Strontium bis(2-ethylhexanoate)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No toxicity data on adverse effects on sexual function and fertility with strontium bis(2-ethylhexanoate) are available, thus the reproductive toxicity will be addressed with existing data on the individual moieties strontium and 2-ethylhexanoic acid.

Strontium bis(2-ethylhexanoate) is not expected to impair fertility, since the two moieties strontium and 2-ethylhexanoic acid have not shown adverse effects on fertility.

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.

 

Toxicity for reproduction - effects on fertility

No toxicity data on adverse effects on sexual function and fertility with strontium bis(2-ethylhexanoate) are available, thus the reproductive toxicity will be addressed with existing data on the individual moieties strontium and 2-ethylhexanoic acid as detailed below.

 

Strontium

No histological changes for uterus, ovaries, testes and prostate after the administration of up to and including 4800 ppm strontium chloride hexahydrate were observed in an sub-chronic oral repeated dose toxicity study OECD 408 (Kroes et al. 1977). The authors reported a NOAEL of 4800 ppm, which is equivalent to a strontium dose of 157.7 mg Sr/kg bw/day.

 

2-ethylhexanoic acid

2-Ethylhexanoic acid was administered via drinking water to an unspecified number of male and female rats at 0, 100, 300, or 600 mg/kg–bw/day. There were no deaths. The relative epididymal weights in high-dose males were significantly increased, but no histologic changes were noted. A slight, but not statistically significant, increase in the number of abnormal sperm was noted in the highest two dose groups; however, the incidence per animal was not provided. Treated groups required more time to successfully complete mating, and the mean litter size in high-dose pregnant females was significantly reduced. The mean pup weights in the high-dose group were significantly lower on postnatal day 7 and 14.

Physical development of the eyes, teeth and hair appeared to be slightly later in the pups from the high-dose groups; the significance of this finding is unclear since no data were presented on the length of gestation in treated and control dams. The high-dose of 600 mg/kg–bw/day significantly reduced overall water consumption and body weights in female animals. The NOAEL for reproductive effects in parental animals was 300 mg/kg-bw/day; this effect occurred in the presence of maternal toxicity. The NOAEL for F1 offspring was 100 mg/kg-bw/day.

 

Strontium bis(2-ethylhexanoate)

Strontium bis(2-ethylhexanoate) is not expected to show adverse effects on sexual function and fertility, since the two moieties strontium and 2-ethylhexanoic acid have not shown adverse effects on sexual function and fertility in relevant bioassays. Further testing is not required.

 

For further information on the toxicity of the individual constituents, please refer to the relevant sections in the IUCLID and CSR.

 

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.

Effects on developmental toxicity

Description of key information

No toxicity data on adverse effects on development of the offspring with strontium bis(2-ethylhexanoate) are available, thus the developmental toxicity will be addressed with existing data on the individual moieties strontium and 2-ethylhexanoic acid.

Since 2-ethylhexanoic acid has a legally binding classification for reproductive/developmental toxicity as category 2 and strontium is self-classified as toxic to reproduction category 1B, strontium bis(2-ethylhexanoate) is classified accordingly for Reproduction toxicity Hazard Category 1B, with the Hazard statement H360d (may damage the unborn child).

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.

 

Toxicity for reproduction - developmental toxicity

No toxicity data on adverse effects on development of the offspring with strontium bis(2-ethylhexanoate) are available, thus the reproductive toxicity will be addressed with existing data on the individual moieties strontium and 2-ethylhexanoic acid as detailed below.

Strontium

Based on the outcome of a prenatal developmental toxicity assay, strontium chloride hexahydrate did induce adverse developmental effects in a GLP OECD TG414 study performed in pregnant Wistar rats from gestation day 6 (GD6) to gestation day 19 (GD19) administered by oral gavage at dose levels of 105, 420, and 1681 mg SrCl₂.6H₂O/kg bw/d (Nextreat, 2021). These developmental effects were seen in the absence of maternal toxicity effects. 

No mortality or clinical signs in the dams were observed under the conditions of this study. 

Based on the results of thyroid hormones analysis, thyroid weights, histopathological evaluation of thyroids and the measurement of anogenital distance of fetuses, no endocrine disruptor effect was observed in the study.

Treatment at 1681 mg SrCl₂.6H₂O/kg bw/day was associated with maternal toxicity effects, such as reduced body weight and reduced body weight gain and reduced food consumption of the dams, as well as with developmental toxicity effects, such as increased number of dead fetuses, increased post implantation loss, increased intrauterine mortality and growth retardation of the fetuses. Consequently, this led also to a reduced litter weight and reduced gravid uterine weight.

In addition, the test item at this dose level caused ossification disturbances on the whole skeletal system in the fetuses, which was expressed as: incomplete ossification of the whole skull, unossified sternebrae, wavy and marked wavy ribs, unossified thoracic, lumbar and sacral vertebrae, unossified metacarpal and metatarsal bones, unossified pubis and/or ischium, misshapen, bent and/or short scapula, bent and/or short clavicula, humerus, radius, ulna, femur, tibia and fibula.

