Tetraammonium decachloro-μ-oxodiruthenate(4-)

Endpoint summary

Description of key information

Tetraammonium decachloro-µ-oxodiruthenate(4-) (tetradoRu) is likely to be poorly absorbed after oral exposure, with rapid excretion of any material that is absorbed. As such, an oral absorption value of 1% is proposed for chemical safety assessment (CSA) and DNEL derivation.

 

Although exposure by the inhalation route is anticipated to be low, inhalation absorption is potentially extensive. In line with ECHA guidance, and in the absence of any experimental data to the contrary, a conservative value of 100% inhalation absorption is proposed for CSA and DNEL derivation.

 

Significant bioavailability after dermal exposure is unlikely, given the low dermal penetration expected for metals, the observed lack of skin irritation potential, and the high water solubility. A value of 10% dermal absorption is proposed for CSA and DNEL derivation.

 

Once absorbed, distribution and excretion are expected to be rapid, with little or no bioaccumulation anticipated. The potential for bioaccumulation of certain other metals and ions is recognised.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

1

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Absorption

The dataset for toxicokinetics of ruthenium and its salts is very limited, with most studies investigating the simple salt ruthenium (III) chloride (RuCl3) hydrate. In a series of studies, covering oral, intraperitoneal and intravenous administration to rodents, dogs and primates, the toxicokinetic profile of RuCl3 was found to be fairly consistent between the species. Oral absorption was low (up to around 3%) (Furchner et al., 1971).

In another study, radiolabelled 103RuCl3 was administered to a single, healthy male volunteer by contamination of edible clams. About 3 µCi of radiation was administered, and the distribution of the tracer was followed by a whole body scanner for 58 days. Only 1% of the administered dose was considered to be absorbed, with a half-life of 30 days. Absorption of chloro-nitrosyl ruthenium (III) complexes was found to be approximately 3-times that of simple chlorinated ruthenium (III) or (IV) complexes (Yamagata et al., 1969).

On the basis of the above studies, a figure of 1% oral absorption is proposed to be taken forward for chemical safety assessment (CSA).

No good-quality data were found regarding absorption of ruthenium compounds following inhalation. Particle size distribution (PSD) data, as measured by simple sieving, indicate that none of the Tetraammonium decachloro-µ-oxodiruthenate(4-) is

100 μm (Tremain and Atwal, 2011). Dustiness testing, a more energetic PSD measurement, with the compound returned a mass median aerodynamic diameter (MMAD) value of 29.0 μm (Selck and Parr, 2011). An MMAD value <100 μm indicates that a significant proportion of the substance is likely to be inhalable. However, respiratory tract deposition modelling with the dustiness data yielded output values of 47.6, 0.18 and 0.26% for the nasopharyngeal (head), tracheobronchial (TB) and pulmonary regions of the respiratory tract, respectively. This indicates that little airborne substance (<1%) will be deposited in the lower regions of the human respiratory tract, i.e. the TB or pulmonary regions via oronasal normal augmenter breathing. As a water soluble substance (20-30 g/L; Gregory, 2012; 2014), any tetradoRu reaching the lungs is likely to be absorbed through aqueous pores or be retained in the mucus and transported out of the respiratory tract.

While it is unlikely that Tetraammonium decachloro-µ-oxodiruthenate(4-) wi

ll be available to a high extent via the lungs, ECHA guidance notes that “if data on the starting route (oral) are available these should be used, but for the end route (inhalation), the worst case inhalation absorption should still be assumed (i.e. 100%)”. Therefore, the health-precautionary figure of 100% as recommended by ECHA has been taken forward for chemical safety assessment.

No substance-specific data on dermal uptake of Tetraammonium decachloro-µ-oxodiruthenate(4-)

tu were identified. The “high” water solubility (> 10 g/L) suggests that the substance may be too hydrophilic to cross the lipid-rich environment of the stratum corneum to a significant extent, indicating that a low default value for dermal absorption is appropriate in this case; 10% is the lower of the two values provided by the guidance (ECHA, 2014). However, in vitro permeation studies on soluble platinum and rhodium salts, generally showed a lower degree of absorption [around 1%] than this default would assume. It is reasonable to expect ruthenium and its salts to behave similarly.

