Strontium bis(2-ethylhexanoate)

Endpoint summary

Description of key information

No repeated dose toxicity study with strontium bis(2-ethylhexanoate) is available, thus the repeated dose toxicity will be addressed with existing data on the individual moieties strontium and 2‑ethylhexanoic acid.

In relevant and reliable repeated dose toxicity studies for both moieties of strontium bis(2-ethylhexanoate), there were no toxicological findings reported that would justify a classification.

Additional information

Read-across approach

Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the metal cation and the organic acid anion. This way forward is acceptable, since metal carboxylates are shown to dissociate to the organic anion and the metal cation upon dissolution in aqueous media. No indications of complexation or masking of the metal ion through the organic acid were apparent during the water solubility and dissociation tests (please refer to the water solubility and dissociation in sections 4.8 and 4.21 of IUCLID). Once the individual transformation products of the metal carboxylate become bioavailable (i.e. in the acidic environment in the gastric passage or after phagocytosis by pulmonary macrophages), the “overall” toxicity of the dissociated metal carboxylate can be described by a combination of the toxicity of these transformation products, i.e. the metal cation and carboxylate anion according to an additivity approach.

 

Strontium bis(2-ethylhexanoate) is the strontium salt of 2-ethylhexanoic acid, which readily dissociates to the corresponding divalent strontium cation and 2-ethylhexanoic acid anions. The strontium cation and the 2-ethylhexanoic acid anion are considered to represent the overall toxicity of strontium bis(2-ethylhexaate) in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts). 

 

A detailed justification for the read-across approach is added as a separate document in section 13 of IUCLID.

 

Repeated dose toxicity

No repeated dose toxicity studies with strontium bis(2-ethylhexanoate) are available, thus the repeated dose toxicity will be addressed with existing data on the dissociation products as detailed below.

 

Strontium

A sub-chronic study was conducted with strontium chloride hexahydrate using groups of 10 male and 10 female Wistar rats. The rats were given the test substance via diet at dose levels of 0, 75, 300, 1200 or 4800 ppm (0, 7.5, 30, 120, or 480 mg/kg/day, respectively) for a duration of 90 days. The following parameters were investigated: clinical signs/mortality, body weight, food consumption/food efficiency, haematology, clinical chemistry, urinalysis, organ weights, and histopathology. Additional 10 males were included as satellite animals for the determination of the strontium levels in blood, bone and muscle, which were examined in weeks 0, 4, 8 and 12.

In a range-finding experiment, rats with an initial body weight of 130-170 g were divided into 5 groups each consisting of 3 females and 3 males, receiving 0, 3, 30, 300 and 3000 ppm strontium chloride hexahydrate in the diets respectively during two weeks. The animals were weighed at the beginning of the experiment and after 1 and 2 weeks. Food intake was recorded during the experimental period and was measured per cage (two rats) and expressed as the average intake per day per rat. Food conversion was calculated, blood samples were taken at the end of the experiment and haematological investigation was restricted to haemoglobin, haematocrit and the number of erythrocytes and leucocytes. The mean cell volume, mean cell haemoglobin concentration, and mean cell haemoglobin were calculated. At the end of the 2 weeks X-ray photographs were made of all animals. Strontium concentration was measured in blood, bone and muscle. Liver and kidneys were weighed and examined histopathologically by preparing paraffin sections (5 µm) stained with hematoxylin and eosin. 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. Strontium in blood and muscle were only noted at the highest dose level whereas from 300 ppm onwards increased concentrations were found in bone.

In the main study, growth, behaviour, food intake and food efficiency were not affected by the treatment. Apart from a slight increase in the ALP activity in the highest dose group, no differences in clinical chemistry were noted. Levels of Ca, Mg and P in blood were similar for all animals and the Ca/P ratio was unaffected. Significant increase of the relative thyroid weights was found for the males at the 1200 ppm (control group: 0.0054 %; treatment group: 0.0072 %; P < 0.01) and 4800 ppm dose levels (control group: 0.0054 %; treatment group: 0.0068 %; P < 0.001). Although, no reasoning for this finding was be given, it was regarded as treatment-related. Relative pituitary weights of the females at 300 ppm dose level (control group: 0.0074 %; treatment group: 0.0062 %; P < 0.05) and at 4800 ppm dose level (control group: 0.0074 %; treatment group: 0.0056 %; P < 0.01) were significantly decreased, but not in the 1200 ppm group. Due to the lack of a dose-response relationship, this finding is not considered biologically relevant. 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. Increased strontium concentrations in blood and muscle were solely measured in animals at 4800 ppm. The strontium content in bone was increased at all dose levels with a plateau on week 4 and onwards (steady state). No treatment-related changes were observed in the X-ray photographs or during microscopical examination. Slight changes in the liver (glycogen depletion) and thyroid (activation). Thus, up to the highest dose of 4800 ppm no rachitic changes occurred.

The NOAEL (males) of 300 ppm strontium chloride hexahydrate (equivalent to 30 mg/kg/day, nominal) was derived, based on the significant increase of the relative thyroid weights, found for the males at the 1200 ppm and 4800 ppm dose levels. The substance NOAEL corresponds to NOAEL (males) of 9.9 mg strontium/kg/day (nominal).

 

2-ethylhexanoic acid

Several repeated oral dose studies for 2-ethylhexanoic acid were available for assessment. A diet containing 0.5% 2-ethylhexanoic acid caused no adverse effect in rats in a 13 week feeding study (dose levels were 0, 0.1, 0.5, or 1.5%, calculated NOAEL ca. 300 mg/kg bw/day). No adverse effect was observed in mice receiving a diet containing 0.5 % 2-ethylhexanoic acid in a 13 week feeding study (dose levels were 0, 0.1, 0.5, or 1.5%). The NOAEL was calculated to be 200 mg/kg bw/day. Both NOAELs were based on reduced food consumption and a decreased rate of body weight gain in the high dose groups. In both studies, all toxicity observed at higher concentrations (changes in clinical chemistry, absolute and relative organ weights, microscopic changes in kidney liver and fore stomach) was reversible within 28 days after exposure ceased.

Based on the absence of any (severe) adverse effects at low doses in subacute and semichronic toxicity study with a.o. rats, classification for repeated dose toxicity is not warranted according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

 

Strontium bis(2-ethylhexanoate)

As the two moieties of strontium bis(2-ethylhexanoate) do not induce adverse effects in any relevant and reliable repeated dose toxicity study, strontium bis(2-ethylhexanoate) is also not expected to induce adverse effects after repeated exposure.

For the purpose of hazard assessment of strontium bis(2-ethylhexanoate), the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation. In case of 2‑ethylhexanoic acid in strontium bis(2-ethylhexanoate), the NOAEL of 100 mg/kg bw/day for the reproductive toxicity will be used. In case of strontium the NOAEL of 9.9 mg/kg bw/day for the repeated dose toxicity will be used.

Justification for classification or non-classification

According to the criteria of REGULATION (EC) No 1272/2008 and its subsequent adaptions, strontium bis(2-ethylhexanoate) does not have to be classified and has no obligatory labelling requirement for repeated oral toxicity.