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Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
233 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 Momburg, R. 2001) of rats is regarded as relevant and reliable to evaluate the effects of strontium sulfide. The NOAEL of 233 mg/kg bw/day is re-calculated to SrS.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

READ ACROSS CONCEPT

Valid toxicological data on reproductive toxicity specifically for strontium sulfide from animal studies are not available. Therefore, because of the lack of appropriate experimental data, read-across from studies with sulfides and strontium compoundsis proposed based on the following reasoning:

 

Read-across to H2S:

The readily water-soluble compound strontium sulfide will initially dissociate upon dissolution in water and/or relevant physiological media into strontium and sulfide ions.

 

However, sulfide anions will react with water in a pH-dependant reverse dissociation to form hydrogensulfide anions (HS-) or H2S, respectively, according to the following equation:

 

H2S  ↔  H+  +  HS-  ↔  2H+  +  S2-

 

The dissociation behaviour is presented in the Hägg g raph reported under IUCLID section 5.1.2 Hydrolysis.

 

The pKa values for the first and second dissociation steps of H2S are 7.0 and 12.9 (for details, refer to the IUCLID section on dissociation constant), respectively. Therefore, at neutral physiological pH values, hydrogen sulfide in the non-dissociated form (H2S) and the hydrogen sulfide anion (HS-) will be present in almost equimolar proportion, whereas only very small amounts of the sulfide anion (S2-) will be present. Conversely, at gastric pH (pH 1-2), non-dissociated H2S will be the predominant species.

 

In conclusion, under physiological conditions, inorganic sulfides or hydrogensulfides as well as H2S will dissociate to the respective species relevant to the pH of the physiological medium, irrespective of the nature of the “sulfide”, which is why read-across between these substances and H2S is considered to be appropriate without any restrictions for the purpose of hazard and risk assessment of strontium sulfide.

Read-across to Sr(NO3)2and Strontium ranelate:

Upon dissolution in water and/or physiological media, dissociation of strontium sulfide to release Sr2+ions may initially be expected.

However, based on the established fact that strontium ions may form poorly soluble species for example with physiologically present carbonate ions, the bioaccessibility/bioavailability may vary between different physiological conditions. Notwithstanding this limitation, it is considered justified to read-across from available data either on strontium dinitrate and/or strontium ranelate. In this context, the water solubility of a substance is used as a first approximation of bioavailability:

-        strontium dinitrate is highly water soluble with ≤ 802 g/L at 25°C/pH ca. 6 (solubility at pH 1.5; 668.6 g/L at 37°C)

-        - strontium ranelate is moderately water soluble with 800 mg/L at 25°C (solubility at pH 1.5; 39.5 g/L at 37°C)

In comparison, the water solubility of strontium sulfide is 120.6 g/L at 24°C/pH 12.9 (solubility at pH 1.5; 4.9 g/L at 37°C)

In conclusion, read across from strontium dinitrate and strontium ranelate to strontium sulfide is considered as justified since the toxicity of these substances may reasonably be considered to be determined by the availability of Sr cations. It is noted that although SrS is a strong base (pH 12.6 for a 1% solution - source: Anonymous, 2009), substantial neutralisation in the gastrointestinal tract at pH-levels of approx.1.5 – 2 may nevertheless be anticipated.

Effects on fertitlity 

Data on strontium:

The effects of strontium ranelate on male and female fertility/embryo 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 (Momburg, R. 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. Male and female fertility as well as reproductive performance was not affected at dose level of up to 1000 mg/kg bw/d.

Data on sulfides:

Performance of further reproductive toxicity studies is not considered to be required for the following reasons:

- The DNEL derived for local effects would be lower than for effects on reproduction and development, and thus the derived DNELlocal is regarded as protective enough for both endpoints.

- The available data indicating major effects resulting from local toxicity, and thus, from an animal welfare point of view, it appears to be not feasible to investigate reproductive toxicity in a dose range which would be sufficient high to cause reproductive effects, but would be acceptable for the animals, due to the irritating properties of the test compounds.

- It appears not appropriate to conduct animal studies, because of the alkaline pH in aquatic media (corrosive potential).

- In addition, there is sufficient information available (see below) from a fertility and developmental toxicity study in combination with a repeated dose toxicity study to rule out the reproductive system as target organ of toxicity.

Based on the lack of any effects on reproductive performance and organs up to the highest dose (NOAEC, H2S = 80 ppm), the reproductive tract is not considered to represent a target organ of toxicity for hydrogen sulfide. Due to expert judgment the fertility and developmental neurotoxicity screening study, similar to OECD guideline 421, reported by Dorman et al. (2000) with the test substance H2S together with the information from subchronic inhalation toxicity studies in Sprague-Dawley rats, Fisher rats and B6C3F1 mice reported by Morgan et al. (1983) and re-evaluated by Dorman in 2004 can be regarded as adequate to fulfil the REACH-requirements for the endpoint "Toxicity to reproduction".

In the reproduction screening assay, female Sprague-Dawley rats were exposed by inhalation (6h/d, 7d/wk) to concentrations up to 80 ppm H2S during the pre-mating (2 weeks) and mating (2 weeks) periods, during gestation (day 0-19) and post partum (5-18). Males were exposed for a total of 70 days starting 2 weeks before mating. The results did not indicate effects on reproductive performance. There were no effects of exposure on mating and fertility indices, post implantation loss and number of late resorptions or still births. The number of females with live pups, litter size, average length of gestation and the average number of implants per female were not different between exposed and control rats. Examination of testis did not indicate affects of sperm production or sperm morphology. Histopathological investigations did not reveal any changes in the reproductive organs of male and female animals.

