Ruthenium trichloride hydrate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.38 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Dose descriptor starting point:

NOAEL

Value:

407 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

28.7 mg/m³

Explanation for the modification of the dose descriptor starting point:

[See discussion section (Hazard via inhalation route: systemic effects following long-term exposure).]

AF for dose response relationship:

1

Justification:

Default ECHA AF; NOAEL from a well-conducted 28-day repeated-dose dietary study (with support from a reproductive/developmental toxicity screening study)

AF for differences in duration of exposure:

6

Justification:

Default ECHA AF for subacute (28-day) to chronic extrapolation.

AF for interspecies differences (allometric scaling):

1

Justification:

Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling) is not required

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

AF for intraspecies differences:

5

Justification:

Default ECHA AF for (healthy) worker

AF for the quality of the whole database:

1

Justification:

Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.

AF for remaining uncertainties:

1

Justification:

Not required

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.27 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

75

Dose descriptor starting point:

NOAEL

Value:

407 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

20.4 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

[See discussion section (Hazard via dermal route: systemic effects following long-term exposure).]

AF for dose response relationship:

1

Justification:

Default ECHA AF; NOAEL from a well-conducted 28-day repeated-dose dietary study (with support from a reproductive/developmental toxicity screening study)

AF for differences in duration of exposure:

6

Justification:

Default ECHA AF for subacute (28-day) to chronic extrapolation.

AF for interspecies differences (allometric scaling):

1

Justification:

Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling) is not required

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

AF for intraspecies differences:

5

Justification:

Default ECHA AF for (healthy) worker

AF for the quality of the whole database:

1

Justification:

Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.

AF for remaining uncertainties:

1

Justification:

Not required

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

 

Hazard via inhalation route: systemic effects following long-term exposure

As no relevant data on effects of repeated inhalation exposure to ruthenium trichloride hydrate in laboratory animals are available, route-to-route extrapolation to calculate an inhalation DNEL from a reliable repeated-dose oral toxicity study was considered a suitable alternative (particularly as first pass effects are not expected to be significant for an inorganic compound).

 

In a guideline (OECD TG 407) 28-day dietary toxicity study, rats received ruthenium trichloride hydrate at concentrations of 0, 500, 1500, 5000 or 15,000 ppm. Males in the highest dose group showed reductions in growth and food conversion efficiency compared to controls. There were no other adverse effects in these animals, and no effects on clinical signs, pathology, organ weights or histopathology in any other treated animals. The study NOAEL was the dietary concentration of 5000 ppm (about 407 mg/kg bw/day) (Zelenák, 2017).

 

In another guideline study (OECD TG 421; reproductive/developmental toxicity screening assay), parental males also displayed reduced growth at the highest tested dose (15,000 ppm), resulting in a systemic NOAEL of 5000 ppm (419 mg/kg bw/day). No effects on reproductive parameters, gross/microscopic changes in the reproductive organs or indications of foetal toxicity were observed at any dose level. Thus, the NOAEL for reproductive and developmental toxicity was 15,000 ppm (1276 mg/kg bw/day) (Hargitai, 2017). The possible limitations of this study, as reassurance of an absence of reproductive effects, are acknowledged. ECHA (2012) guidance recommends “application of an additional assessment factor of 2 to 5, decided on a case-by-case basis that should account for the limitations of this study”. Even applying the most conservative of these (i.e. an additional AF of 5) results in a DNEL higher than that derived for repeated dose effects (as the AF of 6 for differences in duration of exposure would not also be required).

 

The systemic NOAEL of 407 mg/kg bw/day, considered protective of fertility and developmental effects, is most critical and equates to a NOAEL of 162.8 mg/kg bw/day when expressed as elemental ruthenium (assuming a metal concentration of around 40%).

 

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).

 

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.

 

Therefore, for this oral-to-inhalation extrapolation, a figure of 1% oral absorption has been used, taken from the laboratory study in man. In line with the guidance (ECHA, 2012), the worst-case of 100% absorption after inhalation has still been assumed for the ‘end’ route.

