Ruthenium

Endpoint summary

Description of key information

Ruthenium metal is likely to be poorly absorbed after oral exposure, based on a low water solubility and a lack of appreciable bio-elution in simulated gastric fluid; what small proportion of the substance is taken up is likely to be rapidly excreted. Based on experimental human data on a soluble ruthenium salt, an oral absorption value of 1% is proposed for chemical safety assessment (CSA).

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.

Significant bioavailability after dermal exposure is unlikely, given the low dermal penetration expected for metals, and the lack of appreciable bio-elution in simulated dermal fluid. A value of 10% dermal absorption is proposed for CSA.

Once absorbed, distribution and excretion of ruthenium ions 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. In general, a substance needs to be dissolved before it can be taken up from the gastro-intestinal tract after oral administration. Ruthenium metal is essentially insoluble in water (<0.1 μg/L; Skeaff and Beaudoin, 2011). In a bio-elution test, the proportion of metal release (from total metal content) in simulated gastric fluid was 5 x 10-5 % for ruthenium powder after 2 hours (Rodriguez, 2012). This indicates a very low potential for absorption after oral exposure to ruthenium metal.

In studies investigating the simple soluble salt ruthenium (III) chloride (RuCl3) hydrate, 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) of ruthenium metal.

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 the proportion of ruthenium powder with a diameter <100 μm is 83.5% (Tremain and Atwal, 2011). Dustiness testing, a more energetic PSD measurement, returned a mass median aerodynamic diameter (MMAD) value of 20.1 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 54.9, 0.69 and 0.89 % for the nasopharyngeal (head), tracheobronchial (TB) and pulmonary regions of the respiratory tract, respectively. This indicates that little airborne substance (<2%) will be deposited in the lower regions of the human respiratory tract, i.e. the TB or pulmonary regions via oronasal normal augmenter breathing.

Based on its low water solubility (<0.1 μg/L), most of the inhaled ruthenium fraction could be coughed or sneezed out of the body or swallowed, with subsequent systemic uptake being determined predominantly by oral bioavailability. The insoluble nature of the substance would limit any diffusion/dissolution into the mucus lining the respiratory tract. However, any ruthenium which is able to migrate into the mucus has the potential to be absorbed directly across the respiratory tract epithelium by passive diffusion. Only about 0.9% is likely capable of reaching the alveoli. Thus, inhalation will not be a significant route of exposure. Any ruthenium reaching the lungs would mainly be engulfed by alveolar macrophages and translocated out of the respiratory tract by absorption.

While it is highly unlikely that ruthenium metal will 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 ruthenium metal were identified. Its insoluble nature suggests that dermal uptake is likely to be very low (ECHA, 2014). This is supported by in vitro permeation studies on soluble platinum and rhodium salts, which generally showed a low degree of absorption [around 1%]. 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). Furthermore, in bio-elution tests with ruthenium powder, the proportion of metal release (from total metal content) in simulated dermal fluid was 6 x 10-6 % and 9 x 10-6 % after 24 and 168 hours, respectively (Rodriguez, 2012). 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 of ruthenium metal.

Distribution/Metabolism

Once absorbed, distribution of ruthenium ions (the anticipated form of the metal in vivo) throughout the body is expected based on water solubility of the cationic form, and a low molecular weight (101 g/mol).

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).

Ruthenium displayed poor water solubility, while bio-elution test data indicate a lack of appreciable release of the metal (to ionic form) in simulated gastric fluid. Rapid excretion of any absorbed ruthenium ions is likely based on the low molecular weight. 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). However, the potential for bioaccumulation of ruthenium is considered to be low, based on the anticipated poor bioavailability and rapid excretion of any absorbed, water-soluble ions.

Conclusion

Experimental solubility and bio-elution data suggest that ruthenium metal is not likely to be absorbed after oral exposure. This is supported by limited experimental data on another soluble ruthenium salt, as well as substance-specific physico-chemical properties, chemical structure and molecular weight. Bioaccumulation is unlikely, and ruthenium is expected to be rapidly excreted if absorbed. Inhalation is not anticipated to be a significant route of exposure, since respiratory tract deposition modelling data indicate that very little ruthenium would reach the deep lung. However, any ruthenium that does reach this part of the lung might potentially be absorbed. 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.

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.