Strontium sulphide

Endpoint summary

Description of key information

According to the data requirements as outlined in section 8.6, column 2, Annexes VIII-IX, of Regulation (EC) 1907/2006 a repeated dose toxicity study shall be performed via the most appropriate route of administration, having regard to the likely route of human exposure. However, in case of strontium sulfide the inhalation route AND the oral route are considered as the relevant routes of exposures. Adequate repeated dose toxicity studies are available for inhalation of hydrogen sulfide and oral intake of strontium chloride hexahydrate (see discussion).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

16.9 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

390 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

49.1 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

READ ACROSS CONCEPT

Valid toxicological data on sub-acute or sub-chronic exposure 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⁺  +  S^2-

 

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 SrCl₂:

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 on strontium dichloride. In this context, the water solubility of a substance is used as a first approximation of bioavailability:

-     strontium dichloride is highly water soluble with ca. 538 g/L at 20°C/pH ca. 7 (solubility at pH 1.5; 465.9 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 chloride 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[1]), substantial neutralisation in the gastrointestinal tract at pH-levels of approx.1.5 – 2 may nevertheless be anticipated.

Repeated dose toxicity, oral

Data - strontium:

In a sub-chronic feeding study by Kroes et al. (1977) SPF Wistar rats (40-60 g of body weight, 10 males and 10 females per group) received strontium chloride hexahydrate in a semi-purified diet at dose levels of 0, 75, 300, 1200, and 4800 ppm for 90 days. The diet contained adequate levels of Ca, Mg, P and vitamin D3. Growth, behaviour, food intake and food efficiency were not affected in the 90-day study.

No differences in clinical chemistry were noted, except of an indication of increased alkaline phosphatase activity in the highest dose group. Urinalysis showed no differences in the groups. The levels of Ca, Mg and P in blood were similar for all dose levels and the Ca/P ratio was constant.

In males, thyroid weights were significantly increased in the 1200 and 4800 ppm groups. Although, no clear explanation of this finding could be given it was regarded as treatement-related. In females, pituitary weights were significantly decreased in the 300 and 4800 ppm group, but not in the 1200 ppm group, and this finding was regarded as difficult to interpret. Glycogen depletion of the liver was noted in the highest dose group. However, this was may be caused by stress, stravation or diurnal rhythm and not by treatment with the test substance.

Detectable amounts of strontium in blood and muscle were only noticed at the dose of 4800 ppm. The strontium content in bone was increased at all dose levels having a constant level from 4 weeks onwards (steady-state level).

No treatment-related changes were observed in the X-ray photographs and on histopathological examination except, slight changes in the liver (glycogen depletion) and thyroid (activation). Thus, upto the highest dose of 4800 ppm no rachitic changes occurred.

According to an estimation given in the IUCLID Data Set for strontium carbonate, the dose of 4800 ppm corresponds to a dose of 360 mg/kg bw/d strontium chloride (equal to 199 mg Sr/kg bw/d) assuming an average rat body weight of 200 g and a daily food intake of 15 g.

Considering the increased concentrations of strontium in the bone as a non-toxic effect, a NOAEL of 300 ppm SrCl2 can be derived from this study based on the weight changes of thyroids at the doses of 1200 ppm (LOAEL) and 4800 ppm, and thyroid activation at 4800 ppm. No data on daily food intake are available in order to calculate daily dose levels. According to the estimation mentioned above, the NOAEL of 300 ppm strontium chloride corresponds to a dose of 22.5 mg/kg bw/d (equal to 12.4 mg Sr/kg bw/d or 16.9 mg SrS/kg bw/d). This study is defined as key study.

Conclusion - sulfides:

According to the data requirements as outlined in section 8.6, column 2, Annexes VIII-IX, of Regulation (EC) 1907/2006 a repeated dose toxicity study shall be performed via the most appropriate route of administration, having regard to the likely route of human exposure. The inhalation route is considered the most appropriate route for exposure, and repeated dose toxicity studies are available for this route.

The toxicity of sulfide has preferably been assessed for the inhalation route of exposure (by read-across from hydrogen sulfide). Strontium sulfide is produced and handled only in industrial settings and the oral exposure route is not considered relevant for workers. Furthermore, there are no professional or consumer uses for strontium sulfide that are relevant for Regulation (EC) 1272/2008 (see IUCLID section 3.5). Furthermore, the substance is not present in consumer products and is not released to the environment. Since the oral route of exposure is primarily relevant for the general population and any exposure of general population to strontium sulfide is negligible for the above mentioned reasons, the conduct of any new animal studies for repeated dose toxicity by oral route is not required.

