Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
genetic toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
genetic toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

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

Diammonium sodium hexakis(nitrito-N)rhodate showed no evidence of genotoxicity in vitro (Lloyd, 2014a,b; McGarry, 2014). No substance-specific in vivo genotoxicity data were identified. However, on a precautionary basis, the substance is self-classified as a category 2 mutagen based on its anticipated speciation in vivo; this is anticipated to involve decomposition and dissolution in the gastric environment to form chloro-aqua Rh(III) species. This is a similar behaviour to rhodium trichloride which has a positive in vivo micronucleus test (Rodrigo, 2007) and is self-classified as Muta. 2).

 

This implies that assessing the risk of exposure to diammonium sodium hexakis(nitrito-N)rhodate via inhalation to human health, from a quantitative DNEL based on the findings of a short-term repeated dose toxicity study, may not be protective. A DMEL approach is arguably more appropriate. However, since no adequate studies assessing carcinogenicity were available for the substance, no robust DMEL can be calculated. Although the use of read across, subchronic studies or the threshold of toxicological concern (TTC) concept may be explored as alternatives in such a derivation, no specific ECHA guidance is available for these approaches (ECHA, 2012a). Moreover, no suitable read-across candidates or subchronic studies were identified and the TTC concept is not applicable to inorganic compounds. Consequently, based on the mutagenicity classification, the most appropriate and health precautionary approach was deemed to be to formulate a qualitative assessment (with ‘high hazard’ banding and recommended RMMs/OCs in Table E.3-1 of ECHA, 2012b) for systemic exposure to workers by inhalation. (It is anticipated that this qualitative approach with its associated stringent RMMs/OC requirements “will likely be sufficient to also cover for other relevant effects for which DNELs can be derived, for all routes of exposure”). However, to ensure that this qualitative assessment is appropriate, a quantitative DNEL approach has also been evaluated (see below).

As no relevant data on effects of repeated inhalation exposure to diammonium sodium hexakis(nitrito-N)rhodate 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 diammonium sodium hexakis(nitrito-N)rhodate for at least 28 days, no clinical signs of toxicity or any adverse pathological or histopathological effects were observed. No test item-related microscopic changes were noted in the reproductive organs. Moreover, no effects on reproductive parameters or indications of maternal/foetal toxicity were observed at any dose level. Thus, the NOAEL for systemic, reproductive and developmental toxicity was the highest tested dose (1000 mg/kg bw/day) (Török-Bathó, 2015). This equates to a NOAEL of 234.99 mg/kg bw/day when expressed as elemental rhodium based on MWt ratios[1], and is considered protective of fertility and developmental toxicity.

 

In the absence of data allowing quantitative comparison between the extent of absorption following inhalation and oral exposure, this derivation utilises the REACH guidance default assumption that the absorption percentage for the oral route is half that of the inhalation route, and a default factor of 2 is proposed for absorption differences in the case of oral-to-inhalation extrapolation.

 

Corrected inhalatory NOAEC (worker, 8 h exposure/day) = oral NOAEL*(1/sRv[rat])*(ABS[oral-rat]/ABS[inh-human]) *(sRV[human]/wRV) = 1000 mg/kg bw/day*(1/0.38 m3/kg bw/day)*(1/2)*(6.7 m3 [8h]/10 m3 [8h]) = 881.6 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 = 881.6*4 = 3526 mg/m3

 

Application of the appropriate assessment factors (overall AF 75)[2]to this corrected inhaled NOAEC gives a systemic long-term inhalation DNEL for diammonium sodium hexakis(nitrito-N)rhodate of 47.0 mg/m3. This equates to an elemental rhodium exposure of 11.0 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 diammonium sodium hexakis(nitrito-N)rhodate. In a guideline (OECD TG 423) acute oral toxicity study in female rats, the LD50value was found to exceed 2000 mg/kg bw (Matting, 2014). 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, 2012b). However, diammonium sodium hexakis(nitrito-N)rhodate 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 diammonium sodium hexakis(nitrito-N)rhodate in humans or laboratory animals. Consequently, no worker-DNELs for long-term or acute local effects in the respiratory tract have been calculated. Further, the substance is not classified as a skin irritant or skin sensitiser.

 

 

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

Diammonium sodium hexakis(nitrito-N)rhodate showed no evidence of genotoxicity in vitro (Lloyd, 2014a,b; McGarry, 2014); no substance-specific in vivo genotoxicity data were identified. However, on a precautionary basis, the substance is self-classified as a category 2 mutagen based on its anticipated speciation in vivo; this is anticipated to involve decomposition and dissolution in the gastric environment to form chloro-aqua Rh(III) species. This is a similar behaviour to rhodium trichloride which has a positive in vivo micronucleus test (Rodrigo, 2007) and is self-classified as Muta. 2).

