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Description of key information

Due to its very low water solubility, the absorption after oral, dermal or inhalation exposure to the registered substance, reaction mass of dieuropium tricarbonate and digadolinium tricarbonate and disamarium tricarbonate, is expected to be very limited. The evidence was seen in the available oral mammalian toxicology studies where a lack of systemic toxicity was demonstrated in the bolus dosing regimens up to 1 000 mg/kg bw/day, the highest dose level recommended in the regulatory required repeated dose toxicity studies under REACH. 

Following inhalation exposure to the registered substance, macrophage-mediated translocation and transformation of particles to lung-associated lymph nodes and other organs) may occur in the case of lung overload and insufficient clearance. Faeces is considered to be the primary route of excretion. This may however be considered to be applicable to only a limited extent for the registered substance since its absorption after oral, dermal or inhalation exposure is expected to be minimal.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

ASSESSMENT OF TOXICOKINETIC BEHAVIOUR

Substance name: Reaction mass of dieuropium tricarbonate and digadolinium tricarbonate and disamarium tricarbonate (EC number: 945-733-5)

 

INTRODUCTION

In accordance with the section 8.8.1 of Annex VIII in Regulation (EC) No 1272/2008, the toxicokinetic profile of reaction mass of dieuropium tricarbonate and digadolinium tricarbonate and disamarium tricarbonatewas derived from all available information collated in the dossier. In the absence of experimental studies of the absorption, distribution, metabolism or elimination, the physicochemical properties of the substance and the results of mammalian toxicity studies were used to assess the toxicokinetic properties of the substance.

 

PHYSICOCHEMICAL PROPERTIES

The registered substance is a mixture of three rare earth element compounds as its main constituents; disamarium tricarbonate (68.07 % (w/w)), dieuropium tricarbonate (10.87 % (w/w) and digadolinium tricarbonate (15.32 % (w/w)). Samarium, europium and gadolinium belong to the lightlanthanide series of the periodic table. The substance is a white powder, with a molecular weight ranging 480.75 – 494.53 g/mol and a melting point of > 600 °C. It is poorly water soluble (the water solubility derived as 9.8 mg/L samarium/L in water, 0.2 mg europium/L in water and 0.4 mg/L gadolinium/L in water, resulting in the extrapolated water solubility as the registered substance ranging with the mean water solubility ranging 0.2 – 1.3 mg/L at pH 6.5 and 20 °C; Jean-Baptiste, 2014), which would suggest that the substance is unlikely to be absorbed through the gastro-intestinal tract or skin. Itsparticle size distribution was summarised as D10, D50 and D90 of 1.52 µm, 19.0 µm and 68.4 µm, respectively (sieve method; Demangel, 2017), suggesting its dust contains a small proportion of respirable/inhalable particles. In general, light lanthanides are excreted primarily in the faeces (US EPA, 2009).

 

ABSORPTION:

Oral absorption

Given the multiple component nature of the substance, different components will be absorbed to a different extent, however, the overall poorly water soluble molecules suggest minimal oral absorption. The registered substance is only sparingly water solublewith the mean water solubility ranging 0.2 – 1.3 mg/L at pH 6.5 and 20 °C (Jean-Baptiste, 2014). This is supported by the results of an acute oral toxicity study in female rats where no effects were seen in mortality, clinical observation, bodyweight gain or gross pathology up to the end of 14 days observation periods with the LD50 > 2 000 mg/kg bw (OECD TG 423; Tarcai, 2018).

In a GLP-compliant combined repeated dose toxicity with the reproduction/developmental toxicity screening test (OECD 422; Armour, 2019), the registered substance was administered to Wistar rats by oral gavage at 100, 300 and 1 000 mg/kg bw/day. The NOAEL (No Observed Adverse Effect Level) was 1 000 mg/kg bw/day for systemic toxicity of the parent animals as well as for the reproductive and developmental toxicity of the parents and offspring. Treatment with the registered substance at levels up to 1 000 mg/kg/day was not associated with any changes in clinical observations, body weight gain, food consumption, neurobehavioural findings, haematology, clinical chemistry, reproductive function (including maternal care and litter/pup survival), organ weights, gross necropsy findings or histopathological findings. Some indications of site of contact irritation were seen in the glandular stomach, but this would not be expected to cause a significant alteration in absorption. A lack of systemic toxicity was also seen in the 14-day oral gavage repeated dose toxicity study (Edwards, 2018). Following the administration of registered substance to Wistar rats at the dose levels of 250, 500, 1 000 mg/kg bw/day by oral gavage, no treatment-related changes were seen in the mortality, clinical observations, bodyweight gain, food consumption or gross necropsy up to 1 000 mg/kg bw/day, other than an increase in the water consumption in the dosed animals.The results of the 14-day repeated dose toxicity study and the combined reproduction/developmental toxicity screening test in rats confirm a minimal absorption following bolus repeated dosing. There is no indication for the modified absorption during pregnancy. It can be concluded from the study data that significant absorption via the oral route does not occur. However, in the absence of substance-specific oral absorption data, the oral absorption factor for the registered is set at 100 % as a worst case for risk assessment purposes.

