and CaF, were diluted 1:1,000 (1,000 ppm) and 1:50,000 (20 ppm), and were used for intraperitoneal injections and drinking water, respectively. When injections were given, 0.10 c.c. of the 1 :1,000 solution was administered daily. This was the equivalent of 100 jug of NaF or CaF, per injection. Via drinking water, each pregnant Webster mouse consumed 6 to 8 c.c. of solution daily, and sometimes more. It is estimated that approximately one-half of this amount may have been lost by waste and evaporation, so that each mouse actually consumed 3 to 4 c.c. daily. In these cases, consumed fluorides ranged from 60 to 80+ ,ug daily.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
None
Details on mating procedure:
Fifteen breeding cages and jars were organized with young adult Webster mice. One male was allotted to every three or four females. Upon daily examination, females with vaginal plugs were placed in other quarters, and new young adult females were added to the breeding units. In instances where there seemed to be an absence of pregnancies, males and females were exchanged for new animals.
Duration of treatment / exposure:
Administration of fluorides was usually started between the fifth and the tenth days of pregnancy, but in some instances was not given until the fifteenth day, and on still other occasions, was started immediately after observation of the vaginal plugs.
Frequency of treatment:
Continuous (in drinking water)
Duration of test:
Administration until birth.

Examinations

Maternal examinations:
Not assessed
Ovaries and uterine content:
Resporption was assessed.
Fetal examinations:
One or two animals from each litter were sacrificed, and the heads fixed in 10 per cent formalin, decalcified, and sectioned. Embedded heads were cut at 6 pt from the snout tip at right angles to the inferior border of the mandible. Sections were stained with hematoxylin and eosin.
Statistics:
Not detailed
Indices:
Not relevant
Historical control data:
Not presented

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Details on maternal toxic effects:
Administration of CaP2 and NaF during the whole period of pregnancy seemed to cause resorption of the embryos or fetuses. In these cases, the
route of administration was either by injection (0.1 c.c. of 1:1,000 solution daily) or via drinking water (3 to 4 c.c. of 1:50,000 daily). Because of this
resorption, administration of NaF and CaF2 was usually delayed until the last half of the gestation period. It was determined that the female parent could tolerate 1,000 to 1,100 jug of NaP and 600 to 700 ,ug of CaP2 during the latter part of gestation without causing death in utero or stillbirths.

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Administration of CaF2 and NaF during the whole period of pregnancy seemed to cause resorption of the embryos or fetuses.Administration of NaF and CaF, to the female parents during gestation caused changes in the structure of the jaws and teeth of the neonatal mice. Calcification of bone in the jaws was retarded. There was alteration of the cell structure of the ameloblasts, with retardation of the enamel matrix maturation. Cartilaginous-like formations appeared in the dental pulp. There was a bridging of the dentin matrix with these formations.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

CaF2 seemed to be more toxic to the fetuses than NaF, both by injection and by oral administration to the pregnant females. Approximately 600 to 700 ug of CaF2 and 1000 to 1200 ug of NaF were tolerated without causing resorption of foetuses or stillbirths; amounts in excess of this caused these phenomena. In the cases of fluoride-treated animals, the pulpal blood vessels in the teeth of the newborn animals appeared to be hyperemic. There was disruption of the endothelial cells of the vessels, with slight hemorrhaging in the pulpal area as well as in the area immediately surrounding the tooth.

Applicant's summary and conclusion

Conclusions:
Administration of sodium fluoride or calcium fluoride to pregnant female mice in the drinking water or by intraperitoneal injection caused structural changes in the jaw and teeth of offspring, with retardation of skeletal calcification. Calcium fluoride was reported to be more toxic; high doses of both substances caused resorption or foetal death.
Executive summary:

The developmental toxicity of calcium fluoride and sodium fluoride was investigated in the mouse. Pregnant female mice were administered the substances in the drinking water or by intraperitoneal injection during gestation. Treatment caused structural changes in the jaw and teeth of offspring, with retardation of skeletal calcification. Calcium fluoride was reported to be more toxic, possibly due to the higher fluoride content; high doses of both substances caused resorption or foetal death.