Specific expert guidance on the health risk assessment of metals states that “inorganic compounds require dissolution involving dissociation to metal cations prior to being able to penetrate skin by diffusive mechanisms” and, as such, dermal absorption might be assumed to be very low (values of 0.1 and 1.0% are suggested for dry and wet media, respectively) (ICMM, 2007). There is evidence that Tetraammonium decachloro-µ-oxodiruthenate(4-)

does not cause skin irritation (Hargitai, 2015), which could facilitate a greater degree of dermal uptake. Overall, and in the absence of experimental data to the contrary, it is considered suitably health precautionary to take forward the lower of the two ECHA default values for dermal absorption, of 10% for use in CSA and DNEL derivation.

Distribution/Metabolism

Once absorbed, distribution of Tetraammonium decachloro-µ-oxodiruthenate(4-)

throughout the body is expected based on a relatively low molecular weight (≈350 g/mol).

As no adverse toxicological effects were reported in a combined repeated dose and reproductive/developmental toxicity dietary study in rats on Tetraammonium decachloro-µ-oxodiruthenate(4-)

(Hansen, 2017), no insights can be gained regarding potential tissue distribution/target organs.

Elimination (and Bioaccumulation)

Following oral administration of radiolabelled soluble 106Ru (as 106RuCl3) to mice, rats, monkeys and dogs, > 95% of the administered dose was excreted in the faeces within 3 days. The remainder (1 – 5%) was excreted in the urine, with only trace amounts of ruthenium being retained. The urine and faeces were also the primary routes of elimination following intravenous injection of monkeys or dogs, and intraperitoneal injection of mice and rats. Elimination was much slower following injection administration of 106RuCl3, with only 20-30% of the administered dose detected in the urine, and 4 – 19% in the faeces, after 3 days (Furchner et al., 1971).

In a single human volunteer, given 103RuCl3 in food, similar results were obtained. About 95% of the administered dose was detected excreted in the faeces within 2 days. Approximately 4% was retained in the GI tract, but not considered to be absorbed. The biological half-life of this fraction was 2.3 days (Yamagata et al., 1969).

It is noted that certain metals and ions (notably lead) may interact with the matrix of the bone, causing them to accumulate within the body (ECHA, 2014). Tetraammonium decachloro-µ-oxodiruthenate(4-)

is considered to have only a low potential for bioaccumulation based on its predicted physico-chemical properties (especially a high water solubility of 20-30 g/L).

Conclusion

Based on limited experimental data on another soluble ruthenium salt, as well as substance-specific physico-chemical properties, chemical structure and molecular weight, tetraammonium decachloro-µ-oxodiruthenate(4-) (tetradoRu) is likely to be poorly absorbed after oral exposure. Bioaccumulation is unlikely, and Tetraammonium decachloro-µ-oxodiruthenate(4-)

is expected to be rapidly excreted if absorbed. Although inhalation is not anticipated to be a significant route of exposure (based on respiratory tract deposition modelling data), absorption could be extensive. A high dermal bioavailability is unlikely.

Absorption values of 1%, 10% and 100% for the oral, dermal and inhalation routes, respectively, are proposed for the CSA, and considered health-precautionary for use in the calculation of DNEL values.

 

References (for which an ESR has not been created in IUCLID):

ECHA (2014). European Chemicals Agency. Guidance on information requirements and chemical safety assessment. Chapter R.7c: endpoint specific guidance. Version 2.0. November 2014.

Furchner JE, Richmond CR and Drake GA (1971). Comparative metabolism of radionuclides in mammals – VII. Retention of 106Ru in the mouse, rat, monkey and dog. Health Physics 21, 355-365.

ICMM (2007). International Council on Mining & Metals. Health risk assessment guidance for metals. September 2007.

Yamagata N, Iwashima K, Iinuma TA, Watari K and Nagai T (1969). Uptake and retention experiments of radioruthenium in man – I. Health Physics 16, 159-166.