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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.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

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. Thus, strontium bis(2-ethylhexanoate) is not to be classified according to regulation (EC) 1272/2008 as reproductive toxicant: fertility impairment. 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, strontium bis(2-ethylhexanoate) is classified accordingly for Reproduction toxicity Hazard Category 2, with the Hazard statement H361d (suspected of damaging the unborn child).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Strontium

In a prenatal developmental toxicity study performed by Landsdown (1972) strontium nitrate were administered to rats subcutaneously between pregnancy day 9 to 19. No maternal toxicity was observed up to doses of 200 mg/kg bw of strontium nitrate. Litter sizes were similar and the number of resorption sites was not increased. Therefore, no embryotoxicity was observed. According to the authors, the results indicate that high maternal doses of strontium nitrate (25, 50, 100 or 200 mg/kg bw/day; equivalent to 10.3, 20.7, 41.4, or 82.8 mg Sr/kg bw/day) were not teratogenic when given at a maximum period of bone development.

Based on the outcome of a prenatal developmental toxicity assay and a sub-chronic repeated dose toxicity test, strontium does not impair sexual function, fertility or the development of the offspring. Therefore, no classification is required.

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.

Classificiation 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.

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 2 (H361d) of 2-ethylhexanoic acid 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, 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 2, with the Hazard statement H361d (suspected of damaging the unborn child) (Annex VI).

Additional information