reaction mass of neodymium carbonate and praseodymium carbonate

Endpoint summary

Description of key information

No toxicokinetic, metabolism or distribution studies on the reaction mass of neodymium carbonate and praseodymium carbonate were available. However, an assessment was made based on the physico-chemical and toxicological properties of the reaction mass as well as on physico-chemical and toxicological data available on the constituents (dineodymium tricarbonate and dipraseodymium tricarbonate) and rare earth analogues  of the reaction mass (dicerium tricarbonate, neodymium oxide and praseodymium(III,IV) oxide) . Based on molecular structure, molecular weight, water solubility and toxicological data, it can be expected that:
- Oral, dermal and inhalation absorption rates will be low. 
- Distribution in the body will be weak. 
- Elimination will occur mainly through faeces, without metabolisation. 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

1

Absorption rate - inhalation (%):

10

Additional information

There are three forms of lanthanides: insoluble (oxides, carbonates), soluble (chlorides, nitrates, acetates) and chelated compounds. The reaction mass is composed of low soluble forms (i.e. carbonates) of neodymium and praseodymium, as illustrated by its slight water solubility (3.93 mg/L at 20°C). Furthermore, the physico-chemical characterisation of the reaction mass show that this solid substance has a high melting point (> 450°C) and a high molecular weight (926 - 940 g/mol). In addition, the substance displays a pH ranging from 6.3 to 6.6 and no particular reactivity in terms of exothermic or oxidizing reactions. However, as the reaction mass is an inorganic substance, no partition coefficient (log Pow / Kow) could be determined.

 

The following basic toxicokinetic information can be extrapolated from the experimental toxicology data available on the reaction mass of neodymium carbonate and praseodymium carbonate, its constituents (i.e. dineodymium tricarbonate and dipraseodymium tricarbonate) and rare earth analogues (e.g. dicerium tricarbonate, neodymium oxide, praseodymium(III,IV) oxide, dilanthanum tricarbonate, cerium dioxide). The detailed argumentation on the read-across strategy and the overall extremely low potential of rare earth (RE) compounds for causing toxicity is given in the read-across justification attached to section 13 of the IUCLID.

 

Absorption

 

There is no data available on the potential absorption rates of the reaction mass of neodymium carbonate and praseodymium carbonate, regardless of the exposure route. Most of the available data on lanthanide absorption come from the soluble lanthanide salts that are expected to be more bioavailable than insoluble forms and thus these results could be considered as worst case scenario for insoluble forms. Based on the physico-chemical and toxicological properties of the reaction mass, it is, however, hypothesised that the reaction mass is weakly absorbed via oral, inhalation or dermal route.

 

Regarding the oral route, two published studies demonstrated that dilanthanum tricarbonate, a rare earth analogue of the reaction mass, displayed an extremely low absorption from the intestinal tract into the systemic circulation when orally administered to human male subjects (0.00127% ± 0.00080%) or male/female rats (0.0007%) as a single dose of 1000 mg or 1500 mg/kg, respectively (Pennick et al., 2006; Damment et al., 2007). Thus, these results on a rare earth carbonate supported the abovementioned hypothesis.

 

The statement of a low oral absorption of insoluble rare earth forms such as the reaction mass was further confirmed by the extremely low toxicity observed in the studies performed with the reaction mass of neodymium carbonate and praseodymium carbonate. Indeed, following a single administration of the reaction mass by oral route (at the limit dose of 2000 mg/kg bw), no relevant systemic clinical sign or changes in body weight were observed (LD50 (rat) > 2000 mg/kg) (Haag V., 2013).

