Strontium di(acetate)

Endpoint summary

Description of key information

A study on SrCl2, a structural analogue was used in a read-across approach. If the increased concentrations of strontium in the bone can be considered a non-toxic effect, a NOAEL of 300 ppm SrCl2 can be derived form this study which is based on the weight changes of thyroids at the doses of 1200 ppm (LOAEL) and 4800 ppm.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Well-documented study. 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.

Justification for type of information:

As few data are available on the target substance, a research of the potential analogues has been carried out.
The hypothesis is that properties are likely to be similar or follow a similar pattern as a result of the presence of a common metal ion (or ion complex including a hydrated metal ion). This is a reasonable assumption for the majority of inorganic compounds and some organic compounds (e.g. metal salts of some organic acids).
The following points are be considered:
- Chemical speciation and valency,
- The water solubility, as it provides a first indication of the availability of the metal ion in the different compartments of interest. The most simplistic approach to hazard evaluation is to assume that the specific metal-containing compound to be evaluated shows the same hazards as the most water-soluble compounds.
- Counter ions: the assumption that the metal ion is responsible for the common property or effect implies that the toxicity of the counter ion present in the compound will be largely irrelevant in producing the effects to be assessed.
Based on these data, we have selected the analogue Strontium chloride.
Strontium has also physiochemical properties similar to calcium and both appear mainly in ionic form in water.

A detail description is provided as attached report of this endpoint in this Iuclid file.

Reason / purpose for cross-reference:

read-across source

Other examinations:

No

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

A lower leucocyte count noticed in the males of the 300 ppm group is not considered to be caused by the treatment, since at higher dose levels such an effect was not observed.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

The glycogen concentration in the liver after 12 weeks showed a dose-related decrease, which was only significant in the females at the highest dose level.
Otherwise, analysis of alkaline phosphatase, SGPT (serum glutamine pyruvic acid transaminase) and urea in serum did not reveal any significant changes although in the highest dose group, an indication of an increased activity of Alk. Pase was noticed.
Microsomal liver enzyme activities did not show any changes.
The levels of Ca, Mg and P in the blood were not changed at any dose level, and the Ca/P ratio remained constant. The Ca, Mg and P concentrations in blood in all dose groups were higher after 8 weeks than after 12 weeks, which seems a physiological condition.

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

- in males, relative thyroid weights were significantly increased in the 1200 and 4800 ppm groups
- in females, relative pituitary weights were significantly decreased in the 300 and 4800 ppm group, but not in the 1200 ppm group
- the relative prostate weights were significantely decreased at 75 and 1200 ppm (see Table III in attachment); this, however, must be considered with care, because proper preparation of the rat prostate is difficult

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

- there were no changes seen on histopathological examination except slight changes in the liver and thyroid after blind examination (the changes consisted of a loss of glycogen in the liver at the highest dose level and a slightly increased activity in the thryroid of the males of the highest dose group)
- glycogen depletion may be caused by several factors other than strontium, such as stress , starvation or dirunal rhythm

Histopathological findings: neoplastic:

no effects observed

Other effects:

effects observed, treatment-related

Description (incidence and severity):

Detectable amounts of strontium chloride in blood and muscle were only noticed at the highest dose level whereas the strontium chloride concentration in bone was elevated at all dose levels.

Details on results:

CLINICAL SIGNS AND MORTALITY
- no relevant effects
- one control female died during bleeding procedure after more than 11 weeks

BODY WEIGHT AND WEIGHT GAIN
- no relevant effects

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
- food intake was not affected by exposure to strontium chloride hexahydrate
- no data on daily food intake are available in order to calculate daily dose levels

FOOD EFFICIENCY
- no relevant effects

HAEMATOLOGY
- the slightly elevated erythrocyte count noticed in the range-finding experiment was not confirmed in the 90-day study
- a lower leucocyte count noticed in the males of the 300 ppm group is not considered to be caused by the treatment, since at higher dose levels such an effect was not observed

CLINICAL CHEMISTRY
- Analysis of Alk. Pase, SGPT and urea in serum did not reveal any significant changes although in the highest dose group an indication of an increased activity of Alk. Pase was noticed. No clinical differences in clinical chemistry were noted except an indication of increased alkaline phosphatase activity in the highest dose group
- the levels of Ca, Mg and P in blood were similar for all dose levels and the Ca/P ratio was constant
- blood concentrations of Ca, Mg and P were higher at 8 weeks than 12 weeks, which seems a physiological condition