 

Corrected inhalatory NOAEC (worker, 8 h exposure/day) = oral NOAEL*(1/sRv[rat])*(ABS[oral-rat]/ABS[inh-human]) *(sRV[human]/wRV) = 407 mg/kg bw/day*(1/0.38 m3/kg bw/day)*(1/100)*(6.7 m3 [8h]/10 m3 [8h]) = 7.18 mg/m3

 

It is noted that the standard respiratory rate conversion figure (0.38 m3/kg bw/day) already incorporates a factor of 4 for allometric scaling from rat to human. An assessment factor (AF) for allometric scaling is not considered to be justified in this scenario, given that no metabolism of inorganic metal complexes is anticipated to occur in vivo. It is therefore considered appropriate to increase the corrected inhalatory NOAEC by a factor of 4.

 

Dose descriptor starting point (after route to route extrapolation) = Corrected inhalatory NOAEC (worker, 8 h exposure/day)*4 = 7.18*4 = 28.7 mg/m3

 

Application of the appropriate assessment factors (overall AF 75) to this corrected inhaled NOAEC gives a systemic long-term inhalation DNEL for ruthenium trichloride hydrate of 0.38 mg/m3. This equates to an elemental ruthenium exposure of 0.15 mg/m3.

 

 

Hazard via inhalation or dermal route: systemic effects following acute exposure

DNELs for acute toxicity should be calculated if an acute toxicity hazard, leading to classification and labelling (i.e. under EU CLP regulations) has been identified and there is a potential for high peak exposures (this is only usually relevant for inhalation exposures).

 

There are no data in relation to acute inhalation or dermal exposure to ruthenium trichloride hydrate. In a guideline (OECD TG 401) acute oral toxicity study in rats, the LD50value was determined to be 595 mg/kg bw (Berthold, 1993). The compound is classified in for acute oral toxicity in Category 4 according to CLP criteria.

 

 “A qualitative risk characterisation for this endpoint could be performed for substances of very high or high acute toxicity classified in Category 1, 2 and 3 according to CLP… when the data are not sufficiently robust to allow the derivation of a DNEL” (ECHA, 2016a). However, ruthenium trichloride hydrate is classified in Category 4, so a qualitative assessment is not required.

 

 

Hazard via inhalation route: local effects following long-term or acute exposure

There are no data in relation to respiratory tract irritation or sensitisation of ruthenium trichloride hydrate in humans or laboratory animals. Consequently, no worker-DNELs for long-term or acute local effects in the respiratory tract have been calculated.

 

Ruthenium trichloride hydrate is classified as corrosive to the skin (Category 1B). Despite the lack of respiratory tract irritation data, it would appear prudent to assume that this substance would also irritate the respiratory tract if inhaled at sufficient levels/durations. According to ECHA (2016a) guidance “substances classified for skin corrosion Category 1B/1C in CLP” or “Serious eye damage Category 1 in CLP “… “which relate to corrosive or severe irritant effects to the eye or irritant effects to the eyes, respiratory tract and skin simultaneously, are allocated to the moderate hazard band on the basis that exposure to such corrosives, eye damaging or irritant substances should be well-controlled”. Therefore, consider recommended Risk Management Measures/Operational Conditions (RMMs/OCs) in Table E.3-1 of ECHA (2016a).

 

 

Hazard via dermal route: systemic effects following long-term exposure

As no relevant data on effects of repeated dermal exposure to ruthenium trichloride hydrate in humans or laboratory animals are available, route-to-route extrapolation to calculate a dermal DNEL from a reliable repeated-dose oral toxicity study was considered a suitable alternative (particularly as first pass effects are not expected to be significant for an inorganic compound). This study has already been described above [“Hazard via inhalation route: systemic effects following long-term exposure”] (Zelenák, 2017).

 

The oral NOAEL of 407 mg/kg bw/day equates to a NOAEL of 162.8 mg/kg bw/day for elemental ruthenium (assuming a metal concentration of around 40%), and is considered protective of general systemic effects, fertility and developmental toxicity.

 

This derivation has utilised REACH guidance. In order to make the most health-precautionary derivation, the worst-case scenario is obtained by the minimum absorption by the ‘starting’ route. Therefore, for this oral-to-dermal extrapolation, a figure of 1% oral absorption has been used based on experimental data in man (Yamagata et al., 1969).

 

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) (Lehmeier, 2013a,b). 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 the current safety assessment.

 

Dose descriptor starting point (after route to route extrapolation) = NOAEL*(ABS[oral-rat]/ABS[der-human]) = 407 mg/kg bw/day*(1%/20%) = 20.4 mg/kg bw/day.