 

Additional data on other rare earth analogues were available and also confirmed the hypothesis of a low oral absorption of the reaction mass. Following repeated dose administration of dicerium tricarbonate, neodymium oxide or praseodymium(III,IV) oxide by the oral route at doses up to 1000 mg/kg bw/day for up to 4 weeks in male rats and 7 - 8 weeks in female rats, there was no systemic relevant sign of toxicity except some haematological and/or clinical chemistry parameters being slightly and/or transiently increased in rats receiving doses higher than 300 mg/kg bw/day (Davies R., 2008; Wallace I., 2012; Laidlaw K., 2013). These clinical changes were generally without pathological correlates and did not manifest themselves clinically. Therefore, these findings were considered as not adverse. The No Observed Adverse Effect Level (NOAEL) was considered to be 450 mg/kg bw/day for dicerium tricarbonate, 300 mg/kg bw/day for neodymium oxide and 1000 mg/kg bw/day for praseodymium(III,IV) oxide. Local stomachal lesions occurred in male and female rats exposed to dicerium tricarbonate (at 450 and 1000 mg/kg bw/day). These treatment-related effects seemed to be a common finding with rare earth carbonates, maybe due to the carbonate form of the substance. Indeed, similar effects were described in male and/or female rats orally exposed to dilanthanum tricarbonate for 104 weeks (Damment et al., 2003). This substance is not included in the read-across approach but is mentioned here for the discussion of local effects which were found to be similar to the ones observed with dicerium tricarbonate. Repeated oral administration of dilanthanum tricarbonate at 1500 mg/kg/day to rats caused increased adenomatous change in the gastric glandular epithelium of rodents. However, these effects were not observed in dogs repeatedly exposed to the same test item (Damment et al., 2003). Thus, such stomachal lesions seem to be related to "portal-of-entry" irritating effects, likely to be specific to rodents and their particular stomach morphology. Damment et al. (2003) precisely considered that the changes observed in rats were an adaptive response to direct administration of dilanthanum tricarbonate into the stomach (gavage) without food. Regarding neodymium oxide, the substance seemed to affect kidneys of only 2 females in the high-dose group (1000 mg/kg bw/day). Nevertheless, as the observation frequency of such effect was weak (2/10 females in only one group), it was not clear whether these adverse effects were truly related to the treatment. As the significance of the kidney findings observed was unclear, and that these effects were of weak frequency, occurred only at 1000 mg/kg bw/day and were not observed in other insoluble and soluble RE salts (e.g. dicerium carbonate, praseodymium(III,IV) oxide, cerium dioxide, dilanthanum tricarbonate, or lanthanum acetate), the effects described in female rats were not taken into account in the rationale on the oral absorption of the reaction mass. The absence of relevant toxic effects thus indicated that the 3 analogues and/or their degradation products or metabolites were weakly absorbed, at most, and were devoid of significant toxicity following oral administration.

 

Regarding the absorption after inhalation exposure, there were no experimental data available on either the reaction mass or its constituents and analogues. However, toxicity studies on the reaction mass and rare earth analogues could be used to determine an absorption patternvia inhalation route. Following a single administration of the reaction mass by inhalation (at the concentration of 5.03 mg/L for 4 hours), no relevant systemic clinical sign or changes in body weight were observed (Matyas A., 2014). Slight labored breathing, wet fur and/or ruffled fur and/or red-brown staining were observed after inhalation exposure but these findings corresponded to poorly specific signs attributed to the restraint and exposure procedures rather than to the test substance. A dark/red diffuse discoloration of lungs was found in all rats exposed to the reaction mass by inhalation; this effect was considered to be related to the test item. As a similar staining was observed on animal fur (i.e. red-brown), the lung discoloration might be the result of the pulmonary deposition of the reaction mass dust, which occurred during the 4-h exposure. It has to be noted that in order to facilitate aerosolisation and reach the respirable range of 1 - 4 µm, the test substance was ground which thus reduced its particle size (MMAD) from 127.94 µm to 2.72 µm. As a consequence, the ground reaction mass could reach and deposit in deeper regions of the respiratory tract than normally expected with the substance such as produced.

