Tetraammonium decachloro-μ-oxodiruthenate(4-)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.28 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:

300 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

21.2 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 oral combined repeated-dose with 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:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.4 mg/kg bw/day

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:

300 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

30 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 oral combined repeated-dose with 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:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

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 tetraammonium decachloro-mu-oxodiruthenate in laboratory animals are available, route-to-route extrapolation to calculate an inhalation DNEL from a reliable combined repeated-dose with reproductive/developmental toxicity screening study by the oral route 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 422) combined repeated dose and reproductive/developmental toxicity screening study in rats, involving the gavage administration of tetraammonium decachloro-mu-oxodiruthenate for at least 34 days, no clinical signs of toxicity or any adverse pathological or histopathological effects (including the reproductive organs) were observed at up to 300 mg/kg bw/day (aside from some local effects on the stomach). [Premature death and body weight losses (as well as various clinical signs) were reported for the high dose group (1000 mg/kg bw/day), leading to the termination of these animals after only 2 weeks of treatment.] No effects on reproductive parameters, indications of maternal/foetal toxicity, or developmental effects were observed at any dose level. Thus, the NOAEL for systemic, reproductive and developmental toxicity was 300 mg/kg bw/day (Hansen, 2017). This equates to a NOAEL of 86.68 mg/kg bw/day when expressed as elemental ruthenium based on MWt ratios[1], and is considered protective of general systemic effects, fertility and developmental toxicity. 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 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).

 

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-mu-oxodiruthenate 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 tetraammonium decachloro-mu-oxodiruthenate 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) = 300 mg/kg bw/day*(1/0.38 m3/kg bw/day)*(1/100)*(6.7 m3 [8h]/10 m3 [8h]) = 5.29 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 = 5.29*4 = 21.2 mg/m3

 

Application of the appropriate assessment factors (overall AF 75) to this corrected inhaled NOAEC gives a systemic long-term inhalation DNEL for tetraammonium decachloro-mu-oxodiruthenate of 0.28 mg/m³. This equates to an elemental ruthenium exposure of 0.082 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 identifiedandthere 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 tetraammonium decachloro-mu-oxodiruthenate. In a guideline (OECD TG 425) acute oral toxicity study in female rats, the LD₅₀value was calculated to be 3110 mg/kg bw (Haferkorn, 2016). The compound is not classified for acute oral toxicity 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, tetraammonium decachloro-mu-oxodiruthenate is not classified for acute toxicity according to CLP, 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 tetraammonium decachloro-mu-oxodiruthenate in humans or laboratory animals. Consequently, no worker-DNELs for long-term or acute local effects in the respiratory tract have been calculated.

However, according to ECHA (2016a) guidance (Part E), “since sensitisation is essentially systemic in nature, it is important for the purposes of risk management to acknowledge that skin sensitisation may be acquired by other routes of exposure than dermal. There is therefore a need for cautious use of known contact allergens in products to which consumers or workers may be exposed by inhalation”. Tetraammonium decachloro-mu-oxodiruthenate is classified as a moderate skin sensitiser. 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 tetraammonium decachloro-mu-oxodiruthenate in humans or laboratory animals are available, route-to-route extrapolation to calculate a dermal DNEL from a reliable combined repeated-dose with reproductive/developmental toxicity screening study by the oral route 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”] (Hansen, 2017).

 

The oral NOAEL of 300 mg/kg bw/day equates to a NOAEL of 86.68 mg/kg bw/day for elemental ruthenium (based on MWt ratios), 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 tetraammonium decachloro-mu-oxodiruthenate 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 no evidence that tetraammonium decachloro-mu-oxodiruthenate causes skin irritation (which could facilitate a greater degree of dermal uptake) (Hargitai, 2015). Overall, it is deemed suitably health precautionary to take forward the lower of the two ECHA (2014) default values for dermal absorption, 10%, for the current safety assessment.

 

Dose descriptor starting point (after route to route extrapolation) = NOAEL*(ABS[oral-rat]/ABS[der-human]) = 300 mg/kg bw/day*(1%/10%) = 30 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 tetraammonium decachloro-mu-oxodiruthenate of 0.4 mg/kg bw/day, which equates to an elemental ruthenium exposure of 0.12 mg/kg bw/day.

 

 

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

In a guideline (OECD TG 439) in vitro skin irritation study with tetraammonium decachloro-mu-oxodiruthenate, the test system skin cell viability was calculated to be greater than 50% and the compound was therefore not classified for skin irritation under CLP (Hargitai, 2015).

 

In another guideline (OECD TG 429) study, tetraammonium decachloro-mu-oxodiruthenate induced skin sensitisation in the mouse local lymph node assay (LLNA). The calculated Effect Concentration 3 (EC3) value was 30.9% (Váliczkó, 2015). Consequently, the compound is classified for skin sensitisation as Category 1B, under CLP.

 

According to ECHA (2016a) guidance “moderate skin sensitisers (classified in Sub-category 1B in CLP) are allocated to the moderate hazard category band on the basis that exposure to these moderate skin sensitising substances should be well-controlled”. Therefore, consider recommended RMMs/OCs in Table E.3-1 of ECHA (2016a).

 

 

Hazard for the eyes

In a guideline (OECD TG 405) eye irritation study, tetraammonium decachloro-mu-oxodiruthenate produced immediate significant conjunctival and corneal irritant effects in the eye of a single male rabbit, which were irreversible within 3 weeks (Zelenák, 2015). In a previously conducted in vitro isolated chicken eye irritation study (OECD TG 438), the substance was not severely irritating or corrosive (Gönczöl, 2015). Overall, 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).

[1]MWts: Ru metal, 101.1 g mol^-1; Tetraammonium decachloro-mu-oxodiruthenate, 349.9 g mol^-1

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 tetraammonium decachloro-mu-oxodiruthenate, 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, tetraammonium decachloro-mu-oxodiruthenate 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 tetraammonium decachloro-mu-oxodiruthenate 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.