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Description of key information

A toxicokinetics assessment was performed for ytterbium oxide, a poorly water soluble ytterbium compound. The assessment was performed using the physicochemical characteristics of the compound in combination with experimental information reported in literature on the absorption, distribution, and/or elimination/excretion of ytterbium. Preliminary conclusions based on these data were then checked for consistency with the available toxicological data on this compound.

Absorption

Oral, respiratory and dermal absorption are expected to be (very) limited, due to the poor water solubility of ytterbium oxide at physiologically relevant pH levels, as well as the complexation behaviour of ytterbium with phosphates, carbonates, etc. Ytterbium is not expected to be bioavailable to a significant extent at potential uptake sites in the body. The oral, respiratory and dermal absorption factors for ytterbium after exposure to ytterbium oxide are set at 1, 1 and 0.1%, respectively, as a worst case for risk assessment purposes.

Distribution

Based on all available information on distribution, it can be concluded that – although absorption of ytterbium after oral, dermal or inhalation exposure to ytterbium oxide is expected to be (very) limited – any ytterbium that may be taken up in the blood would complex with proteins and form colloids (e.g., with carbonates, phosphates, …) that would be removed from the blood stream by phagocytic cells and temporarily stored in organs of the reticuloendothelial system such as liver and spleen. Absorbed ytterbium is also expected to end up in bone tissue, as it has been demonstrated that heavier rare earths (such as ytterbium) increasingly occur in bone compared to lighter rare earths, for which accumulation in bone is less important.

Excretion/elimination

Fast elimination via the faeces is concluded to be by far the most important route of elimination/excretion after oral administration. Limited amounts of ytterbium that might be absorbed can be expected to end up as depositions in organs/tissues that are part of the reticuloendothelial system or in bone tissue, from which slow clearance is expected. For heavier rare earths, such as ytterbium, the urinary excretion pathway seems to be more important compared to lighter rare earths, for which the biliary excretion pathway is more important compared to heavier rare earths. Further, after inhalation exposure, and especially under conditions of lung overload and impaired clearance, macrophage-mediated clean-up can be expected, involving transfer of particulate material to lung-associated lymph nodes, for temporary storage (or further translocation). Elimination/excretion of such translocated material is expected to occur more slowly, involving the urinary/biliary excretion pathways, with the urinary excretion pathway potentially representing the most dominant one over time. Note that elimination via the faeces is also expected after inhalation exposure, representing elimination of swallowed material that is cleared from the lungs and/or the extrathoracic airways.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
1
Absorption rate - dermal (%):
0.1
Absorption rate - inhalation (%):
1

Additional information

Introduction

Some experimental data (published scientific literature) were identified informing on the toxicokinetic behaviour of ytterbium and its compounds. These data, together with information on the physicochemical characteristics of ytterbium oxide as well as the toxicological information available on this compound, are used to perform a qualitative assessment of the absorption, distribution/metabolism and elimination/excretion of this ytterbium compound.

Note that in this document, a Klimisch score is only reported for the toxicity studies that are included in IUCLID (study summaries in the dossier for ytterbium oxide). However, for this assessment, all available data providing information that could contribute to the assessment of the toxicokinetic profile of ytterbium oxide is considered, and the publications only informing on toxicokinetics are not scored for reliability as they are not entered in IUCLID. Therefore, for such studies, no Klimisch score is provided in this assessment.

Ytterbium oxide is a solid ytterbium compound with ytterbium in its most prevalent oxidation state, i.e. +III. It is insoluble in water at pH 8 and 20°C: the water solubility of ytterbium oxide was determined to be 269 µg/L, based on a mean measured dissolved ytterbium concentration of 236 µg Yb/L (Petrovic, 2014).

Since it is generally assumed that for metals and metal compounds, the metal ion (regardless of the counterparts of the metal in the respective metal compounds) is responsible for the observed systemic effects after uptake, information on other ytterbium compounds can be used in this assessment as long as their similarities or differences in terms of inherent properties, such as water solubility, are discussed to predict the behaviour of the compound of interest. As indicated in ECHA’s guidance on QSARs and grouping of chemicals (ECHA, 2008), comparison of the water solubility can be used as a surrogate to assess the bioavailability of metals, metal compounds, and other inorganic compounds. In the case of ytterbium compounds, this simplistic approach assumes that a specific poorly water soluble ytterbium compound will show similar toxicokinetic behaviour and toxicological hazards as other equally poorly water soluble ytterbium compounds. Therefore, studies evaluating the toxicokinetic behaviour of ytterbium following exposure to poorly water soluble ytterbium compounds other than ytterbium oxide are also considered relevant in this assessment of the toxicokinetic behaviour of ytterbium oxide. Further, studies evaluating the toxicokinetic behaviour of water soluble ytterbium compounds (e.g., ytterbium trichloride, ytterbium trinitrate) – which may give rise to slightly higher levels of bioavailable ytterbium – may also be considered relevant to a certain extent, as long as the potential relevant differences are described.

 

Absorption

Oral/gastro-intestinal (GI) absorption

Ytterbium oxide has a molecular weight of 394.08 g/mol, with ytterbium itself having a molar mass of 173.04 g/mol. The latter value being well below 500 g/mol (molecular weights < 500 g/mol are favourable for absorption), it can be assumed that uptake of bioavailable species (free ytterbium cation and/or potentially other water soluble ytterbium species with relatively low molar mass) is possible. The extent of uptake, if any, would however be determined by the bioavailability of ytterbium in the gastro-intestinal tract. Ytterbium oxide is poorly soluble in water (Petrovic, 2014) at pH levels relevant for the uptake sites in the gut. The pH at the entrance of the duodenum is about 6, gradually increasing to pH 7.4 in the terminal ileum (Fallingborg, 1999). Although a higher solubility of ytterbium oxide can be expected in the stomach, any dissolved ytterbium is expected to be rapidly precipitated when it enters the gut. Precipitation will be further enhanced in the gastro-intestinal tract due to the presence of ligands that have strong affinity for ytterbium. Phosphate for instance forms strong, insoluble complexes with ytterbium, in a pH-independent way. Further, precipitation of carbonate complexes of ytterbium becomes more important with increasing pH. Therefore, it is expected that the bioavailability of ytterbium for uptake in the small intestine will be very limited. Complexation and precipitation as a function of the presence of inorganic ligands and pH has been confirmed by modelling in Visual Minteq (see also the document for justification of waiving further algal growth inhibition experiments with rare earth compounds, attached to IUCLID Section 13). Above-described behaviour has been acknowledged and discussed by Venugopal and Luckey (1975) as well.