 

Inhalation absorption

In an acute inhalation study in male Wistar rats, nose-only exposure for 4 hours, concentrations as high as 5.12 mg/L air (the MMAD of 3.4 µm) did not cause any mortality with the LC50 > 5.12 mg/L (OECD TG 433; Bowden, 2018). No treatment-related changes were apparent in the clinical observations or necropsy. Body weight losses were evident in all animals on Day 2 post-exposure but the animals showed recovery thereafter.

The particle size distribution of the registered substance ranges < 25 µm to 250 µm using sieve method and approximately 0.243 μm to 400 μm using the laser diffraction method (Demangel, 2017). This suggests that the dust contains some respirable/inhalable particles and therefore the inhalation route of exposure should be taken into consideration for this substance. It is possible that particles could be inhaled and reach both thoracic and alveolar regions of the lungs. Due to its low water solubility, the fractions of bioavailable forms in the bronchoalveolar fluid is expected to be very low. As a consequence, absorption from the lungs to the circulatory system is expected to be minimal. However, as evidenced in some studies for a poor water soluble gadolinium oxide (Abid et al.,2013), the low water solubility could enhance penetration and accumulation of small particles to the lower respiratory tract, potentially leading the particles to be engulfed by alveolar macrophages. The macrophages would then either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues. Those materials deposited in the tracheobronchial region may be swallowed through the mucociliary clearance and follow the gastro-intestinal absorption route. Site of contact irritation within the respiratory epithelium is a possibility based on the effects seen in the glandular stomach in the OECD 422 study.

It can be concluded from the study data that the significant absorption via the inhalation route is unlikely. However, in the absence of any quantitative data, absorption of material that makes it into the alveoli should be considered to be 100%.

 

Dermal absorption

The registered substance would have to dissolve in the moisture of the skin prior to penetrating the skin by diffusion, however, it is known to be only sparingly soluble in water. It is considered highly unlikely that any significant dermal absorption would occur based on the physico-chemical properties of the substance. The registered substance was positive in a battery of in vitro skin sensitisation assays; the h-CLAT test (Gerbeix, 2018) and keratonosens test (Michel, 2018). The substance was confirmed not to be a skin sensitiser in the subsequent guinea pig maximisation test (Tarcai, 2019). This suggests that the particles are unlikely to be absorbed through the skin to lead to the molecular events. Although there is a sign of dermal irritation in the GPMT and the irritation in the glandular region of the stomach in the combined reproductive toxicity study in rats, the substance is not classified for skin irritation based on the in vitro tests using reconstructed human skin model (Orovecz, 2018a; Orovecz, 2018b). Therefore, the topical dermal application of the registered substance would not be expected to enhance the penetration of molecules to a major extent.

In the absence of measured data on dermal absorption, ECHA guidance document R.7c suggests the assignment of either 10 % (MW > 500 and log Pow < -1 or > 4) or 100 % default dermal absorption rates for occupational exposure (ECHA, 2017). For the purpose of risk assessment for the registered substance, a conservative dermal absorption factor of 100 % is applied. However, the currently available scientific evidence on dermal absorption of some metals indicates that lower figures than the lowest proposed default value of 10 % could be expected (HERAG, 2017). A default dermal absorption factor of 0.1 % is proposed for metal cations from dry (dust) exposure and 1.0 % from exposure to liquid/wet media based on the HERAG fact sheet (HERAG, 2017). Based on the inherent properties of the registered substance, the absence of dermal absorption is expected.

 

DISTRIBUTION

There is no evidence to show that the substance is distributed systemically. Despite the positive in vitro results for skin sensitisation, the negative GPMT result suggest the substance was poorly absorbed via the skin.

Following inhalation exposure to the registered substance, macrophage-mediated translocation of particles may occur in the case of lung overload and insufficient clearance.