Repeated dose Toxicity, inhalation

Conclusion - strontium:

According to the regulation (EC) 1907/2006 testing on long term inhalation toxicity is considered not being scientifically justified, since strontium sulfide is classified as corrosive to skin and eye based on pH effect (10% solution results in pH 12.6). Therefore, the assumption has to be made that the substance is also corrosive to the respiratory tract.

Nevertheless, relevant DNELs for long term inhalation toxicity for local AND systemic effects were derived based on studies conducted with strontium compounds (see “toxicological information”).

Data - sulfides:

The 90-day inhalation study by Dorman et al. (2004) in Fischer 344 rats, Sprague-Dawley rats and B6C3F1 mice is considered to represent the most reliable study for the derivation of NOAEC values. This study, performed in conformity with GLP regulations, is considered to be of an adequate test design and quality. Different toxicological endpoints were evaluated in rats and mice of both sexes following exposure to hydrogen sulfide without signs of systemic toxicity. When comparing the results of the reliable sub-chronic studies in rats and mice, it becomes obvious that the findings of these inhalation studies are not contradictory. Brennemann et al. (2000), Moulin et al. (2002) and Dorman et al.(2004) found similar targets of toxicity.

 

Taken into consideration the key study, an NOAEC of 10 ppm H2S (~14 mg/m3 air) for local effects was derived, which is based on an increased incidence of olfactory neuronal loss (ONL) at 30 and 80 ppm of hydrogen sulfide. Regarding systemic toxicity, some minor effects on food consumption and body weight were observed, but exposure did not result in toxicologically relevant alterations in haematological indices, serum chemistry or gross pathology. Therefore, the concentration of 80 ppm H2S (111 mg/m3 air) can be considered as NOAEC for systemic effects that is re-calculated to 390 mg SrS/m3 air.

Repeated dose toxicity, dermal

Conclusion - strontium sulfide:

According to the data requirements as outlined in section 8.6, column 2, Annexes VIII-IX, of Regulation (EC) 1907/2006 a repeated dose toxicity study shall be performed via the most appropriate route of administration, having regard to the likely route of human exposure. However, the inhalation route for sulfides and the oral route for strontium compounds are considered as the most appropriate routes of exposures for strontium sulfide, and adequate repeated dose toxicity studies are available for these routes.

Repeated dose toxicity testing via the dermal route is not required for strontium sulfide since the physico-chemical and toxicokinetic properties do not suggest any potential for a significant rate of absorption through the skin. It can safely be anticipated that there will be no systemic risk in case of dermal short-term exposure to strontium sulfide.

Taking into consideration the physico-chemical properties of strontium sulfide (especially dissociation of the highly soluble compound), the toxicokinetic behaviour (very limited penetration into the upper epithelial layers of the epidermis) and the negative in vitro genotoxicity test results (see IUCLID section 7.6 of this technical dossier) it may be concluded that there will be no systemic risks to humans with respect to dermal exposure to strontium sulfide. In addition, applying HERAG (HERAG fact sheet - assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal compounds; EBRC Consulting GmbH / Hannover /Germany; August 2007) methodology, one may assume a conservative default of 1% for dermal absorption of strontium sulfide, leading to the anticipation of a negligible toxicity via the dermal route (see IUCLID section 7.1 of this technical dossier).

According to Regulation (EC) 1907/2006, the repeated dose toxicity study, dermal shall be performed only if inhalation of the substance is unlikely, skin contact in production and/use is likely and the phys. -chem. and toxicological properties suggest potential for a significant rate of absorption through the skin. Strontium sulfide is not used in consumer products and due to the fact that the substance is classified as corrosive (pH 12.6; 1 % solution), the worker have to use adequate gloves and protection equipment (see IUCLID section 11 “guidance on safe use” of this technical dossier). Thus, since skin contact essentially needs to be minimised because of the protection against corrosivity, quantitatively relevant exposure and absorption through skin are not expected under conditions of normal handling and use, so that no chronic dermal toxicity study is required. Furthermore, based on the corrosive action of strontium sulfide on skin, testing on intact skin is not feasible for obvious reasons.