Studies directly evaluating the absorption of ytterbium following oral exposure to ytterbium oxide in animals and humans are not available. However, there are few publications available that give an indication of what extent of absorption can be expected.

Luckey et al. (1975) conducted a study on the use of nitrates of five metals (cerium, terbium, ytterbium, iridium, and lutetium), to determine the feasibility of their use as non-absorbed, multiple markers for recovery, passage and indirect apparent digestibility studies. In a recovery experiment, four male rats were starved overnight and then fed (at one single occasion) five rice grains, one intended to contain 50 µg of cerium and four each intended to contain 25 µg of terbium, ytterbium, lutetium or iridium (nominal doses). The rats were fed ad libitum thereafter. Complete collections of faeces and urine by 24-hour periods were made for 7 days. The obtained results demonstrated that only 61% of the total ytterbium recovered was eliminated the first day, and 90 and 99% was cumulatively eliminated the second and third day, respectively. The missing 1% was indistinguishable from the background at the analytical limits of sensitivity. During the last 3 days of the experiment, the average faecal excretion of ytterbium was 0.19 µg/rat/day. Accepting this as a background level at the analytical limit of the method, ytterbium was concluded to be completely eliminated within 3 days after administration of a 25-µg quantity. Although the experiment did not directly quantify absorption, the high faecal recovery of ytterbium after 3 days provides indirect evidence of its extremely limited absorption under the conditions of the test. It should be noted that this experiment was performed with ytterbium trinitrate, i.e. an ytterbium compound which is highly soluble in pure water. Limited absorption after exposure to water soluble rare earth compounds is not surprising: because of the complexation behaviour and pH-dependent solubility of rare earths in general, water soluble rare earth compounds are not expected to give rise to much higher levels of bioavailable rare earth at the uptake sites in the gut compared to insoluble/sparingly soluble rare earth compounds. Therefore, information supportive of limited uptake after oral exposure to water soluble rare earth compounds is also considered relevant for less soluble rare earth compounds as a worst case. If absorption is observed to be limited after oral exposure to water soluble rare earth compounds, it will be at least equally or even more limited after oral exposure to insoluble/sparingly soluble rare earth compounds. The information from Luckey et al. (1975) is therefore considered as relevant for poorly soluble ytterbium compounds such as ytterbium oxide as well.

In a study performed by the same research group as the previous study, monkeys received a diet containing oxides of lanthanum, samarium, europium, terbium, dysprosium, thulium, ytterbium, scandium and chromium, as well as barium sulfate, at a concentration of 10 times the anticipated use level of these nutritional markers for 56 days (i.e. 1.2 mg/kg diet for ytterbium) (Hutcheson et al., 1975a). The exposure period was followed by a 7-day balance study during which excretion was followed and after which tissue distribution of the elements was investigated. The results of this study demonstrated that there was no apparent absorption of the elements studied (including ytterbium).

Similar results as reported by Luckey et al. (1975) were described by Fairweather-Tait et al. (1997), when investigating the feasibility of the use of rare earth elements as non-absorbable faecal markers in studies on human iron absorption. In this study, on 3 successive days, 13 healthy fasting adults (10 females and 3 males, 20-69 years old) were given different stable isotopes of iron with samarium, ytterbium or dysprosium. On day 1, three meals were given with 57Fe (1 mg per meal) plus samarium (0.33 mg per meal); on day 2, identical meals (taken with a calcium supplement to reduce iron bioavailability) were given with equivalent amounts of 58Fe-labeled iron and ytterbium; on day 3, a well-absorbed reference dose of 54Fe (3 mg) was given with 1 mg dysprosium. A complete faecal collection was carried out for 5-9 days and each stool was analysed for rare earth elements by ICP-MS. Each person was given 966-972 µg ytterbium, and recovery of this element ranged between 97-106%, indicating that it was totally unabsorbed. On average, 3 days were required for 80% excretion/elimination. Analysis of the test meals showed them to be low in ytterbium with the daily diet providing 14.0 µg ytterbium, which is equivalent to ca. 1.4% of the 1-mg administrated dose and may account for a slight overestimation of ytterbium excretion/elimination.

Finally, Leggett et al. (2014) reported gastro-intestinal absorption fractions for lanthanoids as proposed by the International Commission on Radiological Protection (ICRP). In Publication 30 (ICRP, 1981), a reference gastro-intestinal absorption fraction of 3x10-4 (i.e. 0.03%) was recommended for all compounds of lanthanoids. In Publication 68 (ICRP, 1994), a value of 5x10-4 (i.e. 0.05%) was adopted by analogy with trivalent actinides. The latter value was also proposed by Leggett et al. (2014) for all lanthanoids as a reasonably representative value, after considering all experimental information available on the gastro-intestinal absorption of lanthanoids in animals/humans (for further discussion see Leggett et al., 2014). Among this information is a series of studies summarised by Moskalev et al. (1972), in which the fractional uptake of several radio-lanthanoids – among which 169Yb – from the gastro-intestinal tract of rats following intragastric administration of rare earth chloride, nitrate, or citrate solutions (pH 3.0-6.0) was studied. The investigators concluded that gastro-intestinal uptake of lanthanoids does not exceed 5x10-4.

 

In the following paragraphs, it is investigated whether the available toxicological data for ytterbium oxide or related substances support abovementioned indications for limited oral absorption.

Ytterbium oxide was shown not to be harmful or toxic to rodents after single oral administration, in two different studies (key study: LD50 female rats > 2000 mg/kg bw, Di Manno, 2014, Klimisch 1; supporting study: LD50 female rats > 1000 mg/kg bw (i.e. the only dose tested in this study), Bruce et al., 1963, Klimisch 3). No clinical signs, deleterious effects, apparent abnormalities at macroscopic examinations or mortality were noted following exposure to the test item.

 

In a combined repeated dose toxicity study with reproduction/developmental toxicity screening in Wistar rats, ytterbium oxide was tested at 110, 330 and 1000 mg/kg bw/day. The NOAEL (No Observed Adverse Effect Level) for systemic toxicity of the parent animals was ≥ 1000 mg/kg bw/day. There was no mortality among parent animals at the highest test dose, there were no treatment-related clinical findings of toxicological relevance, no effects on body weight and (mean) food consumption, no treatment-related hematological, biochemical, histopathological or gross pathological findings, no treatment-related effects on organ weight or organ/body weight ratios, and no specific findings in the functional observational battery (including grip strength and locomotor activity) (Papineau, 2018, Klimisch 1).

