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Administrative data

Description of key information

Strontium sulfate is not expected to show effects at 26.0 mg SrSO4/kg bw/d based on the 90-day repeated dose toxicity study conducted with strontium chloride.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
26 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

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

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 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.

 

(ii) from Sr(NO3)2to 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 nitrate is highly water soluble with ≤ 802 g/L at pH ~7, whereas strontium sulfate is moderately soluble (~125 mg/L at pH ~ 6.2 for a saturated solution). Hence, any read across from strontium nitrate to strontium sulfate is inherently very conservative.

Repeated dose toxicity, oral:

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, up to 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). This study is defined as key study.

Furthermore, as stated SIDS, 2007 there is a combined repeated dose toxicity study with reproduction/developmental toxicity screening test of strontium sulfate in rat available (OECD TG 422), initiated by the national institute of environmental research (NIER), Korea in 2006. In this study Sprague-Dawley (Crl:CD) rats (16/sex/dose) received doses of 0, 500, 1,000, and 2,000 mg SrSO4/kg bw/day via oral gavage for 42 days (males) and for 40 to 54 days (females), respectively. Despite extensive effort, the original study could not be made available.

However, a short summary is given here:

"No effects were detected on mortality, clinical signs, body weight, and food consumption. A temporary increase of water consumption was noted in males treated with 1,000 and 2,000 mg/kg bw/day during the early administration period. Hematology and blood chemistry revealed significant decreases of reticulocyte (ca. 52% of control) and aspartate aminotransferase (ca. 63% of control) in females given 2,000 mg/kg dose. The absolute and relative spleen weights of females were significantly lower in all treatment groups (not in a dose-dependent manner). There was a significant increase of right testis weight in males receiving at high dose (2,000 mg/kg bw/day). No histopathological changes caused by the treatment were found in any groups. A NOAEL for general toxicity in female rats was not achieved in this study due to reduction of the spleen weight. The NOAEL was 1,000 mg/kg bw/day in male rats.

Conclusion:

The repeated-dose oral toxicity study of strontium sulfate revealed a NOAEL of 1,000 mg/kg bw/day in male rats. However the NOAEL in female rats was not achieved due to the reduction of spleen weights without histopathological findings in all treatment groups. "

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

Repeated dose toxicity, dermal:

According to Regulation (EC) 1907/2006 Annex XI (weight of evidence), testing for sub-chronic dermal toxicity with strontium sulfate is not considered to be required, for the following reasons:

- Repeated dose toxicity study via dermal route does not need to be performed since the physico-chemical and toxicological properties do not suggest potential for a significant rate of absorption through the skin.

- In accordance with ECHA guidance on information requirements and chemical safety assessment-chapter R.8: characterisation of dose [concentration]-response for human health, November 2012, a DNEL for systemic effects could be derived by route-to-route extrapolation from a 90-day oral toxicity study in rats with SrCl2.

Repeated dose toxicity, inhalation:

According to Regulation (EC) 1907/2006 Annex XI (weight of evidence), testing for sub-chronic inhalation toxicity with strontium sulfate is not considered to be required, for the following reasons:

- SrSO4 is moderately water soluble (~125 mg/L) at a pH around 6.5. Therefore, no pH-related effects need to be assumed upon contact with respiratory tract epithelia, and any lung overload associated with inert particles may be excluded. In consequence, local effects are not anticipated for strontium sulfate.

- In accordance with ECHA guidance on information requirements and chemical safety assessment-chapter R.8: characterisation of dose [concentration]-response for human health, November 2012, a DNEL for systemic effects can be derived by route-to-route extrapolation from a 90-day oral toxicity study in rats with Sr(NO3)2.


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

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. Since the 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 SrSO4 is calculated at 26 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.