Neodymium oxide

Endpoint summary

Description of key information

The substance neodymium oxide is a light blue powder and has the molecular formula Nd2O3 with a molecular weight of 336.48 g/mol. It has a melting point of 2233 ºC and has very low water solubility of 7.8 µg/L.  Effects in a repeat-dose toxicology study indicate some oral absorption, but based on physical chemical properties and experimental data with similar substances, absorption is antipated to be very low, and  the following values are adopted: oral absorption is estimated at <0.1%, inhalation absorption is estimated at <0.1% and dermal absorption is estimated at <0.001%.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

0.1

Absorption rate - dermal (%):

0.001

Absorption rate - inhalation (%):

0.1

Additional information

Introduction

 

There are three forms of lanthanide compounds: “insoluble” (oxides, carbonates), soluble (chlorides, nitrates, acetates) and chelated compounds (e.g. citrates).  Neodymium Oxide is an insoluble form of neodymium (III) as illustrated by its low water solubility (0.0078 mg/L).

 

Systemic availability of neodymium oxide depends on its ability to be absorbed across body surfaces. Factors that affect this process include water solubility, lipophilicity (measured by the partition coefficient, Kow, which is however not applicable to inorganic compounds), and molecular size. The substance has a molecular weight of 336.48 g/mol. . Neodymium oxide has an extremely low water solubility of 0.0078 mg/L. For inorganic substances no meaningful Kows can be determined.

Oral absorption

 

No direct oral absorption data exists for neodymium oxide, but some possible evidence for absorption was found in the OECD 422 study (Laidlaw, 2013) with neodymium oxide:

 

In the OECD 422 oral gavage study by Laidlaw (2013), which was GLP-compliant, the NOAEL for males was 1000 mg/kg bw/d and the NOEL for females was 300 mg/kg bw/d. In females, the effects observed at the next dose up (1000 mg/kg bw/day) were a treatment-related findings in the kidney of 2/10 females, where bilateral cortical tubular necrosis and/or diffuse cortical basophilic tubules were observed. In the most affected females, changes in clinical chemistry parameters (i.e. higher blood levels of creatinine and urea) supported the renal pathology. In males there was a slight decrease in red blood cell count and haematocrit and statistically significant decreases in total protein and albumin and an increase in phosphate at 1000 mg/kg bw/day. Glucose was increased when compared to Controls at ≥ 300 mg/kg/day. There were no histological correlates for these changes and no other findings were noted. 

Treatment up to and including the limit dose of 1000 mg/kg bw/day had no effects on male or female reproductive performance or on foetuses.

 

The kidney pathology could indicate some degree of oral absorption at least in females, but the extreme dose required (1000 mg/kg) to elicit the effects indicates the absorption is still likely to be low. Comparing the results of this study against the absence of toxicity in comparable studies used in the Toxicokinetics assessments for lanthanum oxide (water solubility 0.0696 mg/L) and cerium dioxide (water solubility 0.000123 mg/L) which were based on experimental data, the oral absorption of neodymium oxide (water solubility 0.0078 mg/L) is interpreted as being higher than cerium oxide, but based on the comparative water solubility, unlikely to be greater than that for lanthanum oxide. Therefore the oral absorption is considered to be <0.1% (translating to <1 mg/kg absorption at 1000 mg/kg).

 

Dermal absorption

 

No studies investigating the absorption of neodymium oxide through the skin are available. Given its very low solubility and that it is a solid, dermal absorption is expected to be minimal (<0.001%) for neodymium oxide given the results of dermal absorption study with a highly soluble rare earth salt (cerium chloride) which is also of lower molecular weight than neodymium oxide (246.48 vs 336.48) (and hence could considered a worst-case estimate for neodymium oxide) : 

 

Inabaet al., (1979) studied the uptake of radiolabeled Cerium chloride (¹⁴⁴Ce) through stripped and intact guinea pig skin during a 3 hour exposure period. The uptake through intact skin was negligible (<= 0.001%) while from stripped skin ca. 4% of the radioactivity was absorbed. The study demonstrated that absorption of a soluble cerium salt, cerium trichloride through intact guinea pig skin is very low (<= 0.001%). It can be assumed that the uptake of less soluble compounds is even lower, and lower still through human skin which is typically less permeable than test species. It can therefore be concluded that dermal absorption of neodymium oxide through intact human skin can be considered negligible.