 

Application of the appropriate assessment factors (overall AF 75, described above) to this corrected dermal NOAEL gives a systemic long-term dermal DNEL for ruthenium trichloride hydrate of 0.27 mg/kg bw/day, which equates to an elemental ruthenium exposure of 0.11 mg/kg bw/day.

 

 

Hazard via dermal route: local effects following long-term or acute exposure

In guideline (OECD TG 435) in vitro membrane barrier tests, ruthenium trichloride hydrate (when tested as a solid and in aqueous solution) was classified as corrosive sub-category 1B under GHS, on the basis of mean breakthrough times of about 24 and 13 minutes, respectively (Lehmeier, 2013a,b). No dose-response data was available from which to derive a DNEL, therefore a qualitative assessment was considered appropriate. At worst this would be considered in the moderate hazard band according to ECHA (2016a) guidance. Therefore, consider recommended RMMs/OCs in Table E.3-1 of ECHA (2016a).

 

No information regarding the skin sensitisation hazard of ruthenium trichloride hydrate was available; such testing is not considered appropriate as the substance is classified as corrosive to the skin.

 

 

Hazard for the eyes

According to ECHA guidance on the application of CLP criteria (ECHA, 2015), “if a substance or mixture is classified as Skin corrosive Category 1 then serious damage to eyes is implicit and there is no need to proceed with classification for eye effects”. Ruthenium trichloride hydrate is classified for skin effects as corrosive sub-category 1B. Consequently, the compound is classified for eye effects in Category 1 under EU CLP.

 

No dose-response data was available from which to derive a DNEL, therefore a qualitative assessment was considered appropriate. Substances classified for serious eye damage (Category 1 in CLP) should be allocated to the “moderate hazard band on the basis that exposure to such corrosives, eye damaging or irritant substances should be well-controlled”. Therefore, consider recommended RMMs/OCs in Table E.3-1 of ECHA (2016a).

 

 

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

ECHA (2009). European Chemicals Agency. Guidance in a Nutshell: Chemical Safety Assessment. Reference: ECHA-09-B-15-EN. September 2009.http://echa.europa.eu/documents/10162/13632/nutshell_guidance_csa_en.pdf

 

ECHA (2011). European Chemicals Agency. Guidance on information requirements and chemical safety assessment Part B: Hazard assessment. Reference: ECHA-11-G-16-EN. Version 2.1. December 2011.https://echa.europa.eu/documents/10162/13643/information_requirements_part_b_en.pdf

 

ECHA (2012). European Chemicals Agency. Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Reference: ECHA-2010-G-19-EN. Version 2.1. November 2012.http://echa.europa.eu/documents/10162/13632/information_requirements_r8_en.pdf

 

ECHA (2014). European Chemicals Agency. Guidance on information requirements and chemical safety assessment. Chapter R.7c: endpoint specific guidance. Version 2.0. November 2014.http://echa.europa.eu/documents/10162/13632/information_requirements_r7c_en.pdf

 

ECHA (2016a).European Chemicals Agency.Guidance on information requirements and

chemical safety assessment. Part E: Risk Characterisation. ECHA-12-G-04-EN.Version 3.0. May 2016.http://echa.europa.eu/documents/10162/13632/information_requirements_part_e_en.pdf

 

ECHA (2016b). European Chemicals Agency. Guidance on information requirements and chemical safety assessment. Chapter R.16: Environmental exposure assessment. Version 3.0. February 2016.http://echa.europa.eu/documents/10162/13632/information_requirements_r16_en.pdf

 

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.http://www.icmm.com/document/144

 

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.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

DNELs have been derived only for workers, not for consumers/general population. During assessment of the identified uses for ruthenium trichloride hydrate, no uses have been identified in which consumers are exposed to the substance. In all uses with potential consumer exposure due to service life of articles, ruthenium trichloride hydrate is chemically transformed into another substance before reaching the consumers, and the subsequent lifecycle steps after this transformation are included in the assessment of the newly-formed substance. Regarding the general population, and following the criteria outlined in ECHA guidance R16 (2016b), an assessment of indirect exposure of humans via the environment for ruthenium trichloride hydrate has not been performed as the registered substance is manufactured/imported/marketed at <100 tpa and is not classified in category 1 for CMR properties.