Strontium carbonate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

An Extended One Generation Reproductive toxicity study with F2 generation and developmental neurotoxicity was performed on Strontium chloride hexahydrate administered by oral gavage to Sprague-Dawley rats. There was no systemic and reproductive toxicity in the parental generation and in their offspring of both sexes. Their was no systemic toxicity, no developmental neurotoxicity and no neuro-histopathology changes in the adult F1 generation. The NOAEL of Strontium chloride hexahydrate was considered to be 1000 mg/kg bw/day for systemic toxicity, reproduction, and developmental toxicity and neurotoxicity endpoints.

Based on the read-across from Strontium chloride hexahydrate, Strontium carbonate is considered to be not toxic to reproduction and the corresponding NOAEL is considered to be 931.2 mg SrCO3/kg/day (calculated using the molar mass ratio of SrCl2 and SrCO3).

Link to relevant study records

Reference

Endpoint:

extended one-generation reproductive toxicity - with F2 generation and developmental neurotoxicity (Cohorts 1A, 1B with extension, 2A and 2B)

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
Further information is included as attachment in Section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

328.56 mg/kg bw/day (nominal)

Based on:

element

Remarks:

metal ion based

Sex:

male/female

Basis for effect level:

other: No adverse effects observed for systemic toxicity, reproduction and developmental toxicity endpoints at the highest dose level

Key result

Dose descriptor:

NOAEL

Remarks:

Cohort 1B

Effect level:

328.56 mg/kg bw/day (nominal)

Based on:

element

Remarks:

metal ion based

Sex:

male/female

Basis for effect level:

other: No adverse effects observed for systemic toxicity, reproduction and developmental toxicity endpoints at the highest dose level

Key result

Dose descriptor:

NOAEL

Generation:

F1 (cohort 1A)

Effect level:

328.56 mg/kg bw/day (nominal)

Based on:

element

Remarks:

metal ion based

Sex:

male/female

Basis for effect level:

other: No adverse effects observed for systemic toxicity endpoint at the highest dose level

Key result

Dose descriptor:

NOAEL

Generation:

F1 (cohort 2A)

Effect level:

328.56 mg/kg bw/day (nominal)

Based on:

element

Remarks:

metal ion based

Sex:

male/female

Basis for effect level:

other: No adverse effects observed for systemic toxicity and developmental toxicity endpoints at the highest dose level

Key result

Dose descriptor:

NOAEL

Generation:

F1 (cohort 2B)

Effect level:

328.56 mg/kg bw/day (nominal)

Based on:

element

Remarks:

metal ion based

Sex:

male/female

Basis for effect level:

other: No adverse effects observed for developmental toxicity endpoint at the highest dose level

Key result

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

328.56 mg/kg bw/day (nominal)

Based on:

element

Remarks:

Sr

Sex:

male/female

Basis for effect level:

other: No adverse effects observed for systemic toxicity endpoint at the highest dose level

Key result

Reproductive effects observed:

no

Conclusions:

Based on the read-across from Strontium chloride hexahydrate, Strontium carbonate is considered to be not toxic to reproduction.
The NOAEL was 328.56 mg Sr/kg/day for systemic toxicity, reproduction and developmental neurotoxicity endpoints, corresponding to 553.6 mg SrCO3/kg/day.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

931.2 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No reproductive toxicity data are available for strontium hydroxide itself. However, an analogue approach is used for the read-across of reproductive toxicity properties of strontium hydroxide from strontium chloride, based on the hypothesis that properties are likely to be similar as a result of the presence of a common metal ion Sr2+. Further information on the read-across justification is included as attachment in Section 13.

 

In absence of overt general toxicity, the available 90-day repeated dose toxicity study (Kroes, 1977) in rats with an analogue sustance, Strontium chloride, showed evidence of deviations in organ weights of hormonally sensitive organs (i.e. effects were observed on relative organ weights of prostate and thyroid in males and in pituitary of females). Since these effects might be indications for a mode of action related to endocrine disruption and developmental neurotoxicity, an EOGRT study was required for further investigations.

In the EOGRT study (Manjunath, 2022), there were no adverse test item-related changes noted in mean absolute/relative organ weights possibly related to endocrine effects, in the thyroid hormones of parental and cohorts of F1 adult animals in any of the tested dose groups of both sexes. There were no test item-related histopathological findings in high dose animals of parental and cohorts of F1 adult animals. There were no test-item related changes noted in neurotoxicity endpoints of F1 adult animals in any of the tested dose groups of both sexes, and no neuropathological changes in any of the high dose animals of both sexes. No adverse effects were observed on reproduction and developmental toxicity parameters which could be indicative for an endocrine mode of action or endocrine disturbance.

Therefore, based on these results, any concern related to thyroid toxicity, developmental neurotoxicity, or mode(s) of action related to endocrine disruption can be excluded.