 

Regarding fertility and reproductive performance of the parent animals, there were no test item-related effects on the mean length of the estrous cycle or the mean number of cycles at any dose level. There were no effects observed on the mating and gestation indexes at any dose level. At 1000 mg/kg bw/day, a slightly lower fertility index (80% vs. 100% in controls) was recorded, for which a relationship to treatment with the test item could not entirely be ruled out, although the toxicological relevance of the observed effects seemed to be limited. Further, there were no effects on the mean duration of gestation, the mean number of corpora lutea, mean pre-implantation loss, and mean post-implantation loss, at any dose level. Altogether, the NOAEL for reproductive performance of the parent animals was considered to be ≥ 1000 mg/kg bw/day based on the absence of clear adverse findings at this high dose level.

 

Considering toxic effects on progeny, there were no effects on mean body weight or mean body weight change, sex ratio, and anogenital distance, at any dose level, nor were there nipples or areolae (male pups) or external abnormalities (both sexes) observed in pups at any dose level. At the high dose level, slightly lower live birth (89.9 vs. 98.2% in controls) and viability (89.9% vs. 96.7% in controls) indexes were noted, for which a test item-related effect could not be excluded. At the same dose level, an increase in clinical signs, that could be associated to lack of maternal care (absence of milk in stomach) was observed in pups, along with an increased number of litters affected (5/8 litters with 9/95 pups affected at the high dose level vs. 2/8 litters with 2/88 pups affected in the control). However, since the overall outcome was an identical number of live pups (86) for an identical number of females delivering, the results did not convincingly demonstrate that the observed effects in pups were related to treatment with the test item and consequent toxicological action and were not due to other fortuitous events resulting in sporadic effects. Because it could not be excluded either that the observed effects were test item-related, the NOAEL for toxic effects on progeny was set at 330 mg/kg bw/day.

In a study on nutritional safety of some heavy metals in mice, Hutcheson et al. (1975b) investigated the possible toxic effects of ytterbium oxide – together with eight other metal oxides and barium sulfate – upon growth, general development, reproduction and lactation after dietary administration to mice through three successive generations. Ytterbium oxide, the other oxides, and barium sulfate were added to a small quantity of stock diet. Five groups were tested with the following amounts of elements fed: 0, 1, 10, 100 and 1000 times the quantity of the proposed use amount for each marker (the proposed use amount corresponds to one-fifth of the concentration required for estimation by neutron activation analysis with a 5% error). For ytterbium oxide, the use amount was 0.12 ppm (i.e. the highest dose tested was 120 mg Yb/kg diet). No morphological anomalies were seen. Morbidity and mortality were less than 0.5% for the experiment. No consistent growth rate changes were observed, however, different groups showed different growth rates during different generations. The number of mice born showed no significant differences among treatment groups. Survival, growth rate, hematology, morphological development, maturation, reproduction and lactational performance were comparable in mice fed the different levels of the 10 rare earth/metal compounds and in mice fed with the basal diet.

 

The available toxicological data reported above (oral exposure) demonstrate no overt adverse effects for all endpoints investigated after exposure to ytterbium oxide and do not trigger classification. Based on the poor water solubility of ytterbium oxide, it is expected that the bioavailability/bioaccessibility of the common element Yb3+ will be too low to elicit effects in living organisms. The results of these studies do not provide reasons to deviate from the assumption that absorption of ytterbium following oral exposure to ytterbium oxide is extremely limited.

Absorption from the gastro-intestinal lumen can occur by passive diffusion but also by specialised transport systems. Regarding absorption by passive diffusion, the lipid solubility and the ionisation are important. However, metal compounds such as ytterbium oxide are usually not lipid soluble and are thus expected to be poorly absorbed by passive diffusion (Beckett et al., 2007). It has been demonstrated that several metals can cross cell membranes via ion channels or specific carriers intended for endogenous substrates (Beckett et al., 2007). For ytterbium compounds, there is no direct experimental evidence for the existence of a mechanism of transport responsible for uptake of Yb3+. It has however been described that rare earth elements are isomorphic competitors for calcium-binding sites in biological systems. These competitive interactions seem to be related to the ionic radii of the hydrated ions of lanthanoids (ca. 97.7 pm for lutetium up to ca. 116 for lanthanum) being close to that of the hydrated ion of Ca2+ (ca. 112 pm) (Shannon, 1976). Ytterbium, as a hydrated trivalent cation, has an ionic radius of 98.5 pm. Based on studies of ionic concentrations that block the type T calcium channel (0.1-1.0 µM), the potencies of lanthanides to block this channel have been arranged in the following order: Ho3+ > Yb3+ ≥ Er3+ > Gd3+ > Nd3+ > Ce3+ > La3+ (Mlinar and Enyeart, 1993). These findings suggest that bioavailable Yb3+ might be taken up into the systemic circulation via such channels. Note that, even if an uptake mechanism would exist for Yb3+, this would require the presence of bioavailable Yb3+ in the system, which is unlikely to occur to a significant extent after oral exposure to insoluble compounds such as ytterbium oxide.

Based on abovementioned information on the physicochemical characteristics of ytterbium oxide, the indications from literature on the limited absorption after oral exposure to ytterbium, ytterbium oxide or ytterbium trinitrate (a water soluble ytterbium compound), and the available toxicological data for ytterbium oxide, the absorption factor for ytterbium after oral exposure to ytterbium oxide is set at 1% as a worst case for risk assessment purposes.

Respiratory absorption

Low exposure to ytterbium oxide is expected based on the inherent properties of this compound. No vapour pressure value has been determined as this compound does not melt below 300°C (Demangel, 2017). Therefore, inhalation of ytterbium oxide as a vapour is not likely to occur.

The particle size distribution (by volume) of an ytterbium oxide sample which can be considered representative for what is manufactured was as follows: D10, D50 and D90 were determined to be 0.974 µm, 5.17 µm, and 11.89 µm, respectively. Based on this particle size information, the inhalation route of exposure should be taken into consideration for this compound. Therefore, the absorption of ytterbium from potentially inhaled/respired particles of ytterbium oxide is assessed here below.

