Strontium chloride

Endpoint summary

Description of key information

Strontium chloride is not expected to show systemic effects up to 22.4 mg SrCl2/kg bw/d based on the outcome of a 90-day repeated dose toxicity study conducted with strontium chloride hexahydrate (NOAEL: 22.5 mg strontium chloride/kg bw/d; equal to 12.4 mg Sr/kg bw/d)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

22.5 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Please refer to the discussion for "repeated dose toxicity, oral" below.

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

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 treatment-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, starvation 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 IV 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).

 

Repeated dose toxicity, inhalation

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

- SrCl2 is highly water soluble (~538 g/L) at a pH around 7. Therefore, no pH-related effects need to be assumed upon contact with respiratory tract epithelia, and any lung overload associated with inert particles can obviously be excluded. In consequence, local effects are not anticipated for this substance.

- In accordance with ECHA guidance on information requirements and chemical safety assessment-chapter R.8: characterisation of dose [concentration]-response for human health, May 2008, 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, dermal

According to regulation (EC) 1907/2006 Annex XI (weight of evidence), testing for sub-chronic dermal toxicity 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, May 2008, a DNEL for systemic effects could be derived by route-to-route extrapolation from a 90-day oral toxicity study in rats with SrCl2.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study is used as key study for this endpoint, since the study fulfils the requirements of the current test guideline for oral sub-chronic exposure to a great extent, but the study was not performed under GLP requirements (Klimisch score=2).

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
waiver

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
waiver

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
waiver

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
waiver

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 SrCl₂can 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).

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 Cat.2 (> 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 strontium 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.