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Description of key information

Some experimental data (published scientific literature and grey literature) were identified informing on the toxicokinetic behaviour of yttrium and its compounds. These data, together with information on the physicochemical characteristics of yttrium trinitrate as well as the toxicological information available on this compound are used to perform a qualitative assessment of the absorption, distribution/metabolism, and elimination of this yttrium compound. The absorption factor for yttrium after oral exposure to yttrium trinitrate is set at 10% for risk assessment purposes. The respiratory absorption factor is set at 10% and a dermal absorption factor of 1% is suggested.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
10
Absorption rate - dermal (%):
1
Absorption rate - inhalation (%):
10

Additional information

Introduction

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

Yttrium trinitrate is a solid inorganic yttrium compound with yttrium in its most prevalent oxidation state (i.e. +III). It is very soluble in pure water. Its dissolution in pure water is accompanied by a sharp pH decrease (solubility > 1000 g/L, pH 0.39-0.58, Demangel, 2013). Increasing the pH of the solution significantly decreases its solubility. Demangel (2013) reported precipitation of the test item at pH 5 and higher pH levels tested.

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 toxicity after uptake, information on other yttrium compounds can be used in this assessment as long as their inherent properties are taken into account. 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 yttrium compounds, this simplistic approach assumes that a specific very water-soluble yttrium containing compound will show similar toxicokinetic behaviour and toxicological hazards as other very water-soluble yttrium containing compounds. Therefore, studies evaluating the toxicokinetic behaviour of yttrium following exposure to other water-soluble yttrium compounds than yttrium trinitrate can also be used to assess the toxicokinetic behaviour of yttrium following exposure to yttrium trinitrate.

The toxicokinetic behaviour of the counter ion is thus not evaluated (in this case, nitrate).

 

Absorption

Oral/Gastro-intestinal (GI) absorption

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, inorganic metal compounds such as yttrium trinitrate are usually not lipid soluble and are thus expected to be poorly absorbed by passive diffusion (Beckett, 2007). It has been demonstrated that several metals can cross cell membranes via ion channels or specific carriers intended for endogenous substrates (Beckett, 2007). For yttrium, it is not entirely clear which mechanism of transport is responsible for uptake. It is however interesting to note that Y3+ has a similar ionic radius as Ca2+, suggesting that it is likely to mimic and interfere with Ca2+ dependent receptors. Such interference has been observed by Mlinar and Enveart (1993), who observed competitive antagonist binding of Y3+ to T-type voltage gated calcium channels in vitro. Interactions of yttrium with calcium ion channels (channel blockage) has also been described by Jakubek et al. (2009). 

 

Yttrium trinitrate has a molecular weight of 274.92 g/mol, with yttrium itself having a molar mass of 88.91 g/mol. These values being well below 500 g/mol, it can be assumed that uptake of bioavailable species (free yttrium cation and/or potentially other water-soluble yttrium species) is possible. The extent of uptake, if any, would however be determined by the bioavailability of yttrium in the gastro-intestinal tract. Yttrium trinitrate is a very soluble compound in pure water. The water solubility is > 1000 g/L and is accompanied by a sharp pH decrease (pH 0.39-0.58 in the study of Demangel, 2013). Under the acidic conditions in the stomach, yttrium is therefore considered to be in solution in the gastric fluid. However, when entering the duodenum, pH is rapidly changed to about pH 6, gradually increasing to pH 7.4 in the terminal ileum (Fallingborg, 1999). At pH 6, yttrium is expected to be rapidly precipitated from the gastro-intestinal content. As is clear from the water solubility study of Demangel (2013), precipitation already occurs in pure water in which pH is adjusted to pH 5. Precipitation will be further enhanced in the gastro-intestinal tract due to the presence of ligands that have a strong affinity for yttrium. Phosphate for instance forms strong, insoluble complexes with yttrium, in a pH-independent way. Further, precipitation of carbonate complexes of yttrium becomes more important with increasing pH (confirmed by modelling in Visual Minteq). Therefore, it is expected that the bioavailability of yttrium for uptake in the small intestine will be very limited. 

Studies directly evaluating the absorption of yttrium following oral exposure to yttrium trinitrate in animals and humans are not available. For yttrium trichloride however, another water-soluble yttrium compound for which similar behaviour can be expected, yttrium accumulation was measured in different organs of rats repeatedly exposed via oral gavage to yttrium trichloride for 28 days, followed by 14 days recovery (Ogawa et al., 1994). Yttrium was found to accumulate in the kidneys, femur, liver and spleen in a dose-dependent manner. The highest concentrations were found in the kidney after 28 days of exposure to the highest test dose (1000 mg/kg bw/day, as YCl3.6H2O): ca. 7 µg Y/g dw in females and ca. 8 µg Y/g dw in males. These findings suggest that absorption via the gastro-intestinal tract occurs. Considering the body weight of the rats (ca. 170 g for males, ca. 130 g for females), the administered dose of yttrium was ca. 39.5 mg Y/day in males and ca. 30 mg Y/day in females. Although dry and wet kidney weights are not reported, it is clear from these figures that the accumulated yttrium represents a very small % of the daily dose and certainly of the total dose administered over 28 days. The accumulated concentrations are the result of absorption, distribution, and excretion. However, because accumulated concentrations in organs of rats of the recovery group (14 days recovery after 28 days of exposure) were not much lower than after 28 days of exposure, and the relative distribution between organs was still rather similar, it can be safely assumed that the accumulated concentrations are mainly determined by absorption during the exposure period. Therefore, it can be concluded that the absorption via the gastro-intestinal tract is rather limited.