Treatment at 420 mg SrCl₂.6H₂O/kg bw/day no evidence of adverse maternal effect was observed, but was associated with developmental toxicity effects, such as increased number of dead fetuses and post implantation loss. In addition, the test item at this dose level caused skeletal variations in the fetuses such as incomplete ossification of the skull, wavy and marked wavy ribs, and skeletal malformations, identified as bent and/or short scapula, humerus, femur, tibia and fibula.

No adverse maternal or developmental toxicity effect was observed at 105 mg SrCl₂.6H₂O/kg bw/day.

LOAEL_{maternal toxicity}: 1681 mg SrCl₂.6H₂O/kg bw/day
NOAEL_{maternal toxicity}: 420 mg SrCl₂.6H₂O/kg bw/day
LOAEL_{developmental toxicity}: 420 mg SrCl₂.6H₂O/kg bw/day
NOAEL_{developmental toxicity}: 105 mg SrCl₂.6H₂O/kg bw/day

LOAEL_{maternal toxicity}: 552.4 mg Sr/kg bw/day
NOAEL_{maternal toxicity}: 138.1 mg Sr/kg bw/day
LOAEL_{developmental toxicity}: 138.1 mg Sr/kg bw/day
NOAEL_{developmental toxicity}: 34.5 mg Sr/kg bw/day

Based on the information from the key OECD TG 414 study (Nextreat, 2021), the hazard classification for SrCl₂.6H₂O and Sr is re-evaluated and updated. According to the Guidance on the application of CLP criteria, and the clear adverse effects on the development of the offspring, with a clear dose-response relationship, and in the absence of maternal toxicity, the substance SrCl₂.6H₂O and Sr meet the criteria laid down in Annex I Section 3.7.2.1.1 for classification as toxic to reproduction category 1B 'Presumed human reproductive toxicant' (evidence for classifcation is from animal data) with hazard statement H360D May damage the unborn child.

 

2-ethylhexanoic acid

The developmental toxicity of 2-ethylhexanoic acid has been investigated in a standard study in rabbits [USEPA TSCA Health Effects Testing Guidelines CFR 798.4900 (similar to OECD TG 414)]. 2-Ethylhexanoic acid was administered (15/dose) via gavage at 0, 25, 125, or 250 mg/kg-bw/day on days 6 through 18 of gestation. One middose and one high-dose animal died on test. In addition, one mid-dose animal aborted prior to term. High-dose dams experienced hypoactivity, ataxia, and gasping. Body weights and food consumption of animals in this group were reduced. The NOAEL for maternal animals was 25 mg/kg–bw/day and the NOAEL for offspring was 250 mg/kg-bw/day (the highest dose tested). In a guideline study [OECD TG 414] 2-ethylhexanoic acid was administered via drinking water to an unspecified number of animals at 0, 100, 300, or 600 mg/kg-bw/day, for days 6-19 of gestation. No death was observed. Mean foetal weight per litter and mean placental weights were significantly reduced in the mid- and high-dose groups. Clubfoot was the only skeletal malformation; changes in skeletal variations were also noted (wavy ribs, reduced cranial ossification, and twisted hind legs). Corrected maternal body weights at termination and weight gains of high-dose females were significantly reduced. The NOAEL for maternal animals was 300 mg/kg-bw/day; the NOAEL for offspring was 100 mg/kg-bw/day. Based on these results, 2-ethylhexanoic acid is not likely to cause effects on fertility but is likely to be a developmental toxicant. The developmental toxicity of 2-ethylhexanoic acid is at least partially related to disruption of Zn metabolism and distribution in the mother, and that higher zinc levels in the mothers leads to lower developmental toxicity in offspring.

Classification according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 for Reproduction toxicity is required: Hazard Category 2, with the Hazard statement H361d (suspected of damaging the unborn child) (Annex VI).

 

Strontium bis(2-ethylhexanoate)

Since no reproductive toxicity study is available for strontium bis(2-ethylhexanoate), information on the individual moieties strontium and 2-ethylhexanoic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of strontium bis(2-ethylhexanoate).

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 in the F1 offspring will be used. In case of strontium the NOAEL of 9.9 mg/kg bw/day for the repeated dose toxicity will be used. The NOAEL of 9.9 mg Sr/kg bw/day for  repeated dose toxicity (90 d study, based on increased relative thyroid weights in male rats) is lower than the NOAEL of 34.5 mg Sr/kg bw/day (developmental toxicity study).

 

Considering the read-across principles as detailed above for strontium bis(2-ethylhexanoate) based on the toxicological assessment of the individual moieties, it is therefore proposed to also read-across the classification of toxic for reproduction, developmental toxicity category 1B (H360d) of strontium to strontium bis(2-ethylhexanoate).

Justification for classification or non-classification

As the moiety 2-ethylhexanoic acid of strontium bis(2-ethylhexanoate) is legally binding classified for reproductive toxicity (category 2) and strontium is self-classified as toxic to reproduction category 1B 'Presumed human reproductive toxicant', strontium bis(2-ethylhexanoate) is self-classified for reproductive toxicity.

Classification according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 for Reproduction toxicity is: Hazard Category 1B, with the Hazard statement H360d (may damage the unborn child).