Effects on developmental toxicity

Description of key information

Strontium ranelate was not teratogenic in rats and rabbits. Only an increase in the frequency of delays in skeletal ossification and structural abnormalities (way ribs, bent bones, shortened and thickened humerus and misshapen clavicle) was observed in the rat at all dose levels. The effects of strontium ranelate on the embryo-fetal and pre-/postnatal development was investigated in a GLP compliant toxicity study according to the ICH guideline on Detection of Toxicity to Reproduction of Medical Products, June 24, 1993. Groups of pregnant female rats were either exposed from day 14 prior to mating with untreated males until day 17 of gestation (group A) or after mating with treated males from day 6 of gestation until day 20 of lactation. Embryo-fetal development was evaluated in group A and effects on parturition and pre-/post natal development in group B. Animals received the test compound by oral gavage at dose levels of 500, 750 and 1000 mg/kg bw/d. Control animals were treated with the vehicle.
No treatment-related maternal toxicity was observed in group A and B females. No effects on embryo/-fetal development were observed beside an increase in the frequency of delays in skeletal ossification and structural abnormalities (way ribs, bent bones, shortened and thickened humerus and misshapen clavicle) at all dose levels. Although the percentage of affected fetuses by a delay of ossification was higher in the treated groups than in the control, there was no dose-response relationship and values were within the normal historical control range of this strain. In addition, the structural abnormalities observed in twenty day old fetuses were completely reversible in seven to eight week old F1 animals, because all these anomalies were no longer visible during postnatal development as shown by X-ray radiography. These transitory findings were regarded as not effecting basical development of offspring but were related to retarded ossification.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

143.7 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The study to examine the effects of strontium ranelate on embryo-fetal and pre-/postnatal development (K. Momburg, 2001) of rats is regarded as relevant and reliable to evaluate the effects of strontium. In addition, a study on the embryo-fetal development of rabbits (K. Momberg 1999) with strontium ranelate is available to complete the database for this endpoint.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No developmental toxicity / teratogenicity data are available for strontium hydroxide itself. However, an analogue approach is used for the read-across of developmental toxicity / teratogenicity properties of strontium hydroxide from strontium ranelate, based on the hypothesis that properties are likely to be similar as a result of the presence of a common metal ion Sr2+. Further information on the read-across justification is included as attachment in Section 13.

The effects of strontium ranelate on the embryo-fetal and pre-/postnatal development was investigated in a GLP compliant toxicity study according to the ICH guideline on Detection of Toxicity to Reproduction of Medical Products, June 24, 1993 (K. Momberg 2001). Groups of pregnant female rats were either exposed from day 14 prior to mating with untreated males until day 17 of gestation (group A) or after mating with treated males from day 6 of gestation until day 20 of lactation (group B). Embryo-fetal development was evaluated in group A and effects on parturition and pre-/post natal development in group B. Animals received the test compound by oral gavage at dose levels of 500, 750 and 1000 mg/kg bw/d. Control animals were treated with the vehicle. Additional subgroups (group C and D) were included for toxicokinetic investigations.

No treatment-related maternal toxicity was observed in group A and B females. No effects on embryo/-fetal development were observed beside an increase in the frequency of delays in skeletal ossification and structural abnormalities (way ribs, bent bones, shortened and thickened humerus and misshapen clavicle) at all dose levels. Although the percentage of affected fetuses by a delay of ossification was higher in the treated groups than in the control, there was no dose-response relationship and values were within the normal historical control range of this strain. In addition, the structural abnormalities observed in twenty day old fetuses were completely reversible in seven to eight week old F1 animals, because all these anomalies were no longer visible during postnatal development as shown by X-ray radiography. These transitory findings were regarded as not effecting basical development of offspring but were related to retarded ossification.

It was also discussed that these findings appear not relevant in the case of human exposure during organogenesis, because the skeletal development at parturition in humans is much more advanced than in rodent species. In conclusion, these findings were not considered as true congenital skeletal malformations, because they were reversible and were therefore considered as variations without any functional consequences.

Although in the context of the study, the lowest dose level of 500 mg/kg bw/d does not represent an NOAEL, but a LOAEL, the findings at this dose level were of transient nature and regarded as not relevant for human embryo/fetal development, and thus did not provide evidence of an adverse effect on the development of offspring.

The structural abnormalities were also not present in theoral embryo-fetal development study with strontium ranelate (K. Momberg 1999) in rabbits at up to 1500 mg/kg bw/d.

In the post-natal development part of the study, a delay of incisor eruption was seen on lactation day 11 mainly in offspring of the 1000 mg/kg bw/d group, but had no negative effect on animal growth which is directly related to feed intake and use of teeth for gnawing of feed pellets. In addition, the relevance of these effects for humans was deemed as low, because tooth development in man differ from rat with incisor eruption occurring after weaning at 6-24 months after birth. Therefore, the NOAEL for postnatal development was established at the highest dose group of 1000 mg/kg bw/d.

In addition, in the study published by Lansdown et al. (1972) groups of 3 female Wistar rats were treated subcutaneously with 25, 50, 100 or 200 mg strontium nitrate/kg bw/d in 1 ml distilled water from day 9 to 19 of pregnancy when they were killed. Control animals received distilled water only. The progeny from strontium-treated mothers did not differ from that of controls in size or body weight. The litter sizes were normal and the number of resorption sites was not increased. No histological changes were detected in the soft tissues and the skeletal tissues exhibited the characteristic degree of ossification for 19-day old rat fetuses. The results indicated that high doses of strontium nitrate (up to and including 200 mg/kg bw/d s. c.) are not teratogenic. Thus, the dose of 200 mg/kg bw/d can be considered as a NOAEL for developmental toxicity which corresponds to an external dose of about 83 mg Sr/kg bw/d (equal to 140 mg SrCO3/kg bw/d) to female rats. However, the study was conducted only in a small number of females (p=3) per group and only a limited number of parameters were evaluated. In addition, the subcutaneous route of administration is not relevant route of exposure for risk assessment purposes. Nevertheless, the study by Lansdown et al. (1972) on pregnant rats is regarded as appropriate to support the evaluation of the effects of strontium on embryo-fetal development.

Justification for classification or non-classification

Based on the overall evaluation of the available data for strontium on reproduction and developmental toxicity, no classification and labelling for reproduction is deemed to be justified according to regulation (EC) 1272/2008.