In the subchronic toxicity studies (Morgan et al. (1983), re-evaluated by Dorman in 2004, see IUCLID section 7.5 Repeated dose toxicity), rats and mice were exposed by inhalation to similar concentrations of H2S (6h/d, 5d/wk) for 90 days. In these studies, gross pathology and organ weight analysis did not indicate exposure related effects on ovaries and testis, and no lesions were observed by histopathological examinations in non-respiratory tissues. Although details on histopathological evaluations of non-respiratory tissues are not presented in detail the re-evaluated study report (Dorman et al. 2004), the statement on the lack of any effects on non-respiratory tissues can be judged as reliable based on the overall high quality of the study. Major effects of inhalation exposure are local effects in the respiratory tract (olfactory neuronal loss) already occurring at a dose level of 30 ppm. The highest dose level of 80 ppm represents a NOAEC for systemic effects. The original study report from Morgan et al. 1983 is only available as an abstract.

Reference:

EMEA (2012): CJMP Type II variation assessment report, procedure no. EMEA/H/C/000560/II/0031, 2012-05-24

Anonymous (2009): Solfuro di strontio, ECOL Studio S. R. L., Via Dei Bichi 293, 55100 Lucca, Italia, 2009-12-30



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 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 (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
116 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 sulfide. 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 of 116 mg/kg bw/day is re-calculated to SrS.
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

READ ACROSS: see effects on fertility above

Data on strontium:

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 (Momburg, R. 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 the oral embryo-fetal development study with strontium ranelate (Momburg, R. 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) (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 113 mg SrS/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.

Data on sulfides:

Performance of further developmental toxicity / teratogenicty studies (e. g. a prenatal developmental study) is not considered to be required for the following reasons:

- The DNEL derived for local effects would be lower than for effects on reproduction and development, and thus the derived DNELlocal is regarded as protective enough for both endpoints.

- The available data indicating major effects resulting from local toxicity, and thus, from an animal welfare point of view, it appears to be not feasible to investigate reproductive toxicity in a dose range which would be sufficient high to cause reproductive effects, but would be acceptable for the animals, due to the irritating properties of the test compounds.

- It appears not appropriate to conduct animal studies, because of the alkaline pH in aquatic media (corrosive potential).

- In addition, there is sufficient information available (see below) from a fertility and developmental toxicity study in combination with a repeated dose toxicity study to rule out the reproductive system as target organ of toxicity.

No indications of a teratogenic potential of H2S were observed up to the highest dose in the available and reliable studies. Thus, further testing in prenatal developmental toxicity studies according to OECD guideline 414 is not considered necessary for sodium sulfide, since read-across from H2S to Na2S is proposed.

Due to expert judgment the fertility and developmental neurotoxicity screening study, similar to OECD guideline 421, reported by Dorman et al. (2000) with the test substance H2S can be regarded as adequate to fulfil the REACH-requirements for the endpoint “Developmental toxicity / teratogenicity”.

In the reproduction screening assay, female Sprague-Dawley rats were exposed by inhalation (6h/d, 7d/wk) to concentrations up to 80 ppm H2S during the pre-mating (2 weeks) and mating (2 weeks) periods, during gestation (day 0-19) and post partum (5-18). Males were exposed for a total of 70 days starting 2 weeks before mating. The F1 offspring generation was examined extensively for occurrence of external defects post partum and for developmental landmarks (pinnae detachment, surface righting, incisor eruption, negative geotaxis, eyelid separation, vaginal patency, preputial separation) and developmental neurotoxicity (motor activity, passive avoidance, FOB, acoustic startle) during the postnatal period. Gross macroscopic examination and organ weight analysis were conducted on all F1 offspring upon necropsy on PND 63 +/- 3, and histopathological examinations of the brains of control and high dose animals was done. In addition, neuropathology was conducted in selected weanling rats and adult offspring. The results of this study did not indicate effects of treatment on the in-uteri and postnatal development of offspring from parents exposed continuously including the phase of organogenesis. Thus, a NOAEC of 80 ppm hydrogen sulfide (ca. 111 mg H2S/m3air at 25 °C) may be derived from the screening study for developmental toxicity in rats.

In addition, findings of further supporting studies with pre- and postnatal exposure of rats and pups to H2S are not contradictory (Hayden, 1990; Skranjny, 1992). However, the relevance of the finding on neuronal transmitter levels (Skranjny, 1992) in the brain of offspring from rats exposed during gestation to 20 and 75 ppm H2S is on the development of offspring is questionable in light of the lack of any effects on behavioral neurotoxicity and developmental landmarks in the extended study reported by Dorman et al. (2000).

Reference:

EMEA (2012): CJMP Type II variation assessment report, procedure no. EMEA/H/C/000560/II/0031, 2012-05-24

Anonymous (2009): Solfuro di strontio, ECOL Studio S. R. L., Via Dei Bichi 293, 55100 Lucca, Italia, 2009-12-30

 


Justification for selection of Effect on developmental toxicity: via oral route:
Data from a reliable GLP reproduction toxicity study with 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.

Justification for classification or non-classification

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