 

Ytterbium oxide is a poorly soluble inorganic compound. Due to its poor solubility, which decreases with increasing pH, and due to the complexation behaviour of ytterbium with ligands present in the medium (i.e. a common behaviour of rare earths in aqueous media), once deposited on the walls of the airways, the concentration of bioavailable forms – such as (solely or predominantly) the free Yb3+

cation – in the bronchoalveolar fluid is expected to be very low, assuming a pH of about 6.6 (for healthy individuals). Therefore, absorption from the lungs to the circulatory system is expected to be minimal.

Since respired ytterbium oxide particles are expected to accumulate in the lungs mainly as particulate material, they are expected to be engulfed from the alveolar region by alveolar macrophages. The macrophages will then either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues. Deposited material may also be transported out of the respiratory tract and swallowed through the action of the mucociliary clearance system, especially material settled in the tracheobronchial region. In that case it will contribute to the gastro-intestinal absorption rather than to the absorption via inhalation. Unfortunately, no direct experimental evidence for this behaviour and lung clearance mechanism has been identified yet for ytterbium, however, evidence has been documented for other rare earth compounds (e.g. for gadolinium oxide: Ball and Van Gelder, 1966; Abel and Talbot, 1965, 1967; Talbot et al., 1965).

 

Some indirect evidence for the expected limited absorption of ytterbium following inhalation exposure to ytterbium oxide was found in the study of Rhoads and Sanders (1985), who exposed young female adult rats (100 days old) via intratracheal instillation for 30 to 180 minutes to 0.5-1.0 mL of a suspension of radiolabelled ytterbium oxide in 0.9% saline, resulting in an initial deposition of 0.026 µg of ytterbium oxide. Groups of 4-5 rats were sacrificed at different time intervals after exposure, the last group being sacrificed after 30 days. Ytterbium oxide was labelled with a gamma-active radioisotope and fresh tissues (e.g., lung, liver, kidney, skeleton, thoracic lymph nodes, etc.) and excreta were counted in a well-type gamma counter. The lung clearance and whole body clearance (as time to clear 50% of the initial lung burden or whole body burden, respectively) were determined to be 21 and 22 days, respectively. The whole-body clearance time for ytterbium was not much longer than that for the lung, indicating that it translocated only minimally to other tissues. Moreover, the fluctuations of the activity measured over time in thoracic lymph nodes, organs such as liver, kidney and bone, gastro-intestinal tract, and excreta (see sections on distribution and excretion/elimination in this assessment for further details) are in line with a combination of lung clearance via the mucociliary system (and consequent entry in the gastro-intestinal system through swallowing) and the above-described mechanism of macrophage-mediated translocation to lung-associated lymph nodes, from where translocation to other organs could occur, from which the element is then further cleared from the body.

 

Finally, the available toxicological information for ytterbium oxide after inhalation exposure is considered to check if the toxicological findings are in line with the expectation of limited respiratory absorption.

Currently only an acute inhalation toxicity study is available, performed with ytterbium oxide (Tóth, 2017). In this study, the acute effects of a 4-hour nose-only exposure to ytterbium oxide as aerosol at a concentration of 1.31 mg/L (maximal technically achievable concentration) were investigated in 10 rats (5 males and 5 females) with a 14-day post-exposure observation period. The acute LC50 was determined to be greater than 1.31 mg/L (analytically determined concentration), as no mortality was observed. No test item-related findings were noted that could not be considered as general symptoms of respiratory exposure to particulate material. Consequently, the observations made in this study support the assumption of limited respiratory absorption of ytterbium after exposure to ytterbium oxide.

 

Based on the poor solubility of ytterbium oxide, its expected behaviour in the lungs (based on known similarity among rare earths and available experimental information for other rare earth compounds), as well as available information on the fate and toxicity of ytterbium after inhalation exposure to ytterbium oxide, the respiratory absorption factor for ytterbium after exposure to ytterbium oxide is set at 1% for risk assessment purposes, as a worst case.

Dermal absorption

Studies evaluating absorption of ytterbium following dermal exposure in humans or animals are not available. Therefore, a qualitative assessment of the toxicokinetic behaviour based on the physicochemical properties of ytterbium oxide is performed, taking toxicological data on this compound, obtained after dermal exposure, into consideration.

Ytterbium oxide would have to dissolve in the moisture of the skin prior to penetrating the skin by diffusive mechanisms. However, as the solubility of this compound is limited at physiologically relevant pH levels (relevant to skin), no significant dermal uptake is expected.

The acute dermal toxicity of ytterbium oxide was not investigated. This was not considered necessary based on the results of the acute oral toxicity studies (see paragraph on oral absorption, LD50 > 2000 mg/kg bw) and the absence of systemic effects observed in the available in vivo studies with dermal exposure (see the in vivo skin sensitisation study described below), in agreement with the recently adjusted section 8.5.3, Column 2 adaptations of Annex VIII of the REACH Regulation.

No in vivo skin irritation studies are available for ytterbium oxide. However, the fact that this compound is conclusively not classified as skin irritant, based on the results obtained in an in vitro EPISKIN model test according to OECD guideline 439 (Orovecz, 2016, Klimisch 1), indicates that also in vivo an absence of irritation is to be expected.

 

Further, results of an in vivo skin sensitisation study in guinea pigs (Weisz, 2016, GPMT, OECD 406, Klimisch 1) indicated that ytterbium oxide induced no skin sensitisation response in the guinea pig after intradermal, dermal and challenge exposures. No signs of systemic or local toxicity and no mortality were observed in this study.

 

As ytterbium oxide does not meet the CLP criteria for classification as skin irritant or skin sensitiser, the expected low dermal absorption is not expected to be enhanced by any irritating/sensitising effects.

 

In the absence of measured data on dermal absorption, ECHA guidance (2017) suggests the assignment of either 10% or 100% default dermal absorption rates. However, the currently available scientific evidence on dermal absorption of some metals (e.g. Zn sulphate, Ni acetate; based on the experience from previous EU risk assessments) indicates that lower figures than the lowest proposed default value of 10% could be expected (HERAG, 2007).

Based on the inherent properties of ytterbium oxide, the toxicological data available, demonstrating the absence of systemic toxicity, and the experience from HERAG, no significant dermal absorption is expected. Therefore, a dermal absorption factor of 0.1% is suggested for risk assessment purposes as a worst case.