The limited gastro-intestinal absorption of yttrium is further supported by figures reported in several (review) publications. For instance, the Health Council of the Netherlands (2000) reported that experimental data on yttrium in rats demonstrate that after oral uptake, yttrium is poorly absorbed from the gastro-intestinal tract, with more than 90% excretion via the faeces. Further, in a review on the metabolism of the elements in the human body (Spector, 1974), yttrium was classified as element that is very poorly (less than 5%) absorbed across the gut wall.

 

Finally, it is investigated whether the available toxicological data for yttrium trinitrate or related substances such as yttrium trichloride support the indications of limited oral absorption. 

Yttrium trinitrate was shown to be harmful to rats after acute oral exposure (lowest LD50 = 1650 mg/kg bw, resulting in classification as Acute Toxicity Cat. 4, Shapiro, 1991a). In a supporting study (Guillot, 1986) the LD50 was 3839 mg/kg bw. In both studies, local effects have been observed in the stomach and intestines, e.g. discoloration of the intestines and pyloric region, contraction, thickening or hardening of the glandular part of the stomach, distention of the non-glandular part of the stomach, adherence of other organs to the stomach, etc. These findings suggest that the observed mortality was most likely due to these local effects in the stomach and intestines and not to systemic effects after uptake. The observed local effects could be explained by the heavy acidifying effect of the test item when in contact with water/aqueous media. This acidifying effect is due to the nitrate part of the compound and not to yttrium itself. The absence of systemic effects is supportive of limited bioavailability of yttrium for uptake in the small intestine, as concluded above.  

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in Wistar rats, yttrium trinitrate was tested at 250, 500 and 1000 mg/kg bw/day. The NOAEL (No Observed Adverse Effect Level) for systemic toxicity of the parent animals was ≥ 1000 mg/kg/day. At this test dose, there was no mortality among parent animals, no clinical findings (daily or weekly), no differences in the functional observational battery (including grip strength and locomotor activity), no differences in mean absolute or relative organ weights, and no overt macroscopical or microscopical findings of toxicological relevance (Rossiello, 2017). The results of this study do not provide reasons to deviate from the assumption that absorption of yttrium following oral exposure to yttrium trinitrate is limited.  

Oral repeated dose toxicity data are also available for yttrium trichloride, another water-soluble yttrium compound for which similar behaviour is expected as for yttrium trinitrate. After repeated oral gavage of yttrium trichloride in rats at doses of 40, 200 and 1000 mg/kg bw/day for 28 days, no mortality has been observed (Ogawa et al., 1994). At the highest test dose of 1000 mg/kg bw/day (as YCl3.6H2O), a slight decrease in body weight gain and food consumption was observed over the 28 days of exposure when compared to the control group and the groups treated with lower doses. It is not clear from the publication whether the observed differences were significant or not. Nevertheless, during the 14-day recovery period, food consumption was restored, and consequently, the difference in body weight between the rats in the high dose group and the rats in the control and the lower dose groups appeared to become smaller again. It is important to note that in animals at the highest dose tested, local effects have been observed in the stomach: hyperkeratosis of the forestomach, eosinophilic leukocyte infiltration in the submucosa of the stomach (all animals), erosion and dilatation of the gastric gland (males), swelling of the glandular stomach epithelium (females). Therefore, the observed effects on body weight gain and food consumption were most likely related to this local irritating effect of the test item, especially since food consumption was restored during the recovery period. No clear systemic effects were observed in this study. As mentioned above, the accumulation of yttrium in the kidneys, femur, liver and spleen in a dose-dependent manner are indicative of absorption, however, to a limited extent. In conclusion, the results of this study also support the assumption of limited bioavailability for uptake in the small intestine after oral exposure.

Based on the abovementioned information on the physicochemical characteristics of yttrium trinitrate, the information from literature on absorption of yttrium after oral exposure, and the available toxicological data for yttrium trinitrate as well as yttrium trichloride, the absorption factor for yttrium after oral exposure to yttrium trinitrate is set at 10% for risk assessment purposes, as a worst case.