 

This implies that assessing the risk of exposure to diammonium sodium hexakis(nitrito-N)rhodate by the dermal route to human health, from a quantitative DNEL based on the findings of a short-term repeated dose toxicity study, may not be protective. A DMEL approach is arguably more appropriate. However, since no adequate studies assessing carcinogenicity were available for the substance, no robust DMEL can be calculated. Although the use of read across, subchronic studies or the TTC concept may be explored as alternatives in such a derivation, no specific ECHA guidance is available for these approaches (ECHA, 2012a). Moreover, no suitable read-across candidates or subchronic studies were identified and the TTC concept is not applicable to inorganic compounds. Consequently, based on the mutagenicity classification, the most appropriate and health precautionary approach was deemed to be to formulate a qualitative assessment (with ‘high hazard’ banding and recommended RMMs/OCs in Table E.3-1 of ECHA, 2012b) for systemic exposure to workers by the dermal route. (It is anticipated that this qualitative approach with its associated stringent RMMs/OC requirements “will likely be sufficient to also cover for other relevant effects for which DNELs can be derived, for all routes of exposure”). However, to ensure that this qualitative assessment is appropriate, a quantitative DNEL approach has also been evaluated (see below).

 

As no relevant data on effects of repeated dermal exposure to diammonium sodium hexakis(nitrito-N)rhodate 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”] (Török-Bathó, 2015).

The oral NOAEL of 1000 mg/kg bw/day equates to a NOAEL of 234.99 mg/kg bw/day for elemental rhodium (based on MWt ratios), and is considered protective of 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. However, for this oral-to-dermal extrapolation, a figure of 100% oral absorption has been used based on bio-elution data in simulated gastric fluid (Rodriguez, 2012).

 

The analogous bio-elution (proportion of metal release from total metal content) of diammonium sodium hexakis(nitrito-N)rhodate in simulated dermal fluid was 15.95% and 38.4% after 24 and 168 hours, respectively (Rodriguez, 2012); no substance-specific dermal absorption data are available. However, an in vitro permeation study on a related rhodium salt, rhodium trichloride, indicated a low degree of dermal absorption [about 1.2%]. Using a RhCl3 solution (0.3 mg Rh/ml in synthetic sweat) and full thickness skin from four Caucasian females, 1.2% (as a mean value) diffused into the skin in 24 hr; the receptor solution contained a further 0.0001% (Franken et al., 2014). Apart from this study, very little information appears to be available regarding dermal absorption of rhodium compounds.

 

Overall, a high dermal bioavailability is unlikely, notably given the low dermal penetration expected for metals (ICMM, 2007) as well as experimental dermal penetration data (human in vitro study) for a related surrogate [indicating about 1.2% dermal absorption], and considering the observed lack of skin irritation potential (which could facilitate a greater degree of dermal uptake) (Kiss, 2012a). 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]) = 1000 mg/kg bw/day*(100%/10%) = 10,000 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 diammonium sodium hexakis(nitrito-N)rhodate of 133.3 mg/kg bw/day, which equates to an elemental rhodium exposure of 31.3 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 diammonium sodium hexakis(nitrito-N)rhodate, 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 (Kiss, 2012a).

 

In another guideline (OECD TG 429) study, diammonium sodium hexakis(nitrito-N)rhodate failed to induce skin sensitisation in the mouse local lymph node assay (LLNA) at up to concentrations of 25% (Henzell, 2013). Consequently, the compound is not classified for skin sensitisation under CLP.

 

 

Hazard for the eyes

In a guideline (OECD TG 405) eye irritation study, diammonium sodium hexakis(nitrito-N)rhodate produced slight but reversible effects on the eye in rabbits (Kiss, 2012c). In a previously conducted in vitro isolated chicken eye irritation study (OECD TG 438), the substance was not severely irritating or corrosive (Kiss, 2012d). The compound is not classified for eye irritation under EU CLP.

 

Overall, diammonium sodium hexakis(nitrito-N)rhodate is not expected to present a hazard to the eyes of workers.


[1]MWts: Rh metal, 102.9 g mol-1; Diammonium sodium hexakis(nitrito-N)rhodate, 437.9 g mol-1

[2]Comprising AFs of 1 (for dose response relationship: default ECHA AF for the use of a NOAEL from a well-conducted combined repeated-dose with reproductive/developmental toxicity screening study), 6 (for differences in duration of exposure: default ECHA AF for subacute [28-day] to chronic extrapolation), 1 (for interspecies differences [allometric scaling]: default ECHA AF for rat for toxicokinetic differences in metabolic rate is not required), 2.5 (for other interspecies differences: default ECHA AF for remaining toxicokinetic differences [not related to metabolic rate] and toxicodynamic differences), 5 (for intraspecies differences: default ECHA AF for [healthy] worker), 1 (for the quality of the whole database: default ECHA AF since the human health effects data are reliable and consistent, and confidence in the database is high) and 1 (for remaining uncertainties).

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 diammonium sodium hexakis(nitrito-N)rhodate, 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, diammonium sodium hexakis(nitrito-N)rhodate 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 (2016), an assessment of indirect exposure of humans via the environment for diammonium sodium hexakis(nitrito-N)rhodate 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.