Ruthenium trichloride hydrate

Endpoint summary

Description of key information

Ruthenium trichloride hydrate (RuCl3) is likely to be poorly absorbed after administration by the oral route, 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.

 

Absorption via the inhalation route 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 and the high water solubility. Noting the potential for disruption of the skin barrier caused by corrosion, a value of 20% 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 (%):

20

Absorption rate - inhalation (%):

100

Additional information

Absorption

The dataset for toxicokinetics of ruthenium and its salts is very limited. However, most available studies have investigated 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 56.7% of the RuCl3 sample had a particle size <100 μm (Walker and White, 2011). An MMAD value <100 μm indicates that a significant proportion of the substance is likely to be inhalable. As a highly water soluble substance (1140 g/L; Gregory, 2014), any RuCl3 reaching the lungs is likely to be absorbed through aqueous pores or be retained in the mucus and transported out of the respiratory tract.

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 RuCl3 were identified. The high water solubility (> 1000 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 might be appropriate in this case; 10% is the lower of the two values provided by the guidance (ECHA, 2014).

However, RuCl3 is classified as corrosive to the skin based on the results of two in vitro studies (on the solid and solution forms of the test substance). Thus, there is the potential for disruption to the skin barrier and, consequently, increased percutaneous absorption. On this basis, it could be argued that the higher ECHA default, 100%, is applicable.

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).

Overall, the various default values are somewhat conflicting. Absorption in the range of that indicated by ICMM (2007) seems to be too low when considering the likely skin barrier disruption. However, assuming 100% absorption could be considered as overestimating the dermal absorption potential, particularly considering the high water solubility. In the absence of experimental data, it is considered suitably health precautionary to take forward a value of 20% dermal absorption for use in CSA and DNEL derivation.

Distribution/Metabolism

Once absorbed, distribution of RuCl3 throughout the body is expected based on a relatively low molecular weight (≈200-250 g/mol, depending on degree of hydration).

As no adverse toxicological effects were reported in repeated-dose and reproductive/developmental toxicity dietary studies in rats on RuCl3 (Hargitai, 2017; Zelenak, 2017), no insights can be gained regarding potential tissue distribution.

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, administered 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). RuCl3 is considered to have only a low potential for bioaccumulation based on its predicted physico-chemical properties (especially a high water solubility of 1140 g/L).

Conclusion

Based on limited experimental data, physico-chemical properties, chemical structure and molecular weight, ruthenium chloride hydrate is likely to be poorly absorbed after administration by the oral route. Bioaccumulation is unlikely, and any absorbed RuCl3 is expected to be rapidly excreted. Absorption via the inhalation route could be extensive. A high dermal bioavailability is unlikely, but the potential for increased percutaneous absorption of RuCl3 – a known skin corrosive – as a result of skin barrier disruption is noted.

Absorption values of 1%, 20% 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.