A skin sensitisation study with neodymium oxide (Henzell, 2012), was negative, which is consistent the premise that there is practically no dermal absorption. 

 

It can be concluded from the above data that, significant absorption of neodymium oxide via the dermal route is unlikely, and is considered to be <0.001%.

 

Inhalation absorption

 

There is no data for neodymium oxide. Given the absence of any significant absorption for cerium oxide which might be considered a reasonable surrogate (see below) and particle size/mucociliary escalator considerations which result in rapid pulmonary clearance and convert the inhalation exposure to an oral exposure, inhalation absorption will be very low and <0.1% (as for oral absorption) if complete clearance can be affected from the lungs. For reference the neodymium oxide particle sizes typically encountered by workers are in the range of 2-8 µm, and clearance would be more rapid than particles of 0.06 -0.11 µm detailed in Kanapilly and Luna (1975) below.

For cerium oxide inhalation absorption was characterised on the basis of the following:

 

As poorly soluble particles, cerium oxide particles behave like other airborne particles, depositing within the respiratory tract based on aerodynamic character (Schulzet al., 2000). Depending on particle size, inhaled insoluble particles of cerium oxide may lodge in the lung and remain there for long periods slowly dissolving, or may be phagocytosed and end up in the lymphoreticular system (Donaldson and Borm, 2006). 

 

Lundgrenet al. (1992) exposed adult F344/Crl rats to [¹⁴⁴Ce]-cerium oxide aerosol for 5–50 minutes, with clearance of approximately 90% of the initial body burden by 7 days. Kanapilly and Luna (1975) exposed hamsters to [¹⁴⁴Ce]-cerium oxide aerosols with particle activity median aerodynamic diameters of 0.11 and 0.06 μm and observed decreases in initial body burden of 95 and 60%, respectively, 4 days after exposure. Differences in clearance rates are likely to have been dependent on particle size differences, with the smaller particles taking more time for elimination. Particle size used in the study presented in the cerium oxide IUCLID dossier (Viau, 1994), are likely to be cleared more thoroughly still within the same time frame. 

 

The results of the following studies are also consistent the premise that there is no practical inhalation absorption:-

 

Following repeated dose administration of cerium oxide by inhalation (Viau, 1994) (nose only) at concentrations up to 0.5075 mg/L (507.5 mg/m³), MMAD = 1.8-2.2 µm, for 13 weeks in rats, only loco-regional "portal-of-entry" effects were observed, as changes in segmented neutrophil counts, lung and spleen weights, lung and lymph node gross appearance at necropsy and respiratory tract and lymphoreticular system histopathology. These effects were illustrative of an inflammatory response subsequent to lung overloading with poorly soluble particles, without functional impairment of the immune system. No relevant systemic effects specific to cerium dioxide were evidenced. 

 

An acute inhalation study with neodymium oxide (Griffiths, 2012) in rats up to the limit dose of 5 mg/L produced nothing other than non-specific clinical signs associated with breathing a fine dust. These results are consistent with minimal absorption from the lungs.

 

Overall an inhalation exposure is converted to an oral exposure and considered to be the same as oral absorption at <0.1% for neodymium oxide.

Distribution

 

No data was available for neodymium oxide although it is likely to be similar to cerium and lanthanum oxides and soluble forms of these metals may give an indication of distribution.