 

Distribution and accumulation

From the above discussion, absorption of ytterbium following exposure to ytterbium oxide via the oral, inhalation, or dermal pathway is expected to be (very) limited. In the absence of accurately determined absorption factors, absorption factors for risk assessment have been set sufficiently high, as a worst-case approach. Although absorption is expected to be (very) limited, the available information on distribution and accumulation of ytterbium is discussed below, in order to describe its most likely behaviour once ending up in the body/circulatory system. Although the focus would ideally be on information obtained in studies performed with poorly soluble ytterbium compounds such as ytterbium oxide, administered via a relevant pathway for assessment in view of REACH registration, the scope of this assessment was broadened as only a limited number of studies are available providing information on distribution/accumulation of ytterbium after oral, dermal or inhalation exposure to poorly soluble ytterbium compounds. The scope was broadened at the level of the type of ytterbium compound studied (including water soluble compounds and radionuclides of ytterbium) as well as at the level of the administration route (including intravenous, intratracheal, intramuscular administration, and environmental exposure). Care was taken to add the necessary considerations on the relevance of this information in view of the current assessment.

Oral administration

In the study of Feng et al. (2006), 60 female Wistar rats (7-9 weeks old) were mated with males of the same age and strain and exposed orally to ytterbium trichloride via gavage from gestation day 0 through postnatal day 25 (control, 0.1, 2 and 40 mg Yb/kg bw/day). From postnatal day 25, the infant rats were weaned and exposed to ytterbium trichloride under the same doses as their maternal rats until they were killed. At postnatal day 0, 25 and 150, seven male offspring rats from each group were sacrificed. Blood, brain, liver and femur sample were collected and analysed using ICP-MS. Samples from offspring rats which received the highest test dose that were taken at postnatal day 150 showed the highest concentrations of ytterbium: ca. 0.0175 µg/mL in serum, ca. 0.138 µg/g dw in liver, and ca. 1.3 µg/g dw in femur. In the different parts of the brain studied, concentrations were generally lower than in liver and femur, with maxima up to almost 0.12 µg/g dw. The highest concentrations were measured in femur. The authors did not report how the measured ytterbium concentrations in the different tissues relate to the total administered dose. An indicative calculation can be done for the liver. Assuming an average weight of ca. 300 g for male Wistar rats of 150 days old, the daily dose of ytterbium at the end of the study was ca. 12 mg Yb. Assuming an average relative liver weight of 3.0% in adult male Wistar rats and an average water content of ca. 75% in liver, the measured concentration of ca. 0.138 µg/g dw in liver represents a total ytterbium burden in liver of ca. 0.31 µg Yb. This is ca. 0.26% of the daily administered dose and a negligible percentage of the cumulative dose administered throughout the experiment (not calculated), which is in line with the above-discussed expectation and findings of limited absorption after oral exposure. Note that this study was performed with ytterbium trichloride, which is a water soluble ytterbium compound. However, as discussed above, due to the higher than expected similarity between the bioavailability of rare earth elements after exposure to insoluble/poorly soluble and water soluble compounds, the results of the study discussed above are considered relevant for ytterbium oxide as well.

 

The study of Hutcheson et al. (1975a) in monkeys as described in the section on oral absorption and using ytterbium oxide as test item, also reports concentrations of ytterbium and the other administered rare earths/metals in tissue samples obtained at the end of the study. Ytterbium was detected in bone, duodenum, skin and hair, heart, liver, and lung, and was not detectable in kidney, fat, spleen, muscle tissue and blood. The reported concentrations (ranging from 0.03 to 0.07 ppm) in tissues where ytterbium was detected were however all well below the limit of quantification for the analytical method used in this study (3 ppm) and therefore no comparisons can be made between different organ tissues. Nevertheless, the results are in line with the above-discussed expectations and findings of limited absorption after oral exposure.

 

Administration via inhalation/intratracheal instillation

The most relevant study in this section has already been discussed above in the section on respiratory absorption (Rhoads and Sanders, 1985). In this study, rats were exposed to ytterbium oxide via intratracheal instillation for 30 to 180 minutes, and the translocation of ytterbium to extrapulmonary tissues as well as its presence in excreta was investigated. The tissues studied were liver, kidney, skeleton, gastro-intestinal tract, thoracic lymph nodes and carcass. The accumulation over time (0.0035, 0.042, 0.17, 1, 2, 7, 14 and 30 days after exposure) was expressed as mean percentage of the initial lung burden. The gut and skeleton burden peaked before day 1 after exposure at ca. 7% of initial alveolar deposition (IAD). After day 1 an overall decline towards the end of the observations, with some fluctuations, was observed. In liver and kidney, there were some fluctuations throughout the study but the maximum burden (ca. 0.4 and 0.6% of the IAD in liver and kidney, respectively) was clearly observed at the end of the 30-day observation period. In urine and faeces, ytterbium was detected from day 1 after exposure onwards, increasing from ca. 0.5 to 4% at the end of the observation period in urine and from ca. 0.3 to 53% in faeces. In thoracic lymph nodes there was some fluctuation between ca. 0.7 and 1.8% of the IAD over the first day after exposure, with an overall decrease observed towards the end of the study. These observations are in line with the lung clearance mechanisms as described in the section on respiratory absorption. Material cleared from the lungs via the mucociliary clearance system contributes to gastro-intestinal exposure and consequently – considering the extremely limited absorption via the oral pathway – elimination via the faeces. Macrophage-mediated clearance results in translocation to thoracic lymph nodes and consequently to other organs such as bone, liver, etc. and consequent excretion. Further, as was observed after oral exposure, ytterbium seems to be stored predominantly in the bone. On the preferred excretion pathway it is difficult to draw conclusions, as no distinguishment can be made between biliary excretion and elimination of swallowed material via the faeces.