 

METABOLISM

No studies are available providing information on metabolism/transformation of the registered substance after oral, dermal or inhalation exposure. However, the available oral repeated dose toxicity studies for the substance in rats showed no indication of hepatic enzyme induction or enhanced liver metabolism following the oral gavage administration of the substance up to 1 000 mg/kg bw/day. This may likely be due to a lack of absorption via the oral route for the substance rather than a lack of toxicity from the metabolic transformation of the compounds in the liver. There is no indication for the modified metabolism during pregnancy in the combined repeated dose toxicity in rats for the substance. The in vitro genotoxicity of the registered substance was neither enhanced nor diminished in the presence of S9 metabolising system (Brown, 2018;Lacey, 2018; Orovecz, 2018c).

Following inhalation exposure to the registered substance, macrophage-mediated transformation may occur in the case of lung overload and insufficient clearance.

 

ELIMINATION

No information is available on excretion/elimination after exposure to the registered substance. Light lanthanides are excreted primarily in the faeces (US EPA, 2009). Metal ions are expected to be incorporated into the hair and this route of elimination is likely for the registered substance once it becomes systemically available.

Filov (1993) reported that lanthanoids with higher ionic radius (lighter lanthanoids, such as disamarium, dieuropium and digadolinium) are increasingly stored in the liver and biliary excretion whereas lanthanoids with smaller ionic radius (heavier lanthanoids) are increasingly stored in the bone with urinary excretion based on the observations made after intramuscular administration.

 

CONCLUSION

Due to its very low water solubility, the absorption after oral, dermal or inhalation exposure to the registered substance, reaction mass of dieuropium tricarbonate and digadolinium tricarbonate and disamarium tricarbonate, is expected to be very limited. The evidence was seen in the available oral mammalian toxicology studies where a lack of systemic toxicity was demonstrated in the bolus dosing regimens up to 1 000 mg/kg bw/day, the highest dose level recommended in the regulatory required repeated dose toxicity studies under REACH. 

Following inhalation exposure to the registered substance, macrophage-mediated translocation and transformation of particles to lung-associated lymph nodes and other organs) may occur in the case of lung overload and insufficient clearance. Faeces is considered to be the primary route of excretion. This may however be considered to be applicable to only a limited extent for the registered substance since its absorption after oral, dermal or inhalation exposure is expected to be minimal.


REFERENCES

Abid AD, Anderson DS, Das GK, Van Winkle LS, Kennedy IM 2013: Novel lanthanide-labeled metal oxide nanoparticles improve the measurement of in vivo clearance and translocation. Particle and fibre toxicology 10:1.

 

Armour G 2019: Samarium Gadolinium Europium Carbonate: Combined Repeated Dose Toxicity Study and Reproductive/Developmental Toxicity Screening Study in the Han Wistar Rat by Oral Gavage Administration (study report), Testing laboratory: Envigo CRS Limited, Eye, Suffolk, IP23 7PX, UK, Report no: GY87GP. Owner company; NPM Silmet OÜ, Kesk tn 2, Sillamäe, 40231, Estonia, Report date:

 

Bowden L 2019: Samarium-Europium-Gadolinium Carbonate: Acute (Four-Hour) Inhalation Study in Han Wistar Rats. (study report), Testing laboratory: Envigo, Woolley Road, Alconbury, Huntingdon, Cambridgeshire, PE28 4HS, UK., Report no: DS54QF. Owner company; NPM Silmet OÜ, Kesk tn 2, Sillamäe 40231, Estonia., Report date: Jan 16, 2019

 

Brown R 2018: Samarium-Europium-Gadolinium Carbonate: L5178Y TK+/- Mouse Lymphoma Assay In vitro. (study report), Testing laboratory: Envigo Research Limited., Shardlow Business Park, Shardlow, Derbyshire, DE72 2GD UK., Report no: PD75TM. Owner company; NPM Silmet OÜ, Kesk tn 2, Sillamäe, 40231, ESTONIA., Report date: Aug 17, 2018

 

Demangel B 2017: Physico-chemical tests on Samarium-Europium-Gadolinium Carbonate (study report), Testing laboratory: DEFITRACES Z.A., des Andrés 150, rue Pré-Magne 69126 BRINDAS, FRANCE, Report no: 17-914012-002. Owner company; NPM SILMET OÜ, Kest tn 2, 40231 SILLAMÄE, ESTONIA, Report date: Dec 8, 2017

 

ECHA 2018: Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c: Endpoint specific guidance, Version 3.0, November 2017.

