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Description of key information

The substance dierbium trioxide is a pink powder and has the molecular formula Er2O3 with a molecular weight of 382.5169 g/mol.  It is commonly regarded as “insoluble” in water (although one source (Merck Index) indicates 4.9 mg/L at 29°C), but soluble in mineral acids (ChemSpider).
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 <1%, inhalation absorption is estimated at <1% and dermal absorption is estimated at <0.01%.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
1
Absorption rate - dermal (%):
0.01
Absorption rate - inhalation (%):
1

Additional information

Introduction

 

There are three forms of lanthanide compounds: “insoluble” (oxides, carbonates), soluble (chlorides, nitrates, acetates) and chelated compounds (e.g. citrates).  Erbium oxide is considered as an insoluble form of erbium (III) (water solubility = 4.9 mg/L at 29°C).

 

Systemic availability of erbium 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 382.52g/mol. Erbium oxide has a low water solubility of 4.9 mg/L measured at 29°C. For inorganic substances no meaningful Kows can be determined.

 

Oral absorption

 

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

 

In the OECD 422 oral gavage study by Brady (2013), which was GLP-compliant, the NOAEL for male reproductive and systemic toxicity, was 1000 mg/kg bw/d (a dose-related decrease in Lactate Dehydrogenase (LDH) was seen at ≥ 300 mg/kg bw/day, but in isolation was not considered toxicologically significant). For females, the NOEL for systemic toxicity was 300 m/kg bw/day. The NOEL for reproductive and developmental parameters was 100 mg/kg bw/day. Treatment at 300 mg/kg/day and above was associated with a slight reduction in gestation index, a reduced live birth index and a decrease in pup viability over Days 1-4 of lactation. At the top dose of 1000 mg/kg bw bodyweight gain in pregnant animals during days 1-4 of lactation was also reduced.

 

No definitive conclusion can currently be drawn on the oral absorption of erbium oxide, until further clarification of the results of Brady 2013 are obtained , either by expert assessment of the results or through generating data.

 

In the interim the oral absorption of erbium oxide is considered unlikely to be greater than 1%.

Dermal absorption

 

No studies investigating the absorption of erbium oxide through the skin are available. Given its low solubility and that it is a solid, dermal absorption is expected to be minimal In view of the generally limited absorption of ions through the skin and the absence of any known specific uptake mechanism.

For erbium oxide a value of <0.01% was chosen to preserve the ratio between oral and dermal absorption maximal values.

 

With respect to cerium oxide, data from cerium chloride was used as a surrogate. Due to the higher solubility of the chlorides compared to the oxides the dermal absorption of the chloride is a worst-case estimate for the 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 the dermal absorption of erbium oxide through intact human skin can be considered negligible.

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

It can be concluded from the data that significant absorption via the dermal route is unlikely. A value of <0.01% was chosen for erbium oxide to preserve the ratio between oral and dermal absorption maximal values as apparent in the statement of figures for the analogue, cerium oxide.

 

Inhalation absorption

 

There is no data for erbium oxide. Given the absence of any great 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 <1% (as for oral absorption) if complete clearance can be affected from the lungs. For reference the erbium oxide particle sizes typically encountered by workers are in the range of 2-10 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 and (also erbium) 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 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 erbium 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 <1% for erbium oxide.  

 

Distribution

 

No data was available for erbium 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 erbium 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. Erbium oxide as an inorganic compound is not expected to undergo significant metabolism.

 

 

This was also supported for erbium in-so-far-as the presence or absence of exogenous metabolic activation system made no difference in the results ofin vitromutagenicity testing (e.g. Thompson, 2013; Bowles, 2013; 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 erbium oxide by oral route, no microscopic findings in the major metabolizing tissues (liver, 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 (Brady, 2013).

 

Elimination

 

Given the limited oral absorption, ingested material (via either oral or inhalation routes) is likely to pass through the GIT and emerge in the faeces.

 

References

 

Brady, L. (2013) A Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening ofDierbiumTrioxide by Oral Gavage in Rats.Charles River Laboratories,Tranent, UK.Study no. 496030.GLP.Unpublished.

 

Bowles, A. (2013)Dierbiumtrioxide: Chromosome Aberration Test in Human Lymphocytes in vitro.Harlan Laboratories Ltd.,Shardlow, UK.Study no. 41203091.GLP.Unpublished.

 

DammentSJ andPennickM. (2007) Systemic lanthanum is excreted in the bile of rats.ToxicolLett.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 andmicroanalyticalstudy. ArchInstPasteur 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 MolBiol(Noisy-le-grand) 47: 419-425.

 

Griffiths DR (2012) Erbium Oxide: Acute Inhalation Toxicity (Nose Only) Study in the Rat.  Harlan laboratories, Report No.: 41203088. GLP.  Unpublished

 

 

HenzellG (2012)     Erbium oxide: Local Lymph Node Assay.  Harlan Laboratories, Report No.: 41203089. GLP.  Unpublished

 

Inaba, J;Lengermann, FW.(1972) Intestinal uptake and whole-body retention of 141Ce by suckling rats.  HealthPhys22:169–175

 

Inaba, J. andYasumoto, M.S. (1979).A kinetic study of radionuclide absorption through damaged and undamaged skin of the guinea pig.HealthPhy37:592-595.

 

Kanapilly, GM, Luna, RJ. (1975)  Deposition and retention of inhaled condensation aerosols of 144CeO2 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)Orallyadministered rare earth element cerium induces metallothionein synthesis and increases glutathione in the mouse liver.  LifeSci77:922–937.

 

Laidlaw, K (2013)ACombined 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 SkeletalDosimetry.Radiation research, 132(3), 312-324.

 

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

 

Morris, A. (2013)Dierbiumtrioxide: CHO HPRT FORWARD MUTATION ASSAY.Harlan Laboratories Ltd.,Shardlow, UK.Study no. 41203110.GLP.Unpublished.

 

 

Rabinowitz, J. L., FernandezGavarron, F., & Brand, J. G. (1988).Tissue uptake and intracellular distribution of 140lanthanum 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 respiratorytract.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 innewborn, juvenile and adult rats.  HealthPhys22:373–378

 

Thompson, PW. (2013)Dierbiumtrioxide: Reverse Mutation Assay "Ames Test" Using Salmonella TyphimuriumAndEscherichia Coli.Harlan Laboratories Ltd.,Shardlow, UK.Study no. 41203090.GLP.Unpublished.

 

ViauA (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.