Intravenous administration

Nakamura et al. (1997) intravenously administered an ytterbium trichloride solution at a low dose of 10 mg Yb/kg and a high dose of 20 mg Yb/kg in rats and investigated the distribution in liver, spleen, kidney, lung and femur one day following administration. Control rats received 1 mL/kg 5% glucose. Blood samples were taken 2 hours and 1 day after administration. The distribution observed for ytterbium depending on the administered dose (10 / 20 mg Yb/kg) was as follows:

·        Liver: 62.9 / 63.8 %

·        Spleen: 5.26 / 4.59 %

·        Bone: 14.5 / 11.6 %

·        Lung: 1.09 / 1.09 %

·        Kidney: 0.56 / 0.47 %

·        Blood: 6.73 / 4.96 %

The rare earth elements tested mainly distributed to the liver, bone and spleen (> 78% of the administered dose in all cases). Most of the rare earth elements accumulated in the bone were distributed into bone marrow. Compared to medium (Eu and Dy) and light rare earth elements (Ce and Pr), the distribution ratios of heavy rare earth elements (Yb and Lu) in bone were higher, especially at the low dose. For yttrium and the heavy rare earths tested, percentages of rare earth elements in the bone tended to decrease as the dose increased in the rats. In blood, the distribution percentage was higher in serum than in blood cells for all rare earths tested at the low dose. Similar observations were made at the high dose except for yttrium, europium and dysprosium. For ytterbium, 74.9% and 83.5% was distributed to serum at the low and high dose, respectively, whereas 25.1% and 16.5% was distributed to blood cells at the low and high dose, respectively.

The same authors (Nakamura et al., 1991) exposed rats intravenously to a single dose of 10 mg Yb/kg using ytterbium trichloride and monitored excretion into the faeces and urine as well as the concentration and distribution (in % of dose) of ytterbium in whole blood, liver, kidney, lung, spleen and bone as a function of time (up to 45 days after administration). The % of ytterbium in the blood decreased to approximately zero within 24 h. This was accompanied with an increased presence in liver > femur > spleen. Whereas the % ytterbium in the spleen stayed relatively constant (ca. 4%) throughout the study, the % ytterbium in liver decreased from ca. 65% after 24 h to ca. 12.5% after 45 d whereas that in femur increased from ca. 12.5% after 24 h to ca. 20% after 45 d. The relative distribution shows that liver, bone and spleen are the most important organs for temporary storage of ytterbium, with bone becoming more important than liver on the longer term.

 

Magnusson (1963) studied the distribution of ytterbium after intravenous injection of 169YbCl3 in female rats. One hour after intravenous injection, the concentration of 169Yb in blood serum was about 10% of the administered dose. This concentration reduced to near zero after 48 h. A concentration near or below 1% was measured in the kidneys during the first hours after administration. Concentrations in the liver increased to ca. 50% of the injected dose after 3 h. Four days after administration, the concentration in the liver was close to 30%. 

Baltrukiewicz et al. (1975) measured the concentration of 169Yb in the kidneys, adrenal glands, liver, stomach, large and small intestine, heart muscle, lungs, spleen, brain, skin, blood, testes, femoral bone, skull integument bone, uterus and tail, 10, 30, 60 min and 3 and 24 h after a single intravenous injection of 3 µCi of 169YbCl3 in rats. The most intensive accumulation of 169Yb was found in the liver: during the first day, accumulation ranged from 37% (10 min after injection) to 22% (after 24 h) of the applied dose, with a retention peak noted after 1 h (43% of the applied dose). In the kidneys, lungs, and small intestine, 169Yb retention exceeded 1% of the injected dose. In the kidneys, an increase from approximately 1.2% after 10 min to about 2.3% after 3 h was observed, reducing to 1% after 24 h. In the lungs, the retention was approximately 3-4% during 10-30 min after the injection, decreasing thereafter to about 2% in the 1st and 3rd hour and to 0.7% 24 h following the injection. In the small intestine the concentration amounted to 3% of the injected dose 1 h after injection. The clearance of ytterbium from blood was shown to occur rapidly: within 1 h the blood concentration decreased to half of the value measured 10 min following the injection (i.e. from 2.17% after 10 min, to 1.20% after 1 h). 24 h after injection, the blood was cleared completely. Retention in femur was below 1% of the injected dose throughout the study but clearly increased over time, which is in line with findings in other studies.

 

Shinohara et al. (2006) intravenously administered doses of 1 or 10 mg Yb/kg to male mice (as ytterbium trichloride). After 20 hours and 6 days of administration, five mice of each group were sacrificed and liver, spleen, lung and kidney were taken out for analysis of ytterbium content. Distributed amounts of administered ytterbium were the largest in liver for all groups, then followed by spleen. Six days after injection, ca. 25 and 40% of the administered dose was deposited in livers of the 1 and 10 mg Yb/kg group, respectively. Concentrations in lungs and kidneys were negligible compared to those in liver and spleen.

Li et al. (2002) intravenously administered a dose of 0.2 µg 168YbCl3 (i.e. stable isotope) in male Wistar rats and analysed concentrations in blood, heart, liver, lung, kidney, spleen, brain, femur and testicles 1, 12, 24, 48, 96 and 144 hours after administration. In the liver, the % ytterbium of the administered dose decreased from 40% immediately after injection to 15% 144 h after injection. In the femur the % ytterbium increased from 5% of the administered dose immediately after injection to > 10% 144 h after injection. In the other organs analysed, the % ytterbium was around or less than 1% of the administered dose throughout the study.

 

The results of above-discussed studies are in line with each other but showing relatively higher importance of distribution to liver compared to studies applying the oral or inhalation route of exposure, in which distribution is observed to occur mainly to bone.

As discussed by Nakamura et al. (1997), when entering the blood stream, rare earth elements form soluble complexes with proteins like albumin in the plasma. This was for instance demonstrated by Rosoff et al. (1958). When the complexing ability of the plasma is exceeded, insoluble colloidal precipitates in the form of hydroxides, carbonates and phosphates are formed (e.g., Rosoff et al., 1963; Kanapilly, 1980; Evans, 1990; Hirano et al., 1993). These precipitates are then removed from the blood stream by phagocytic cells of the reticuloendothelial system and stored (e.g. in lysosomes) in organs such as liver and spleen. Such mechanisms have been demonstrated for instance for gadolinium (e.g., Dean et al., 1988; Spencer et al., 1997) and yttrium (Hirano et al., 1993) after intravenous injection of their respective chloride salts. Although no direct evidence of this mechanism is available for ytterbium, a similar behaviour can reasonably be assumed after intravenous administration. Further, it should be noted that the intravenous route of administration is not relevant in view of REACH registration, but – although absorption of ytterbium after oral, dermal or inhalation exposure to ytterbium oxide is expected to be very limited – any ytterbium that is taken up in the blood is expected to undergo a similar fate as described above for rare earth elements in general.

