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Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
358 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study to examine the effects of strontium ranelate on male and female fertility (K. Momburg, 2001) of rats is regarded as relevant and reliable to evaluate the effects of strontium. The NOAEL is re-calculated to strontium sulfate.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Toxicological relevance of the counterion “sulfate”

The registrant is of the opinion that the toxicity of strontium sulfate is driven by the strontium moiety and that the sulfate anion does not contribute to the overall toxicity of the substance strontium sulfate to any relevant extent, for the following reasons:

Sulfate anions are abundantly present in the human body in which they play an important role for the ionic balance in body fluids. Sulfate is required for the biosynthesis of 3′-phosphoadenosine-5′-phosphosulfate (PAPS) which in turn is needed for the biosynthesis of many important sulfur-containing compounds, such as chondroitin sulfate and cerebroside sulfate. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) concludes that the few available studies in experimental animals do not raise any concern about the toxicity of the sulphate ion in sodium sulphate. Sodium sulphate is also used clinically as a laxative. In clinical trials in humans using 2-4 single oral doses of up to 4500 mg sodium sulphate decahydrate per person (9000 – 18000 mg per person), only occasional loose stools were reported. These doses correspond to 2700 - 5400 mg sulphate ion per person. High bolus dose intake of sulphate ion may lead to gastrointestinal discomfort in some individuals. No further adverse effects were reported (JECFA 2000, 2002). This position was adopted by the European Food Safety Authority (EFSA 2004) without alteration.

Based on the above information, one can therefore safely assume that the sulfate anion in strontium sulfate does not contribute to the overall toxicity of strontium, sulfate. It is concluded that only the effect of “strontium” is further considered in the human health hazard assessment of strontium sulfate.

Read across from Sr ranelate to SrSO4:

The toxicity of strontium substances such as strontium sulfate can reasonably assumed to be determined by the availability of strontium ions in solution. Both substances (strontium ranelate and strontium sulfate) are “ moderately soluble” to "very soluble" (170 mg SrSO4/L at 37°C/ pH 1.5 and 6.74 g SrRenelate/L at 37°C/ pH 3.8) at low pH (pH in the gastrointestinal tract is ~1.5). Hence, it can be concluded that possible adverse effects observed with SrRanelate are certainly representative of possible similar effects to be expected in SrSO4 exposure.

For more information on solubility testing please refer to the attached file.


Short description of key information:
Male and female fertility was examined in a reproduction toxicity study in male and female Wistar rat with oral administration of dose levels of 500, 750 and 1000 mg/kg bw/d Strontium ranelate. Male and female fertility as well as reproductive performance was not affected at dose level of up to 1000 mg/kg bw/d. Females of the female fertility subgroup were treated for 14 days prior to pairing with untreated males and continued throughout pairing and until day 17 of gestation. Males of the subgroup for male fertility assessment were treated for 28 days prior to pairing with untreated females and continued throughout pairing including the day before sacrifice. Treatment of females of this subgroup started after mating on day six of gestation until day 20 of lactation.

Justification for selection of Effect on fertility via oral route:
Based on data from a reliable GLP reproduction toxicity study with the structural analogue strontium ranelate (Oral reproduction toxicity study in the Wistar rat (male and female fertility/embryo-fetal and postnatal development) adressing male and female fertility according to the ICH guideline on Detection of Toxicity to Reproduction of Medicinal Products, June 24, 1993, and with the ICH Guideline Addendum: Toxicity to male fertility, July 1996.

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 (wavy 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
179 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. The NOAEL is re-calculated to strontium sulfate.
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

Toxicological relevance of the counterion “sulfate”

The registrant is of the opinion that the toxicity of strontium sulfate is driven by the strontium moiety and that the sulfate anion does not contribute to the overall toxicity of the substance strontium sulfate to any relevant extent, for the following reasons:

Sulfate anions are abundantly present in the human body in which they play an important role for the ionic balance in body fluids. Sulfate is required for the biosynthesis of 3′-phosphoadenosine-5′-phosphosulfate (PAPS) which in turn is needed for the biosynthesis of many important sulfur-containing compounds, such as chondroitin sulfate and cerebroside sulfate. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) concludes that the few available studies in experimental animals do not raise any concern about the toxicity of the sulphate ion in sodium sulphate. Sodium sulphate is also used clinically as a laxative. In clinical trials in humans using 2-4 single oral doses of up to 4500 mg sodium sulphate decahydrate per person (9000 – 18000 mg per person), only occasional loose stools were reported. These doses correspond to 2700 - 5400 mg sulphate ion per person. High bolus dose intake of sulphate ion may lead to gastrointestinal discomfort in some individuals. No further adverse effects were reported (JECFA 2000, 2002). This position was adopted by the European Food Safety Authority (EFSA 2004) without alteration.

Based on the above information, one can therefore safely assume that the sulfate anion in strontium sulfate does not contribute to the overall toxicity of strontium, sulfate. It is concluded that only the effect of “strontium” is further considered in the human health hazard assessment of strontium sulfate.

Read across concept:

(i) from Sr ranelate to SrSO4:

The toxicity of strontium substances such as strontium sulfate can reasonably assumed to be determined by the availability of strontium ions in solution. Both substances (strontium ranelate and strontium sulfate) are “ moderately soluble” to "very soluble" (170mg SrSO4/L at 37°C/ pH 1.5and 6.74 g SrRenelate/L at 37°C/ pH 3.8) at low pH (pH in the gastrointestinal tract is ~1.5). Hence, it can be concluded that possible adverse effects observed with SrRanelate are certainly representative of possible similar effects to be expected in SrSO4 exposure.

(ii) from SrCl2to SrSO4:

The toxicity of strontium substances such as strontium sulfate can reasonably assumed to be determined by the availability of strontium ions in solution. As a first surrogate for bioavailability, the water solubility of a test substance may be used. Strontium chloride is highly water soluble with ~538 g/L at pH ~ 7, whereas strontium sulfate is moderately soluble (~125 mg/L at pH ~ 6.5). Hence, any read across from strontium chloride to strontium sulfate is inherently very conservative. Summary: 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 investigation.

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 addidion, in the study published by Lansdown et al. (1972) (see 7.8.2 "s_Lansdown_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 150 mg SrCl2/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 Lansdownet al. (1972) on pregnant rats is regardedas appropriate to support the evaluation of the effects of strontium on embryo-fetal development.

 


Justification for selection of Effect on developmental toxicity: via oral route:
Data from a reliable GLP reproduction toxicity study with the structural analogue strontium ranelate (Oral reproduction toxicity study in the Wistar rat (male and female fertility/embryo-fetal and postnatal development) addressing embryo-fetal and pre-/postnatal development of offspring according to the ICH guideline on Detection of Toxicity to Reproduction of Medicinal Products, June 24, 1993, and with the ICH Guideline Addendum: Toxicity to male fertility, July 1996.

Toxicity to reproduction: other studies

Additional information

According to the SIDS, 2007 there is a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test of strontium sulfate in rat is available, initiated by the national institute of environmental research (NIER), Korea in 2006. Despite extensive effort, the original study could not be made available.

However, a short summary is given here:

"Effects on toxicity to reproduction were evaluated in a combined repeated dose toxicity study with reproductive and developmental toxicity screening test in SD rats (16/sex/dose) according to OECD TG 422 under GLP. The test was performed with strontium sulfate at doses of 0, 500, 1,000, and 2,000 mg/kg bw/day, which was administered by oral gavage two weeks prior to mating until day four of lactation.

No effects were observed in male and female reproductive performance (fertility, mating rate, parturition rate, mating period, and gestation period) and histopathologic findings of reproductive organs. There were no signs of developmental effects (no. of corpus lutea verum, implantation loss rate, viability, litter size, birth rate and sex ratio, body weight, crown rump length, and external findings) in any dose-treatment group.

Hence, based on the results of the screening in the combined study, there is no indication on developmental toxicity or impairment of male and female reproductive performance. The NOAEL for reproductive/developmental toxicity was 2,000 mg strontium sulfate/kg bw/day in rats, the highest dose tested."

Reference: Anonymous (2007) SIDS, initial assessment report for SIAM 24, Paris, France, 17 -20 April 2007

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.