In addition, a repeated dose toxicity study on the analogue neodymium oxide was available for the inhalation route (Davison and Ramsey, 1965). Mice and guinea pigs daily exposed to 30 mg/m³ neodymium oxide for up to 120 days showed no relevant systemic toxicity, suggesting a weak absorption. Moreover, data on another lanthanide insoluble form (i.e. cerium dioxide) showed that following inhalation exposure of up to 507.5 mg/m³ cerium dioxide for up to 90 days in rats, the only effects observed were consistent with "portal-of-entry" effects and a lung-overload inflammatory response syndrome. No systemic effect resulting from significant absorption was evidenced (Viau A., 1994).

 

No specific study on dermal absorption was available either on the reaction mass or on its constituents and analogues. However, as the reaction mass or neodymium carbonate and praseodymium carbonate is an inorganic substance (no log Pow / Kow) with low water solubility (3.93 mg/L), high melting point (> 450°C) and a relatively high molecular weight (~467.09 g/mol), no significant dermal absorption is expected. As an illustration, following acute exposure of rats to a dermal dose of 2000 mg/kg bw of dicerium tricarbonate, an analogue of the reaction mass, no noteworthy systemic clinical sign was observed up to 14 days after application (LD50 > 2000 mg/kg bw), suggesting a low absorption of this rare earth carbonate through dermal route (Rokh N., 2007).

 

Overall, given the physico-chemical properties and the toxicological data abovementioned on the reaction mass of neodymium carbonate and praseodymium carbonate and its constituents and analogues, the oral, inhalation and dermal absorption rates of the reaction mass are expected to be extremely low.

 

Distribution

 

There is no data available on the potential distribution of the reaction mass of neodymium carbonate and praseodymium carbonate, regardless of the exposure route. However, as oral, inhalation and dermal absorption rates of the test substance are expected to be extremely low, its biodistribution is thus supposed to be highly limited regardless of the exposure route.

 

Regarding the oral route, it is hypothesised that, based on the physico-chemical properties of insoluble rare earths, substances like RM, its constituents and analogues will be poorly distributed. However, although poorly absorbed from the gastrointestinal tract, bioavailable dilanthanum tricarbonate was described as being accumulated in liver and, in lesser extent, in bone of rats repeatedly exposed via oral route (Behets et al., 2004; Slatopolsky et al., 2005; Bervoets et al., 2007). Nevertheless, since the assessment of bioaccumulation potential of lanthanum in aquatic organisms indicated a low potential for bioaccumulation as well as decreasing bioaccumulation potential when ascending the food chain, it can be assumed that lanthanum insoluble compounds most likely have a low accumulation potential in humans too.

 

Our hypothesis of a low distribution was further supported by data on analogous substances: praseodymium (III, IV) oxide and dicerium tricarbonate. Following repeated administration of either praseodymium(III, IV) oxide or dicerium tricarbonate by the oral route at doses up to 1000 mg/kg bw/day for up to 8 weeks in rats, only loco-regional "portal-of-entry" effects were observed in the case of dicerium tricarbonate, with stomachal lesions observed in rats from both sexes (Davies R., 2008; Wallace I., 2012). These effects were probably illustrative of an adaptative response subsequent to the stomach deposition of the test item given in high doses as bolus by gavage (see details above in the “Absorption” section). This effect was not observed with praseodymium(III,IV) oxide for which the NOAEL was set at 1000 mg/kg bw/day. In both studies, no relevant signs of distribution were evidenced (no systemic effect and histopathology analyses show no effect on organs). A third study was available on neodymium oxide daily administered to male and female rats by the oral route (Laidlaw K., 2013). In this study, treatment associated findings were described in the kidney of 2 females dosed at 1000 mg/kg bw/day: marked bilateral cortical tubular necrosis and mild diffuse cortical basophilic tubules (bilateral) were recorded in one animal and mild diffuse cortical basophilic tubules (bilateral) were noted in another. These observations could suggest a distribution of neodymium oxide to the renal tissues. However, as the observation frequency of the renal effects was weak, it was not clear whether these adverse effects were truly related to the treatment. Moreover, repeated dose toxicity studies on other rare earth carbonates and oxides did not show such adverse effects (e.g. dicerium tricarbonate, praseodymium (III,IV) oxide, cerium dioxide).