 

Intramuscular administration

Leggett et al. (2014) summarised results obtained by Durbin (1960, 1962, 1973), who compared the behaviour of radioisotopes of trivalent lanthanoid elements (dissolved in sodium citrate) in rats following intramuscular administration. Here also, the main sites of deposition of all lanthanoids were found to be the liver and skeleton, with the division between liver and skeleton depending on the ionic radius. Whereas for elements with ionic radii between 104 and 116 pm, a decrease in ionic radius was associated with a decrease in uptake by liver and an increase in uptake by bone, little difference in the distribution was found for elements with ionic radius of ≤ 104 pm (Tb, Dy, Ho, Er, Tm, Yb and Lu). For the latter elements, the content of bone and liver as % of injected activity 4 days post-administration ranged from 56-68% and 1-7%, respectively. For ytterbium specifically, 58% and 3% of injected activity was measured in bone and liver, respectively, whereas 13% of injected activity was distributed to other organs (not specified). These findings agree with findings from other studies as well.

 

It should be noted that the intramuscular route of administration is not relevant under REACH, however, the results of this study are considered relevant as they provide insight in the likely distribution of absorbed ytterbium (if any) throughout the body.


Environmental exposure

Zaichick et al. (2011) measured the concentration of ytterbium and other rare earths in the rib bone tissue of healthy human individuals (38 females and 42 males, between 15 and 55 years old) living in a non-industrial region. The mean concentration of ytterbium in the samples analysed was determined to be 0.72 µg/kg dry weight. The minimum value was 0.10 µg/kg whereas the maximum value was 2.40 µg/kg. The authors in general found an age-related accumulation of rare earths in bone. It was calculated that during a lifespan the content of rare earths in skeleton of non-industrial region residents may increase by one to two orders of magnitude. Following a lifetime exposure to rare earth elements naturally present in the environment, the potential for accumulation is very low.

Zhu et al. (2010), as discussed in Leggett et al. (2014), estimated the total masses of the lanthanoid elements in individual tissues and the total body using median tissue concentrations and reference tissue masses for Chinese adult males. The estimates suggest that the lungs contain on average about 15% of the total body content of stable lanthanoids, with a range of ca. 5-45% across the 13 lanthanoids addressed, whereas the skeleton on average contains about 55% (30-85%) of the systemic content (i.e. total body content minus lung content). The liver contains 11, 22 and < 3% of the systemic content for lanthanum, cerium, and the remaining lanthanoids, respectively. For ytterbium specifically, the skeleton and liver were calculated to contain ca.33.8 and 6%of the systemic content, respectively, again in agreement with other studies mentioned above.

 

Kruger et al. (2010) measured the concentrations of naturally occurring lanthanides, including ytterbium, in ~160 samples each of three placental tissue types (placenta body, placenta membrane, and umbilical cord) for evaluation of possible maternal and fetal exposure to these metals. Heavier lanthanides (Eu-Lu) were not detectable in most placental tissues (< 1 ng/g dw for Yb), whereas lighter lanthanides (La-Sm) were detected in the ng/g range. The lanthanide concentrations measured appeared to follow a pattern similar to that found in the Earth’s crust, indicating natural human exposure to these analytes. For the lanthanides detected in the study, the greatest concentrations of analytes were measured in the placenta body, suggesting that these elements are sequestered to protect the foetus from potential harm due to exposure.

 

In conclusion, based on all available information on distribution, it can be concluded that – although absorption of ytterbium after oral, dermal or inhalation exposure to ytterbium oxide is expected to be (very) limited – any ytterbium that is taken up in the circulation and retained in the body will be temporarily stored mainly in bone and liver. The exact mechanism of incorporation in bone is not entirely clear. The incorporation in liver is expected to occur via removal of colloidal precipitates from the blood stream by phagocytic cells and consequent storage e.g. in lysosomes in the liver. Upon exposure via inhalation and under conditions of lung overload and insufficient clearance, macrophage-mediated translocation of solid material to lung-associated lymph nodes (and from there to other organs) is expected to occur as well.

 

Metabolism 

As an element, ytterbium is neither created nor destroyed within the body. There are no indications of transformation to more hazardous forms in the liver or kidney, which is also supported by the fact that ytterbium oxide was demonstrated not to be mutagenic in vitro (Váliczkó, 2017, Klimisch 1; Hargitai, 2018a, Klimisch 1). Ytterbium oxide induced chromosome aberrations in Chinese hamster V79 cells at several concentrations with and without metabolic activation (Hargitai, 2018b, Klimisch 1; test proposal included for an in vivo OECD 474 study to get more clarity on this endpoint), consequently, nothing can be deduced from this study either concerning transformation of ytterbium.

As discussed above, as demonstrated for several rare earths, these elements appear to be concentrated in granular inclusions in lysosomes of phagocytic cells (e.g., in the lungs, in liver and spleen), where they may appear under different forms (e.g., complexed with proteins, inorganic ligands such as phosphates or carbonates, etc.). This can be considered as a detoxification mechanism. No other information relevant for this section has been identified.

 

Elimination/excretion

Because only one study (Rhoads and Sanders, 1985) was identified reporting on excretion/elimination after exposure to ytterbium oxide, the scope of the search for available information was broadened to include information on other ytterbium compounds, in the same way as justified for the part on distribution (see above). The available information is described below.

In a recovery study to investigate the suitability of several rare earths as marker in nutritional studies, Luckey et al. (1975) found that after single dietary administration of 25 µg ytterbium (in its nitrate form) to rats, 61% of the total ytterbium recovered was eliminated the first day, and 90 and 99% was cumulatively eliminated the second and third day, respectively. The missing 1% was indistinguishable from the background at the analytical limits of sensitivity and therefore it can be concluded that after single oral administration of a 25-µg quantity to rats, ytterbium was completely eliminated within 3 days following administration. Fairweather-Tait et al. (1997) reported similar elimination rates for humans after a single dietary administration of ca. 1 mg ytterbium: a total recovery was described 9 days after administration (of which 80% was eliminated within 3 days after administration).

Similar observations were made for other rare earths. For instance, following oral administration of lanthanum carbonate to rats and dogs, the great majority of the dose was found to be eliminated unabsorbed via the faeces: 99% and 93% of the dose was recovered in the faeces of rats (Damment and Pennick, 2007) and dogs (FDA, 2002, 2004), respectively. The extremely small absorbed fraction was found to be excreted predominantly via the liver into bile (Pennick et al., 2006; Damment and Pennick, 2007).