 

Cerium oxide:

 

Lundgrenet al.(1992) exposed adult F344/Crl rats to radiolabelled-cerium oxide aerosol for 5–50 minutes or to bimonthly exposures of 25 minutes for 1 year; rats were sacrificed at 1 hour and 3, 7, 14, 28, 56, 112, 224, 448, 560, and 672 days after exposure. The lungs, heart, liver, spleen, kidney, and skeleton (remaining carcass) were measured for cerium. Cerium was detected in the liver and skeleton in increasing percentages of body burden with respect to time, while cerium was not detected in the spleen and kidneys.

 

Soluble forms of cerium:

 

Although soluble cerium appears to be poorly absorbed from the GI tract, the bone and liver were the organs with the highest cerium levels in rats following oral gavage of cerium chloride (Shiraishi and Ichikawa, 1972). The concentration of cerium in the kidney, liver, lung, and spleen of male ICR mice was significantly elevated relative to controls following 6 and 12 weeks of oral exposure to dietary concentrations of 20 or 200 ppm cerium chloride (Kawagoeet al., 2005). The lung and spleen contained the highest cerium concentrations in male ICR mice. Manoubiet al. (1998) gave a single intragastric dose of stable cerium nitrate (20 mg/mL) to Wistar rats. Three hours after dosing, cerium was found in the lysosomes of the duodenal villosity but not in the liver or spleen. In 1-day-old Sprague-Dawley rats given a single intragastric dose of [¹⁴¹Ce]-ceric nitrate of unreported concentration, Inaba and Lengermann (1972) found cerium to be localized centrally, likely in the vacuoles, within epithelial cells of the small intestine. 

 

 

Lanthanum oxide:

 

After oral administration of soluble lanthanum salts it was reported that in lysosomes of the intestinal epithelial cells insoluble lanthanum phosphate is formed which is not systemically available. Normal cell exfoliation results in excretion in the faeces again (Florentet al., 2001; Fehriet al., 2005). The small fraction of absorbed lanthanum is extensively (> 99.7%) bound to plasma proteins (Damment and Pennick, 2007). After oral administration (drinking water) of radiolabeled lanthanum chloride to rats some distribution apart from teeth and the GI tract was also observed mainly in lungs, kidney, liver, spleen and bones (Rabinowitzet al, 1988).

Following intravenous infusion of lanthanum trichloride in humans Lanthanum was widely distributed to tissues with an apparent volume of distribution of 164 ± 84 L, from where it was eliminated at a slower rate.

  

Metabolism

There is no data for neodymium oxide, however, some data was available for a closely related material, cerium. In their toxicological review of cerium, the US EPA (EPA, 2009) did not consider that any change in the oxidation state of the cerium cation had been demonstrated in the data they had examined. Neodymium oxide as an inorganic compound is not expected to undergo significant metabolism.

 

This was also supported for neodymium in-so-far-as the presence or absence of exogenous metabolic activation system made no difference in the results ofin vitromutagenicity testing (Haddouk, 2007; Morris, 2013), which at least rules-out the potential for toxicologically relevant redox cycling in these assays.

 

In addition, in an OECD 422 study conducted for neodymium oxide by oral route (Laidlaw, K (2013), no microscopic finding in the liver or kidneys illustrative of metabolic activity were seen following repeated dose administration by the oral route at doses up to the limit dose of 1000 mg/kg. Kidney pathology was observed in only 2 females at the limit dose in which bilateral cortical tubular necrosis and/or diffuse cortical basophilic tubules but this is not informative about any oxidation of the neodymium ion.

  

Elimination

 

Given the limited oral absorption, ingested material (via either oral or inhalation routes) is likely to pass through the GIT and excreted in the faeces . From the repeat dose toxicity study where there was some kidney damage in 2 female rats, it cannot be excluded that a small part of the absorbed dose is excreted in the faeces, if these findings are really test substance related.

 

 

References

 

Damment SJ and Pennick M. (2007) Systemic lanthanum is excreted in the bile of rats. Toxicol Lett.171(1-2):69-77.

