Strontium bis(2-ethylhexanoate)

Endpoint summary

Description of key information

The experimentally measured oral LD50 for strontium bis (2-ethylhexanoate) is >2000 mg /kg.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

06 December 2021 - 21 December 2021

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Wistar

Remarks:

Han:WIST rats

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Toxi-Coop Zrt., H-1122 Budapest, Magyar Jakobinusok tere 4B
- Hygienic level at supplier: SPF
- Hygienic level during the study: Standard housing conditions
- Number of animals: 6 animals, 3 animals/group
- Sex: Female, nulliparous and non-pregnant animals
- Age of animals at dosing: Young adult rats, approx. 9-10 weeks old
- Body weight range at dosing: 189-207 g. The maximum difference of individual animal weights from the mean of the treatment group did not exceed 20%.
- Acclimatisation period: At least 19 days
- Animal health: Only healthy animals were used for the test. The health status was certified by the Veterinarian.
- Housing: Group caging (3 animals/cage)
- Cage type: T3H polycarbonate
- Bedding and nesting: “SAFE 3/4-S-FASERN” certified wooden chips and “Sizzle pet” nest material were available to animals during the study.
- Enrichment: Animals were housed by group to allow social interaction and with deep wood sawdust bedding to allow digging and other normal rodent activities.
- Animals received standard laboratory rat diet, ad libitum, and tap water from the municipal supply, as for human consumption from drinking bottles designed for rodents, ad libitum.
- The night before treatment, the animals were fasted. Food, but not water, was withheld overnight. Animals were weighed before dosing. Food was replaced 3 hours after the treatment.

ENVIRONMENTAL CONDITIONS
- Lighting period: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
- Temperature: 20 – 23 °C (target: 22 ± 3 °C)
- Relative humidity: 38 – 61 % (target: 30 – 70 %)
- Ventilation: 15-20 air exchanges/hour

IN-LIFE DATES: From 06 December 2021 to 21 December 2021

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: The powdered test item did not dissolve in distilled water, in 1% methyl cellulose solution and in PEG 400, but formed a homogenous suspension in corn oil after stirring with magnetic stirrer for approx. 30 minutes.
- Lot/batch no.: MKCM9808
- Manufacturer: Sigma-Aldrich
- Expiry date: 30 April 2026

DOSAGE PREPARATION: The test item was freshly formulated in the vehicle at the appropriate concentration (200 mg/mL), in the Pharmacy of NEXTREAT Laboratories on the day of administration. The formulations were stirred with magnetic stirrer up to finishing the treatment.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: As starting dose level for acute toxicity study, a dose of 2000 mg/kg body weight (bw) has been selected based on the information published by ECHA.
- Initially three animals were treated at the starting dose of 2000 mg/kg bw (Group 1). As no mortality was observed in this group, a confirmatory group (Group 2) was treated at the same dose level. No mortality was observed in this confirmatory dose group, therefore no further testing was required according to the criteria for termination given in Annex 2d of OECD Guideline No. 423.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

6 (3 animals per group)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Clinical observations: Following the end of the dosage, the animals were observed individually once during the first 30 minutes, at 1, 2, 3, 4 and 6 hours after the treatment and once daily for 14 consecutive days thereafter. Individual observations were performed on the skin and fur, eyes and mucous membranes and also respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma. The time of death was recorded as precisely as possible.
- Body weight: The body weight of the animals was recorded on Days 0 (prior to dosing), 7 and 14 (prior to necropsy), with a precision of 1 g.
- Necropsy: Animals were subjected to a necropsy and a macroscopic examination. After examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs were observed. All gross macroscopic changes were recorded for each animal.

Statistics:

The method used was not intended to allow the calculation of a precise LD50 value.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Sex:

female

Dose descriptor:

LD50 cut-off

Effect level:

5 000 mg/kg bw

Based on:

test mat.

Mortality:

Strontium bis(2-ethylhexanoate) did not cause mortality at 2000 mg/kg bw.

Clinical signs:

other:

Body weight:

lower than 10% body weight loss

Remarks:

There were no effects on body weight or body weight gain that could be attributed to treatment with the test item.

