Strontium neodecanoate

Endpoint summary

Key value for chemical safety assessment

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 a sub-chronic oral repeated dose toxicity study OECD 408 (Kroes, 1977). The authors reported a NOAEL of 4800 ppm, which is equivalent to a strontium concentration of 157.7 mg/kg bw.

In accordance with regulation 1907/2006 (EC), Annex IX, Section 8.7.3, Column 1, an extended one generation reproductive toxicity study shall be proposed, only in case the available repeated dose toxicity studies (e.g. 28-day or 90-day studies) indicate adverse effects on reproductive organs or tissues or reveal other concerns in relation with reproductive toxicity. Sufficient weight of evidence is available to demonstrate an absence of reproductive toxicity and that testing on vertebrate animals in an extended one- generation reproductive toxicity study (OECD 443) with strontium neodecanoate shall be omitted.

 

 

Neodecanoate

In a modified three-generation reproductive toxicity study, male and female Sprague-Dawley rats were administered neodecanoic acid at 0, 100, 500 and 1500 ppm (approximately 0, 5, 25 and 75 mg/kg-bw/day, respectively) in the diet. No adverse effects were observed on survival, appearance, behaviour, body-weight gain and food consumption in the parental, F1 or F2 generations. The reproductive performance of the parents was not affected. No treatment-related gross or microscopic pathological findings were observed at any of the dietary levels.

  

Strontium neodecanoate

Strontium neodecanoate is not expected to show effects on fertility, since the two moieties strontium and neodecanoic acid have not shown fertility toxicity in a range of test systems.  For further information on the toxicity of the individual moieties, please refer to the relevant sections in the IUCLID and CSR.

 

Information on the individual moieties strontium and neodecanoic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of strontium neodecanoate. For the purpose of hazard assessment of strontium neodecanoate, the point of departure for the most sensitive endpoint of each moiety will be used for the DNEL derivation. In case of neodecanoic acid in strontium neodecanoate, the NOAEL of 250 mg/kg bw/day for the developmental toxicity will be used. In case of strontium the NOAEL of 9.9 mg Sr/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)

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

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

Based on the outcome of a prenatal developmental toxicity assay: Strontium chloride hexahydrate did induce adverse developmental effects in a GLP OECD TG414 studie 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

 

Neodecanoate

In developmental toxicity study, pregnant rats, n=22 per dose, were treated by oral gavage to 50, 250, 600 or 800 mg/kg/day neoheptanoic acid, a substance similar in structure to neodecanoic acid, during gestation days 6-15. On gestation day 21, the dams were euthanized and the pups were examined for signs of developmental toxicity. Under the conditions of the experimental methods, the test material produced maternal toxicity at dose levels of 600 and 800 mg/kg with maternal lethality at 800 mg/kg. The test material was severely embryotoxic at 800 mg/kg with less than 20% of embryos surviving. Offspring of the 800 mg/kg group had reduced body weight, reduced crown-rump distance, displayed variations signifying delayed development, and a significant percentage (25%) were malformed. In the 600 mg/kg group, there was an increase number of dams with 3 or more resorptions. Offspring of the 600 mg/kg group displayed significant incidences of major (hydrocephalus) and minor (knobby or angular ribs, extra lumbar vertebrae) malformations but showed few signs of delayed development and were not runted. There was no statistically significant evidence of maternal toxicity at dose levels of 50 or 250 mg/kg. There was a slight, but not statistically significant, increase in embryonic resorption noted for the 250 mg/kg group. There was no statistically significant evidence of developmental toxicity at doses for 50 or 250 mg/kg. The NOAEL for maternal toxicity is 250 mg/kg and the NOAEL for developmental toxicity is 250 mg/kg. 

 

Strontium neodecanoate

In a reliable prenatal developmental toxicity study conducted with strontium chloride hexahydrate, adverse developmental effects were reported in the absence of maternal toxicity. In addition, adverse effects were reported in a developmental toxicity study conducted with neoheptanoic acid. However, the study performed with neoheptanoic acid is of limited quality due to major restrictions in study design. Nevertheless, strontium is the moiety of concern.

Thus, final conclusion on classification and labelling can be made. 

 

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

 

Information on the individual moieties strontium and neodecanoic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of strontium neodecanoate. For the purpose of hazard assessment of strontium neodecanoate, the point of departure for the most sensitive endpoint of each moiety will be used for the DNEL derivation. In case of neodecanoic acid in strontium neodecanoate, the NOAEL of 250 mg/kg bw/day for the developmental toxicity will be used. In case of strontium the NOAEL of 9.9 mg Sr/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)

Justification for classification or non-classification

Fertility

No adverse effects were observed in a sub-chronic repeated dose toxicity study with strontium chloride and prenatal developmental toxicity study conducted with strontium chloride hexahydrate as well as in a modified three-generation study performed with neodecanoic acid. Thus, strontium neodecanoate in all probability has also no potential to impair sexual function or fertility. Therefore, no classification is required for fertility.

Developmental

Based on the outcome of a prenatal developmental toxicity study according to the OECD 414 guideline (Nextreat, 2021), clear evidence was shown of adverse effects on development induced by strontium chloride hexahydrate in the absence of maternal toxic effects. These adverse effects were: skeletal malformations (bent and/or short scapula, humerus, femur, tibia, and fibula), next to  increased number of dead fetuses and post implantation loss, and  skeletal variations (incomplete ossification of the skull, wavy and marked wavy ribs). A clear dose-response was observed. 

LOAEL developmental = 420 mg SrCl₂.6H₂O/kg bw/d (138.1 mg Sr/kg bw/d)

NOAEL developmental = 105 mg SrCl₂.6H₂O/kg bw/d (34.5 mg Sr/kg bw/d) 

LOAEL maternal = 1681 mg SrCl₂.6H₂O/kg bw/d (552.4 mg Sr/kg bw/d) based on decreased body weight and body weight gain, decreased food consumption of the dams

NOAEL maternal = 420 mg SrCl₂.6H₂O/kg bw/d (138.1 mg Sr/kg bw/d) 

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 classification is from animal data).

Label elements in accordance with table 3.7.3 of Annex I: 3.7.4.1: 

Classification: 1B

GHS Pictograms: GHS08: Health Hazard

Signal word: Danger

Hazard statement: H360D May damage the unborn child

Classification for strontium neodecanoate

Reproductive toxicity classification of strontium neodecanoate is based on the presence of strontium which is classified for reproductive toxicity (see CLP Article 6(3) and Annex I, 3.7.3). Generic concentration limits triggering classification (Annex I Table 3.7.2) Category 1B: ≥0.3%. Therefore, 

Classification strontium neodecanoate: 1B

GHS Pictograms: GHS08: Health Hazard

Signal word: Danger

Hazard statement: H360D May damage the unborn child