 

Regarding the inhalation route of exposure, a study was available on the analogue neodymium oxide (Davison and Ramsey, 1965). Daily administered to mice and guinea pigs by inhalation for up to 120 days, the test item displayed only a local retention in the lungs of exposed animals without any systemic effects. This local retention in lungs was also described in a repeated dose toxicity study performed with another analogue, cerium dioxide, via inhalation route (Viau A., 1994). These results demonstrated that no or rare distribution of insoluble rare earth forms occurred after repeated inhalation exposure. 

 

No specific study on distribution following dermal exposure was available on the reaction mass or on its constituents and analogues. However, as the reaction mass or neodymium carbonate and praseodymium carbonate is an inorganic substance (no log Pow/Kow) with low water solubility (3.93 mg/L), high melting point (> 450°C) and a high molecular weight (926 - 940 g/mol), no systemic distribution via the dermal route is expected. As an illustration, following acute exposure of rats to a dermal dose of 2000 mg/kg bw of dicerium tricarbonate, an analogue of the reaction mass, the macroscopic examination of the main organs from exposed animals revealed no apparent abnormalities (LD50 > 2000 mg/kg bw), suggesting no or low distribution of this rare earth carbonate through dermal route (Rokh N., 2007).

 

Overall, based on the physico-chemical properties and the toxicological data abovementioned on the reaction mass of neodymium carbonate and praseodymium carbonate and its constituents and analogues, the systemic distribution of the reaction mass is expected to be extremely low regardless of the administration route. Moreover, given its particle size distribution (90.47 µm), low water solubility (3.93 mg/L) and low absorption rate, the reaction mass of neodymium carbonate and praseodymium carbonate is expected to show a minimal pulmonary deposition when inhaled and thus an extremely low distribution from the lungs.

 

Metabolism

 

The presence or absence of exogenous metabolic activation system made no difference in the results of in vitro mutagenicity testing on the reaction mass of neodymium carbonate and praseodymium carbonate. No conclusion can therefore be made regarding the transformation of the test substance and/or its degradation products or metabolites by hepatic microsomal fractions. However, it was previously demonstrated that lanthanum, as an element or ion, was neither created not destroyed within human body and it was neither a substrate nor an inhibitor of cytochrome P450 (Pennick et al., 2003).

 

Elimination

 

There is no data available on the elimination of the reaction mass of neodymium carbonate and praseodymium carbonate, regardless of the exposure route. Nevertheless, as the reaction mass is an inorganic solid substance with low water solubility (3.93 mg/L) and a molecular weight above 300, it can be first hypothesised that the test substance will not be excreted in the urine but rather eliminated through faeces.

 

Damment and Pennick (2007) demonstrated that the analogue dilanthanum tricarbonate was almost completely excreted through faeces (97.8 ± 2.84%) when orally administered as a single dose of 600 mg/kg in male rats. The small absorbed fraction was excreted predominantly via the liver into the bile (Pennick et al., 2006; Damment and Pennick, 2007). Biliary elimination (80%) and direct transport across the gut wall into the lumen (13%) represented the main routes of elimination. Renal excretion of the absorbed fraction was less than 2% (Behets et al., 2004).

 

Overall, based on the physico-chemical properties of the reaction mass of neodymium carbonate and praseodymium carbonate and the toxicokinetic data on the analogue dilanthanum tricarbonate, elimination of the reaction mass is expected to occur, as such (without metabolisation), mainly through faeces, when excreted following oral or inhalation exposure.

 

 

In conclusion, and based on the available information (e.g., from physico-chemical tests, from literature studies or from toxicological studies), for absorption, values of 10% were proposed for the oral and inhalation route of both substances except for dermal absorption that is expected to be even lower (1%). These assumptions are also supported by the low (eco-)toxicity of the reaction mass of neodymium carbonate and praseodymium carbonate.