Gross pathology:

There were no macroscopic changes seen at necropsy.

Interpretation of results:

Category 5 based on GHS criteria

Remarks:

The test substance is not classified according to Regulation (EC) No 1272/2008 (CLP)

Conclusions:

Under the conditions of this study, the acute oral LD50 value of the test item
Strontium bis(2-ethylhexanoate) was found to be above 2000 mg/kg bw in female
Han:WIST rats.
The LD50 cut-off value is 5000 mg/kg bw.
The study result triggers the following classification/labelling:
- Regulation (EC) No 1272/2008 (CLP): Unclassified
- GHS (rev. 7) 2017: Category 5

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

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.

 

Acute toxicity

An acute oral toxicity study is available with strontium bis(2-ethylhexoate). Acute dermal and inhalation toxicity will be addressed with existing data on the dissociation products as detailed in the table below. Further details on the acute toxicity of the individual constituents within the framework of regulation (EC) 1907/2006 are given below.

 

Table: Summary of acute toxicity data of strontium bis(2-ethylhexanoate) and the individual constituents.

	Strontium ion	2-ethylhexanoic acid (CAS# 149-57-5)	strontium bis(2-ethylhexanoate) (CAS#2457-02-5)
Acute oral toxicity	LD50(rat)= 194 mg Sr/kg bw	LD50(rat)= 2043 mg/kg bw	LD50 > 2000 mg/kg bw (measured) LD50 660 mg/kg bw (predicted)
Acute inhalation toxicity	waived	LD0= 0.11 mg/L air (nominal)	waived, since the substance is used and placed on the market in a non-inhalable form
Acute dermal toxicity	waived	LD50> 2,000 mg/kg bw	LD50 > 2000 mg/kg bw (calculated)

 

Strontium

Acute oral toxicity

One reliable animal study according to OECD 425 is considered to be reliable without restrictions. The LD50 value was determined to be 1030 mg/kg bw for strontium neodecanoate, corresponding to 194 mg Sr/kg bw. Based on this, strontium neodecanoate is classified as acute toxic via the oral route (Category 4, H302).

The classification criteria according to Regulation (EC) No. 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value, oral for a Category 1 classification (C≤ 300 mg/kg bw) and at the guidance value, oral for a Category 2 classification (2000 mg/kg bw ≥ C > 300 mg/kg bw). No classification required.

Acute dermal toxicity

In the absence of measured data on dermal absorption, current guidance suggests the assignment of either 10 % or 100 % default dermal absorption rates. In contrast, the currently available scientific evidence on dermal absorption of metals yields substantially lower figures, which can be summarised briefly as follows:

Measured dermal absorption values for metals or metal compounds in studies corresponding to the most recent OECD test guidelines are typically 1 % or even less. Therefore, the use of a 10 % default absorption factor is not scientifically supported for metals. This is corroborated by conclusions from previous EU risk assessments (Ni, Cd, Zn) and current metal risk assessments under REACH, which have derived dermal absorption rates of 2 % or far less (but with considerable methodical deviations from existing OECD methods) from liquid media.

However, considering that under industrial circumstances many applications involve handling of dry powders, substances and materials, and since dissolution is a key prerequisite for any percutaneous absorption, a factor 10 lower default absorption factor may be assigned to such “dry” scenarios where handling of the product does not entail use of aqueous or other liquid media. This approach was taken in the in the EU RA on zinc. A reasoning for this is described in detail elsewhere (Cherrie and Robertson, 1995), based on the argument that dermal uptake is dependent on the concentration of the material on the skin surface rather than its mass. The following default dermal absorption factors for metal cations are therefore proposed (reflective of full-shift exposure, i.e. 8 hours): From exposure to liquid/wet media: 1.0 %; From dry (dust) exposure: 0.1 %. This approach is consistent with the methodology proposed in HERAG guidance for metals (HERAG fact sheet - assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal compounds; EBRC Consulting GmbH / Hannover /Germany; August 2007).

