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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:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
- purity and stability of the test substance was not given - number of pregnant animal too low (3 animals/group instead of 20 animals/group) - clinical signs/mortality, body weight, and food consumption of females were not determined - gross pathology of the females was not conducted - sex of foetuses were not determined

Data source

Reference
Reference Type:
publication
Title:
Reduced foetal calcium without skeletal malformations in rats following high maternal doses of a strontium salt
Author:
Lansdown, A.B.G. et al.
Year:
1972
Bibliographic source:
Experientia 15: 558 - 560.

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
no. of animals too low, necropsy of dams not reported, sex ratio of litter not determined
Principles of method if other than guideline:
In this study groups of three pregnant female Wistar rats were treated subcutaneously with doses of 25, 50, 100 or 200 mg/kg bw/day strontium nitrate in distilled water from days 9 to 19 of pregnancy. A control group was run concurrently. The females were killed and the foetuses were histologically examined.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report): strontium nitrate

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Diet: standard diet containig 0.9 % calcium and negligible quantities of strontium
- Water (ad libitum): distilled water

Administration / exposure

Route of administration:
subcutaneous
Vehicle:
other: distilled water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Strontium nitrate in 1 mL of distilled water
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Details on mating procedure:
- Impregnation procedure: virgin female rats were mated with proven males.
- Proof of pregnancy: the day when spermatozoa were first detected in vaginal smears was designated day 0 of pregnancy.
Duration of treatment / exposure:
days 9 to 19 of pregnancy
Frequency of treatment:
daily
Duration of test:
19 days
No. of animals per sex per dose:
3 female rats
Control animals:
yes, concurrent vehicle
Details on study design:
no data

Examinations

Maternal examinations:
The females were killed with an overdose of pentobarbitone sodium (Nembutal).

CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: No data

FOOD CONSUMPTION AND COMPOUND INTAKE: No data
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE: No data
POST-MORTEM EXAMINATIONS: No data
- Sacrifice on gestation day 19 of pregnancy
Ovaries and uterine content:
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: No data
- Number of implantations: No data
- Number of resorptions: Yes
- litter size was noted
Fetal examinations:
The foetuses were preserved in 10 % buffered formalin for histology or in 95 % ethanol for potash maceration and alizarin staining.
Histological sections of foetuses cut transversely through the cephalic, thoracic and lumbar regions were stained with haematoxylin and eosin, haematoxylin and van Geisen, toluidine blue with silver impregnation (Lansdown, 1968)* and the sodium rhodizonate method for the presence of strontium (Mulyihill et al., 1970)*.
To ascertain the levels of strontium ion actually accumulating in the foetuses, 3 foetuses from mothers given 50 and 200 mg/kg strontium nitrate were ashed and the residue dissolved in 6N hydrochloric acid. The solutions were then analysed by atomic absorption spectrophotometry for their calcium and strontium contents.

*References:
- A. B. G. Lansdown, Histochemie 13, 192 (1968).
- J. E. Mulyihill; S. H. Gamm and V. H. Ferm, J. Embryol. exp. Morph. 24, 393 (1970).
Statistics:
mean ± SD
Indices:
no data
Historical control data:
no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
- litter sizes were similar and the number of resorption sites was not increased (please refer to table 1 in the field "Any other information on results incl. tables").

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
82.8 mg/kg bw/day (nominal)
Based on:
element
Remarks:
strontium
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- progeny from the treated mothers did not differ from the controls in size or body weight.
- in the alizarin stained foetuses, the skeletons were normal and the zones of calcification in the bones were of normal proprotions. No histological changes were detected in the soft tissues and the skeletal tissues exhibited the characteristic degree of ossification for 19-day-old rat foetuses.
- sodium rhodizonate staining for strontium ion was very pale and only observed in ossifying regions and not in soft tissues.
- level of strontium in the foetuses is unchanged despite a four-fold increase in the maternal dose of the strontium salt (50 mg/kg: 5.4 ± 0.1 ppm strontium; 200 mg/kg: 4.6 ± 0.5 ppm strontium; please refer to table 2 in the field "Any other information on results incl. tables").
- foetal calcium from mothers given 200 mg/kg (82 ± 18 ppm calcium) was appreciably less than in those given 50 mg/kg (215 ± 15 ppm calcium; please refer to table 2 in the field "Any other information on results incl. tables").

Effect levels (fetuses)

Remarks on result:
other: Embryotoxic / teratogenic effects
Remarks:
Embryotoxic / teratogenic effects: no effects Details on embryotoxic / teratogenic effects: - progeny from the treated mothers did not differ from the controls in size or body weight. - in the alizarin stained foetuses, the skeletons were normal and the zones of calcification in the bones were of normal proprotions. No histological changes were detected in the soft tissues and the skeletal tissues exhibited the characteristic degree of ossification for 19-day-old rat foetuses. - sodium rhodizonate staining for strontium ion was very pale and only observed in ossifying regions and not in soft tissues. - level of strontium in the foetuses is unchanged despite a four-fold increase in the maternal dose of the strontium salt (50 mg/kg: 5.4 ± 0.1 ppm strontium; 200 mg/kg: 4.6 ± 0.5 ppm strontium; please refer to table 2 in the field "Any other information on results incl. tables"). - foetal calcium from mothers given 200 mg/kg (82 ± 18 ppm calcium) was appreciably less than in those given 50 mg/kg (215 ± 15 ppm calcium; please refer to table 2 in the field "Any other information on results incl. tables").

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 1: The total numbers of foetuses and resorption sites in rats given subcutaneous doses of strontium nitrate in pregnancy

Dosage (mg/kg)

Animals treated

Total No. of foetuses

Total No. of resorption

Control

3

36

3

25

3

36

6

50

3

30

2

100

3

31

4

200

3

33

2

Table 2: Strontium and calcium content of foetuses from mothers given strontium nitrate in pregnancy

Dosage (mg/kg)

No. of foetuses

Strontium content (ppm)

Calcium content (ppm)

Ratio Sr:Ca

50

3

5.4 ± 0.1

215 ± 15

1:40

200

3

4.6 ± 0.5

82 ± 18

1:18

Applicant's summary and conclusion

Conclusions:
According to the authors, the results indicate that high maternal doses of strontium nitrate (25, 50, 100 or 200 mg/kg bw/day; equivalent to 10.3, 20.7, 41.4, or 82.8 mg Sr/kg bw/day) were not teratogenic when given at a maximum period of bone development.