Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Strontium hydroxide is not expected to show systemic effects upto 17.2 mg Sr(OH)2/kg bw/d or 37.74 mg Sr(OH)2*8 H2O(stoichiometric calculation) based on read-across from a 90-day repeated dose toxicity study conducted with strontium chloride (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
17.2 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:

Read across from SrCl2 to Sr(OH)2 is envisaged due to the fact that possible effects occurred could be regarded as strontium ion related effects. As a first surrogate for bioavailability, the water solubility of a test substance may be used. Both substances are "very soluble" (above 10 g/L at 20°C) in water (538 g/L for SrCl2and 22.5 g/L for Sr(OH)2). Hence, any read- across from strontium chloride to strontium hydroxide is considered to be justified. It is noted; although Sr(OH)2is a strong base (pH 13.1 for a 1 % solution) it will be neutralised within the gastrointestinal tract.

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). This value refers to approximately 17.2 mg Sr(OH)2/kg bw/d. This study is defined as key study.

Repeated dose toxicity, inhalation

According to the Regulation (EC) 1907/2006 testing on long term inhalation toxicity is considered not being scientifically justified. Strontium hydroxide is classified as corrosive by worst case. Therefore, the assumption has to be made that the substance is also corrosive to the respiratory tract. Due to animal welfare testing is not foreseen.

Considering that an official indicative occupational exposure limit value exist for soluble barium compounds (e.g. Ba(OH)2); published in the Official Journal of the European Union (Commission Directive 2006/15/EC, 7 February 2006), this value was used for the derivation of a DNEL for long-term inhalation, local effects for Ba(OH)2 as worst case due to the corrosivity of the substance. Reflected that the pH of Ba(OH)2 and Sr(OH)2 results in identical values of 13.6 which based on saturated solutions (water solubility of both substances: 37.1 g/L for Ba(OH)2 and 22.5 g/L for Sr(OH)2) and the corrosive effect is based on the OH- concentration which is the same for both substances, the IOEL could be regarded as worst case DNEL for Sr(OH)2 as well. Thus, for risk assessment purposes a DNEL for long-term inhalation toxicity, local effects is used based on the available IOEL of 0.5 mg Sr2+/m3 for Sr compounds. In conclusion, there is no need to initiate testing on long term inhalation toxicity and derogation is considered to be justified.

Repeated dose toxicity, dermal

According to Annex VIII, column 2, and Annex XI (weight of evidence) of Regulation (EC) 1907/2006, 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.

- The substance is classified as corrosive to skin. Thus, due to animal welfare reasons testing is not allowed. A qualitative approach for hazard assessment was chosen.


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. 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 Sr(OH)2 is calculated at 17.2 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 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.

Categories Display