URINALYSIS
- urinalysis showed no differences in the groups

ORGAN WEIGHTS
- in males, relative thyroid weights were significantly increased in the 1200 and 4800 ppm groups
- in females, relative pituitary weights were significantly decreased in the 300 and 4800 ppm group, but not in the 1200 ppm group
- the relative prostate weights were significantely decreased at 75 and 1200 ppm (see Table III in attachment); this, however, must be considered with care, because proper preparation of the rat prostate is difficult

HISTOPATHOLOGY: NON-NEOPLASTIC
- there were no changes seen on histopathological examination except slight changes in the liver and thyroid after blind examination (the changes consisted of a loss of glycogen in the liver at the highest dose level and a slightly increased activity in the thryroid of the males of the highest dose group)
- glycogen depletion may be caused by several factors other than strontium, such as stress , starvation or dirunal rhythm

OTHER FINDINGS
- The glycogen concentration in the liver after 12 weeks showed a dose-related decrease, which was only significant in the female ath the highest dose level, which is may be caused by stress, starvation or diurnal rhythm
- microsomal liver enzyme activities did not show any changes
- detectable amounts of Sr in blood and muscle were only noticed at the dose of 4800 ppm
- the Sr content in bone was increased at all dose levels having a constant level from 4 weeks onwards (steady-state level)
- there were no changes seen in the X-ray photographs
- thus, up to the highest dose of 4800 ppm no rachitic changes occurred

Key result

Dose descriptor:

NOAEL

Effect level:

300 ppm

Based on:

test mat. (dissolved fraction)

Sex:

female

Basis for effect level:

organ weights and organ / body weight ratios

Key result

Dose descriptor:

LOAEL

Effect level:

1 200 ppm

Sex:

male

Basis for effect level:

organ weights and organ / body weight ratios

Remarks on result:

other: If the increased concentrations of strontium in the bone can be considered a non-toxic effect, a LOAEL of 1200 ppm SrCl2 can be derived from this study which is based on the weight changes of thyroids at the doses of 1200 ppm and 4800 ppm.

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

1 200 ppm

System:

endocrine system

Organ:

thyroid gland

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

RANGE-FINDING EXPERIMENT

Behaviour, growth, food intake and food efficiency were not affected in the range-finding experiment. Haematological investigation revealed only a slight elevation of the total number of erythrocytes in males and females and a slight increase of the white cell count in the males at the highest dose level. No differences were found in liver and kidney weights and histopathological examination revealed no abnormalities. Sr in blood and muscle were only noted at the highest dose level whereas from 300 ppm onwards increased concentrations were found in bone.

Conclusions:

If the increased concentrations of strontium in the bone can be considered a non-toxic effect, a NOAEL of 300 ppm SrCl2 can be derived form this study which is based on the weight changes of thyroids at the doses of 1200 ppm (LOAEL) and 4800 ppm.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

As few data are available on the target substance, a research of the potential analogues has been carried out.

The hypothesis is that properties are likely to be similar or follow a similar pattern as a result of the presence of a common metal ion (or ion complex including a hydrated metal ion). This is a reasonable assumption for the majority of inorganic compounds and some organic compounds (e.g. metal salts of some organic acids).

The following points are be considered:

- Chemical speciation and valency,

- The water solubility, as it provides a first indication of the availability of the metal ion in the different compartments of interest. The most simplistic approach to hazard evaluation is to assume that the specific metal-containing compound to be evaluated shows the same hazards as the most water-soluble compounds.

- Counter ions: the assumption that the metal ion is responsible for the common property or effect implies that the toxicity of the counter ion present in the compound will be largely irrelevant in producing the effects to be assessed.

Based on these data, we have selected strontium chloride as relevant analogue.

Strontium has also physiochemical properties similar to calcium and both appear mainly in ionic form in water.

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.

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 (equal to 12.4 mg Sr/kg bw/d). This study is defined as key study.

Justification for classification or non-classification

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 (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 Cat2 (> 100 mg/kg bw/d rat oral, 90-day).

Hence, the NOAEL is considered at >100 mg/kg bw and no classification is needed.