 

EPA (2009). Toxicological Review of Cerium Oxide and Cerium Compounds (Vol. 2). US Environmental Protection Agency EPA/635/R-08.

 

Fehri, E. et al. (2005). Lanthanides and microanalysis: effects of oral administration of two lanthanides: ultrastructural and microanalytical study. Arch Inst Pasteur 82: 59-67.

 

Florent, C. et al. (2001). Analytical microscopy observations of rat enterocytes after oral administration of soluble salts of lanthanides, actinides and elements of group III-A of the periodic chart. Cell Mol Biol (Noisy-le-grand) 47: 419-425.

 

Griffiths DR (2012) Neodymium Oxide: Acute Inhalation Toxicity (Nose Only) Study in the Rat.  Harlan laboratories, Report No.: 41205873.  GLP.  Unpublished

 

Haddouk, H. (2007) Bacterial Reverse Mutation Test. CIT, Evreux, France. Study no. 41203047. GLP. Unpublished

 

Henzell G (2012) Neodymium oxide: Local Lymph Node Assay.  Harlan Laboratories, Report No.: 41203045.  GLP.  Unpublished

 

Inaba, J; Lengermann, FW. (1972) Intestinal uptake and whole-body retention of 141Ce by suckling rats.  Health Phys 22:169–175

 

Inaba, J., Yasumoto, M.S. (1979). A kinetic study of radionuclide absorption through damaged and undamaged skin of the guinea pig. Health Phy 37:592-595.

 

Kanapilly, GM, Luna, RJ. (1975)  Deposition and retention of inhaled condensation aerosols of¹⁴⁴CeO2 in Syrian hamsters.  In: Boecker, BB; Rupprecht, FC; eds. Annual report of the Inhalation Toxicology Research Institute.

 

Kawagoe, M; Hirasawa, F; Wang, SC; et al. (2005) Orally administered rare earth element cerium induces metallothionein synthesis and increases glutathione in the mouse liver.  Life Sci 77:922–937.

 

Laidlaw, K (2013) A Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening of Neodymium Oxide by Oral Gavage in Rats.  Charles River Laboratories, Report No.:495985.  GLP.  Unpublished.

 

Lundgren, D. L., Hahn, F. F., Diel, J. H., & Snipes, M. B. (1992). Repeated Inhalation Exposure of Rats to Aerosols of: I. Lung, Liver, and Skeletal Dosimetry. Radiation research, 132(3), 312-324.

 

Manoubi, L; Hocine, N; Jaafoura, H; et al. (1998) Subcellular localization of cerium in intestinal mucose, liver, kidney, suprarenal and testicle glands, after cerium administration in the rat.  J Trace Microprobe Techniques 16(2):209–219.

 

Morris, A. (2013) Neodymium oxide: CHO HPRT FORWARD MUTATION ASSAY. Harlan Laboratories Ltd., Shardlow, UK. Study no. 41203047.GLP. Unpublished

  

Rabinowitz, J. L., Fernandez‐Gavarron, F.,& Brand, J. G. (1988). Tissue uptake and intracellular distribution of 140‐lanthanum after oral intake by the rat. Journal of Toxicology and Environmental Health, Part A Current Issues, 24(2), 229-235.

 

Schulz, H; Brand, P; Heyder, J. (2000) Particle deposition in the respiratory tract.In: Gehr, P; Heyder, J; eds. Particle-lung interactions.  New York, NY: Marcel Dekker; pp. 229–290.

 

Shiraishi, Y; Ichikawa, R. (1972) Absorption and retention of¹⁴⁴Ce and 95Zr-95Nb in newborn, juvenile and adult rats.  Health Phys 22:373–378

 

Viau A (1994) A 13-week inhalation toxicity and neurotoxicity study by nose-only exposure of a dry powder aerosol of Ceric Oxide in the albino rat. Bio-Research Laboratories Ltd. Montréal, Canada. Report no. 90831. GLP.  Unpublished