Based on the information described above, a similar elimination/excretion pathway can be expected for ytterbium after oral administration of ytterbium oxide.

Similarly, after dermal and inhalation exposure to ytterbium oxide, (very) limited absorption is expected. No experimental information is available on excretion after dermal exposure. As described above, after inhalation exposure, macrophage-mediated transport of undissolved material to the tracheobronchial lymph nodes may occur, from where elimination/excretion can be expected to occur rather slowly. In the study performed by Rhoads and Sanders (1985), excreta activity of rats administered radiolabelled ytterbium oxide intratracheally was more than 10 times greater in the faeces than in urine and represented ca. 53% of the amount deposited by day 30. The high faecal excretion/elimination is likely due to the gastro-intestinal intake of deposited material after swallowing material transported out of the respiratory tract through the action of mucociliary clearance mechanisms.

With regard to excretion/elimination after inhalation exposure to ytterbium compounds, an interesting study to mention is the study of Potter (2002). These authors attempted to update the Intake Retention Fractions (IRFs) for all elements and compound classes for which dose coefficients for particulate inhalation are set by the International Commission on Radiological Protection (ICRP). Potter (2002) reports data for stable elements only. IRFs as proposed by the ICRP are based partly on experimental work or biokinetic data from literature. Potter (2002) used models to generate IRFs and data on excretion for various points in time after a single exposure via inhalation. IRFs over time are given for whole body including the respiratory tract (with and without extrathoracic airways), the gastro-intestinal tract, and systemic organs and tissues. Additionally, 24-h excreta and accumulated excreta values over time are provided for both urine and faeces. Since the compound determines the uptake, separate predictions are made for the element depending on the compound class it was assigned to. For ytterbium, separate values are provided for class M (moderately fast uptake) and class S (slow uptake). Below the data given for class M ytterbium are described. They are very similar for class S ytterbium.

The IRFs for class M ytterbium were 0.474 and 0.738 in whole body excluding and including extrathoracic airways, respectively, immediately following exposure (meaning that 47.4 and 73.8% of the total amount exposed to is retained in the body, respectively, representing both unabsorbed and absorbed/translocated material). Fast elimination of particulate material retained in the extrathoracic airways is then predicted, resulting in equal IRFs of ca. 0.071 from day 7 post-exposure onwards (i.e. 7.1% of the total amount exposed to is still retained in the body, regardless of whether extrathoracic airways are included or not). After that a slower elimination/excretion is predicted, resulting in IRFs of ca. 0.044, 0.028, 0.0046 and 0.000088 after 100, 1000, 10000 and 30000 days, respectively. After 1 day, ca. 0.6% (of the initial dose) is predicted to be excreted via urine, whereas ca. 11% is predicted to be excreted/eliminated via faeces. Over a time span of 30000 days, ca. 45% and ca. 3.1% of the original amount exposed to is predicted to be eliminated/excreted via faeces and urine, respectively (i.e. basically all ytterbium that was initially retained in the body). While excretion/elimination via faeces seems to be more important initially, over time, excretion via urine becomes equally important as via faeces.

In the section on absorption, it has been concluded that ytterbium from ytterbium oxide is not expected to be absorbed to a significant extent upon exposure via inhalation. Instead, the particulate material accumulated in the lungs is eliminated via the mucociliary clearance system, or in case of lung overload conditions and impaired clearance, also transport by macrophages to lung-associated lymph nodes can be expected. The predicted initial dominance of excretion/elimination via the faeces could partly be affected by elimination of material swallowed after clearance by the mucociliary system of the airways. The longer-term excretion/elimination may present slow excretion/elimination of material stored in the lung-associated lymph nodes and/or excretion of truly absorbed material, which may have been stored elsewhere in the body (e.g., in liver or spleen, see above).

In general, excretion of rare earths has been more frequently studied after intravenous/intraperitoneal administration, which is less relevant under REACH but at the same time provides more insight in the fate of rare earths that would end up in the circulatory system. Therefore, some additional sources are described below.

In the study of Nakamura et al. (1991), ytterbium trichloride, at a dose of 10 mg Yb/kg, was administered intravenously in rats and excretion into faeces and urine were investigated as a function of time. Ytterbium was not detected in urine. Faecal excretion rates were 2.81, 7.27 and 5.48% of the administered dose in time intervals 0-1 day, 1-4 days and 4-7 days after administration, respectively. Altogether, 17.63% of the administered dose was excreted via the faeces within 7 days.

In the experiment of Shinohara et al. (2006), in which ytterbium trichloride was administered at doses of 1 and 10 mg Yb/kg to male mice, excretion via urine within 6 days of administration amounted to 5.7 and 0.8% of the administered dose in mice of the low and high dose group, respectively, whereas excretion via faeces amounted to 10.5 and 16.8% of the administered dose in the low and high dose group, respectively. Compared to the other rare earths investigated (terbium and samarium, which are both lighter rare earths than ytterbium), the urinary excretion for ytterbium was however relatively more important.

 

It is important to note that several authors have reported differences in excretion pattern depending on the ionic radius of the rare earth under consideration. The reported differences seem to be coherent with the differences in distribution pattern, as already discussed above.

For instance, Leggett et al. (2014) summarised results obtained by Durbin (1960, 1962, 1973), who compared the behaviour of radioisotopes of trivalent lanthanoid elements (dissolved in sodium citrate) in rats following intramuscular administration. The general conclusion drawn based on the information from the studies by Durbin agrees with the statement by Filov (1993) that the lanthanoids with higher ionic radius (lighter lanthanoids) are increasingly stored in the liver and biliary excretion therefore becomes increasingly important, whereas lanthanoids with smaller ionic radius (heavier lanthanoids, such as ytterbium) are increasingly stored in the bone, with urinary excretion becoming increasingly important. Based on the data from the Durbin studies, Leggett et al. (2014) reported that 7 and 19% of the injected activity four days post-administration in rats was excreted via faeces and urine respectively for ytterbium. It is important to note that these observations are made after intramuscular administration and are therefore somewhat contrasting with the expectations and observations after oral or inhalation exposure or intravenous administration, as discussed above, where urinary excretion is expected/concluded to be less important, however, a common observation seems to be that the excretion via urine is relatively more important for ytterbium than for lighter rare earths.

 

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