 

Edwards K 2018: Samarium Gadolinium Europium Carbonate: Fourteen Day Repeated Dose Oral (Gavage) Range-Finding Toxicity Study in the Rat. (study report), Testing laboratory: Envigo Research Limited, Shardlow Business Park, Shardlow, Derbyshire, DE72 2GD, UK., Report no: CM06WP. Owner company; NPM Silmet OÜ, Kesk tn 2, Sillamäe, 40231, ESTONIA., Report date: Oct 5, 2018

 

Filov, 1993: Rare-earth elements and their compounds. In: Harmful Chemical Substances, Ellis Horwood Series in Inorganic Chemistry, New York, pp. 326-343.

Gerbeix C 2018: ASSESSMENT OF THE SKIN SENSITIZATION POTENTIAL USING THE HUMAN-CELL LINE ACTIVATION TEST (h-CLAT). (study report), Testing laboratory: Citoxlab France BP 563 - 27005 Evreux - France., Report no: 45375 TIH. Owner company; NPM Silmet OÜ, Kesk tn 2, Sillamae 40231, Estonia., Study number: 17/148-9528, Report date: Mar 13, 2018

 

HERAG 2007: Health risk assessment guidance for metals (HERAG) fact sheet, assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal compounds. EBRC Consulting GmbH, August, 2007.

 

Lacey FE 2018: Samarium-Europium-Gadolinium Carbonate: Chromosome Aberration Test in Human Lymphocytes in vitro. (study report), Testing laboratory: Envigo Research Limited, Shardlow Business Park, Shardlow, Derbyshire, DE72 2GD, UK., Report no: LH08CL. Owner company; NPM Silmet OÜ, Kesk tn 2, Sillamäe, 40231, ESTONIA., Report date: Sep 27, 2018

 

Michel C 2018: KERATINOSENS TEST AN IN VITRO SKIN SENSITISATION ASSAY. (study report), Testing laboratory: CiToxLAB France BP 563 - 27005 Evreux - France., Report no: 45374 TIK. Owner company; Neo Performance Materials SILMET OÜ, Kesk tn 2, Sillamäe 40231, Estonia., Study number: 17/148-951B, Report date: Apr 11, 2018

 

Orovecz B 2018a: Samarium-Europium-Gadolinium Carbonate: In Vitro Skin Irritation Test in the EPISKIN™(SM) Model (study report), Testing laboratory: Citoxlab Hungary Ltd., H-8200 Veszprém, Szabadságpuszta, Hungary, Owner company; NPM Silmet OÜ,Kesk 2, Sillamäe, Estonia, Study number: 17/148-043B, Report date: Jan 18, 2018

 

Orovecz B 2018b: Samarium-Europium-Gadolinium Carbonate: In Vitro Skin Corrosivity Test in the EPISKIN™(SM) Model (study report), Testing laboratory: Citoxlab Hungary Ltd., H-8200 Veszprém, Szabadságpuszta, Hungary, Report no: 17/148-039B. Owner company; NPM Silmet OÜ, Kesk 2, Sillamäe, Estonia, Report date: Jan 18, 2018

 

Orovecz B 2018c: Samarium-Europium-Gadolinium Carbonate: Bacterial Reverse Mutation Assay (study report), Testing laboratory: Citoxlab Hungary Ltd., H-8200 Veszprém, Szabadságpuszta, Hungary, Report no: 17/148-007M. Owner company; NPM Silmet OÖ, Kesk 2, Sillamäe, Estonia, Report date: Feb 1, 2018

 

Tarcai Z 2018: Samarium-Europium-Gadolinium Carbonate: Acute Oral Toxicity Study in Rats (study report), Testing laboratory: Citoxlab Hungary Ltd., H-8200 Veszprém, Szabadságpuszta, Hungary, Report no: 17/148-001P. Owner company; NPM Silmet OÜ (formerly: NPM Silmet AS) Kesk 2, Sillamäe, Estonia, Report date: Jan 16, 2018

 

Tarcai Z 2019: Samarium-Europium-Gadolinium Carbonate: Skin Sensitisation Study in the Guinea Pig using the Magnusson and Kligman Method (study report), Testing laboratory: Citoxlab Hungary Ltd., H-8200 Veszprém, Szabadságpuszta, Hungary, Report no: 19/005-104TM. Owner company; NPM Silmet AS, Kesk Str.2, 40231, Sillamäe, Estonia, Report date: May 28, 2019

 

US EPA (2009) Provisional Peer-Reviewed Toxicity Values for Stable (Nonradioactive) Praseodymium Chloride (CASRN 10361-79-2). US EPA, Cincinnati, United States of America, 17 September 2009.