^[1]Anonymous (2009): Solfuro di strontio, ECOL Studio S.R.L., Via Dei Bichi 293, 55100 Lucca, Italia, 2009-12-30

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
reliable GLP guideline study with strontium chloride available

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The 90-day inhalation toxicity studies with exposure of rats and mice to hydrogen sulfide (Dorman et al., 2004) results in no toxicologically relevant alterations in haematological indices, serum chemistries, or gross pathology. Therefore, the highest concentration of 80 ppm H2S may be considered as NOAEC for systemic effects.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
When comparing the results of the available sub-chronic studies in rats and mice, it becomes obvious that the findings of these inhalation studies are not contradictory. Brennemann et al. (2000), Moulin et al. (2002) and Dorman et al. (2004) found similar targets of toxicity. The main adverse effect caused by 30 and 80 ppm hydrogen sulfide was an exposure-related increased incidence of olfactory neuronal loss (ONL). Thus, the concentration of 10 ppm H2S represents an NOAEC for local effects in the olfactory system.

Repeated dose toxicity: via oral route - systemic effects (target organ) glandular: thyroids

Justification for classification or non-classification

Repeated dose toxicity, oral
The reference Kroes (1977) is considered as the key study for repeated dose toxicity via oral application and will be used for classification. Rats were dosed at 0, 75, 300, 1200, and 4800 ppm for 90 days. Sincethe increased concentrations of strontium in the bone can be considered a non-toxic effect, a NOAEL of 300 ppm SrCl2 can be derived from this study which is based on the weight changes of thyroids at the doses of 1200 ppm (LOAEL) and 4000 ppm. No data on daily food intake are available in order to calculate daily dose levels. According to the estimation mentioned above, the NOAEL of 300 ppm strontium chloride corresponds to a dose of 22.5 mg/kg bw/d (equal to 12.4 mg Sr/kg bw/d). Hence, the NOAEL for SrS is calculated at 16.9 mg/kg bw.

The classification criteria according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – repeated exposure, oral are not met, and thus no classification for specific target organ toxicant (STOT-RE) is required. However, some evidence of an effect of Sr on thyroid function is observed in the 90-day oral toxicity study in rats, but the incidence is very slight and seen only in males, but not in females, of the highest dose group tested, which is clearly above the cut-off levels for STOT-RE classification Cat2 (> 100 mg/kg bw/d rat oral, 90-day).

 

An indirect effect of Sr through activation of thyrocalcitonin production was regarded as unlikely by the authors of the study, since no parafollicular cell hyperplasia was noticed and no effects on CA serum levels were found. In addition, the effects of Sr on thyroid function was discussed in the context of a scientific discussion paper of the EMEA on strontium ranelate, because in the carcinogenicity study in rats an increased incidence of C-cell carcinoma in thyroids of male rats was seen, but this effect was not clearly dose-related and was found to be within the control range in other studies with the strain of rats used. Furthermore, no increased incidence of C-cell hyperplasia or adenoma was seen in the carcinogenicity study rats, and it is also mentioned in the discussion paper that no increase in thyroid C-cell proliferative lesions or in circulating calcitonin levels were found in a 52-week toxicity study in rats. Therefore, it can be concluded that based on the available animal data Sr does not have the potential to produce significant toxicity, or to be harmful to humans, following repeated exposure at low or moderate exposure concentrations relevant for classification.

 

Repeated dose toxicity, dermal

(i) Based on physico-chemical properties of strontium sulfide and the toxicokinetic behaviour (very limited penetration into the upper epithelial layers of the epidermis) there is no systemic risks to humans with respect to dermal exposure to sodium sulfide.

(ii) One may assume a conservative default of 1% for dermal absorption of strontium sulfide, leading to the anticipation of a negligible toxicity via the dermal route.

(iii) No risk is expected for workers due to the fact that the substance is classified as corrosive (pH 12.6; 1 % solution) and risk management measures are in place (worker have to use sufficient gloves and protection equipment, see IUCLID section 11 “guidance on safe use”). Thus, skin contact is unlikely and therefore absorption through skin, if any, is only possible in case of an accident.

Thus, it may be concluded that there will be no systemic risks to humans with respect to dermal exposure to strontium sulfide, and no classification for specific target organ toxicant (STOT) – repeated exposure, dermal is required.

 

Repeated dose toxicity, inhalation

According to regulation (EC) 1272/2008, a classification for specific target organ toxicity – repeated exposure shall be taken into account only when reliable evidence associating repeated exposure to the substance with a consistent and identifiable toxic effect demonstrates support for the classification. These adverse health effects include consistent and identifiable toxic effects in humans, or, in experimental animals, toxicologically significant changes which have affected the function or morphology of a tissue/organ, or have produced serious changes to the biochemistry or haematology of the organism and these changes are relevant for human health.

Since classification as corrosive to respiratory tract is proposed for strontium sulfide and due to the lack of substance specific data for strontium sulfide (animal welfare -- corrosive substance) no further classification for specific target organ toxicant (STOT) – repeated exposure, inhalation is required for strontium sulfide.