 

2-ethylhexanoic acid

Acute oral toxicity

In an acute oral toxicity study 4 rats/sex/dose were dosed with 90, 722, 1445 or 2890 mg/kg bw. No mortality was observed in the 90, 722 and 1445 mg/kg bw dose groups. The test material caused mortality in rats administered a dose of 2890 mg/kg bw (4/4), and transitory weakness at lower doses in a dose-dependent manner. The LD50 was calculated to 2043 mg/kg bw.

 

In another acute oral toxicity study 5 rats/sex/dose have been administered 0.2, 1.6, 3.2 and 4.0 ml 2-ethylhexanoic acid/ kg bw. No substance related clinical signs nor mortality was observed at 0.2 and 1.6 ml/kg. However, 1/10 animals died. After administration of 3.2 ml/kg and 4 ml/kg apathy dyspnea abdominal position and re crusted eyes and snouts were observed. Mortality in these dose groups was 3/10, 5/10, respectively. LD 50 was estimated to be 4 mL/kg bw, being equivalent to 3640 mg/kg bw (density 0.91 g/ml). This result is supported by another study which however was poorly documented.

 

Acute dermal toxicity

Dermal toxicity of 2-ethylhexanoic acid was tested in an OECD 402 guideline study. Five Wistar rats/sex/dose have been exposed dermally (semi-occlusive to a limit dose of 2000 mg/kg bw 2‑ethylhexanoic acid. No mortality and no clinical symptoms beside eschar formation have been observed. LD50 dermal therefore is > 2000 mg/kg bw.

 

Strontium 2-ethylhexonate

Under the assumption that the constituents of strontium bis(2-ethylhexanoate) show their toxicological profile individually upon dissolution, the acute oral toxicity of strontium bis(2-ethylhexanoate) can be calculated using the equation given in regulation (EC) 1272/2008, Annex I, Section 3.1.3.6.1. The calculated oral LD50 for strontium bis(2-ethylhexanoate) is 660 mg/kg bw. In an experimental acute oral toxicity study with strontium bis(2-ethylhexanoate) according to the OECD 423 guideline, no mortalities were however observed at a dose of 2000 mg/kg bw, hence the substance is not to be classified according to regulation (EC) 1272/2008 for acute oral toxicity as well as for specific target organ toxicity, single exposure (STOT SE). Because the predicted LD50 based on data for the two transformation products is well below the measured acute oral LD50 for strontium bis(2-ethylhexanoate), it can be concluded that read-across for the two transformation products together with the additivity approach to predict the (eco)toxicological effects of the target substance is conservative and no synergistic effects are expected between the transformation products.

 

A study for acute toxicity via inhalation was not conducted with strontium bis(2-ethylhexanoate), since it is produced and placed on the market in a form in which no inhalation hazard is anticipated, thus acute toxic effects are not likely to occur during manufacture and handling of that substance.

 

Conduct of an acute dermal toxicity study is unjustified as the physicochemical properties of the strontium cation do not suggest a significant rate of absorption through the skin. Further the LD50 for the constituent 2-ethylhexanoic acid is above 2000 mg/kg bw, hence does not require a classification for acute dermal toxicity. Based on the above given information strontium bis(2-ethylhexanoate) is not expected to show any acute toxic effects via dermal route (cf. Annex VIII section 8.5 Column 2 of regulation (EC) 1907/2006)

 

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

Justification for classification or non-classification

The experimentally measured oral LD50 for strontium bis(2-ethylhexanoate) is > 2000 mg/kg, hence the substance is not to be classified according to regulation (EC) 1272/2008 for acute oral toxicity as well as for specific target organ toxicity, single exposure (STOT SE).

Conduct of an acute dermal toxicity study is unjustified as the physicochemical properties of the strontium cation do not suggest a significant rate of absorption through the skin. Further the LD50 for the constituent 2-ethylhexanoic acid is above 2000 mg/kg bw, hence does not require a classification for acute dermal toxicity. Based on the above given information strontium bis(2-ethylhexanoate) is not expected to show any acute toxic effects via dermal route (cf. Annex VIII section 8.5 Column 2 of regulation (EC) 1907/2006).