 

Respiratory absorption

Low exposure to yttrium trinitrate is expected based on the inherent properties of the substance. No vapour pressure value has been determined as the substance does not melt below 300°C. Instead, it first solubilises in its hydration water upon heating, and between 300 and 500°C, it is conversed to YONO3, Y4O3(NO3)3 and finally Y2O3, allowing no reliable measurement of vapour pressure below its decomposition temperature (Bouchet 1994). Therefore, it is not likely that yttrium trinitrate is available for inhalation as a vapour. Moreover, no particle size distribution test has been performed with yttrium trinitrate due to the special hygroscopic properties of the substance (i.e. due to clump formation the test item cannot be characterised with respect to particle size distribution). Thus, as the formation of respirable suspended particulate matter is unlikely, human exposure by inhalation is considered not significant. Even though this route of exposure is considered not significant, the absorption of the potentially inhaled particles of yttrium trinitrate is assessed here below.

Yttrium trinitrate is a very soluble compound in pure water. However, its high water-solubility is influenced by the pH as previously discussed and confirmed by Demangel (2013). Therefore, once deposited on the walls of the airways, it is expected that the solubility of yttrium trinitrate substantially decreases due to the pH of the lung mucosae (pH about 6.6 in healthy individuals). Because the concentration of bioavailable forms – such as (solely or predominantly) the free Y3+ cation – in the bronchoalveolar fluid is expected to be rather low, absorption or translocation from the lung to the circulatory system is expected to be minimal.

Due to the pH of the pulmonary mucosae, the majority of the respired yttrium after exposure to yttrium trinitrate is expected to occur in the lungs as precipitated material. Such deposited material in the alveolar region may be engulfed 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 clearance mechanisms, especially material settled in the tracheo-bronchial region. In that case it will contribute to the gastro-intestinal absorption rather than to the absorption via inhalation.

No studies were identified regarding absorption of yttrium in humans or animals following inhalation exposure to yttrium trinitrate. However, some literature exists on yttrium trichloride, another water-soluble yttrium compound.

The distribution and lung clearance of yttrium trichloride was investigated after intratracheal instillation in rats (Hirano et al., 1990). Pulmonary clearance of the compound was shown to be very slow with a half-life of 168 days. The yttrium content in the supernatant of the bronchoalveolar fluid did not exceed 5 µg Y/lung even when a dose of 200 µg Y/rat was administered, suggesting that the alveolar surface fluid could retain at most 5 µg Y. The remaining yttrium was localised as an insoluble form in lysosomes of alveolar and interstitial macrophages and basement membranes, probably by a pinocytic route or absorbed, explaining the long-term retention of yttrium in the rat lung. Despite the relative important half-life of yttrium, the pulmonary inflammatory responses investigated in the study were markedly reduced by 7 days, suggesting that the insoluble storage of yttrium might be less toxic. No accumulation in liver or kidneys was observed.

The observations made by Hirano et al. (1990) support the expectations based on the physicochemical properties of yttrium trinitrate as described above, i.e. only a limited amount of yttrium can dissolve in the bronchoalveolar fluid, the remainder occurring as precipitated material which is engulfed by macrophages. The inflammatory responses observed in the lungs are most likely due to the initial acidifying effect of yttrium trinitrate – similar to what has been observed in the stomach after oral exposure. The absence of measurable accumulation further supports the assumption that respiratory absorption of yttrium is very low due to its expected low bioavailability in the bronchoalveolar fluid.

 

Based on the anticipated low solubility of yttrium trinitrate at pH levels typical for the pulmonary mucosae, as well as available information on the fate and toxicity of yttrium after intratracheal instillation of yttrium trichloride, a compound with expected similar behaviour as yttrium trinitrate, the respiratory absorption factor is set at 10% for risk assessment purposes, as a worst case.

 

Dermal absorption

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

As yttrium trinitrate is a solid showing clump formation due to its hygroscopic properties, the potential human exposure by the dermal route is expected to be low. Anyhow, yttrium trinitrate would have to dissolve in the moisture of the skin prior to penetrating skin by diffusive mechanisms. However, as the solubility of yttrium trinitrate rapidly decreases at physiologically relevant pH, no significant uptake by the skin is expected.

The acute dermal toxicity of yttrium trinitrate was investigated in an in vivo test on rabbits (Salvador, 2015a). The intact skin of 10 rabbits (5 males and 5 females) was exposed during 24 hours to the substance dissolved in corn oil. No mortality was observed and no abnormalities were found at the external examination performed in all animals at the end of the study, apart from multiple scabs observed on the treatment site of one female. No internal abnormalities were found in any treated animal. The LD50 was > 2000 mg/kg bw. These results support the expectation of limited uptake of yttrium after dermal exposure to yttrium trinitrate based on the physicochemical properties of the compound.

 

Yttrium trinitrate is not classified as a skin irritant when tested in an in vivo acute dermal irritation study (Shapiro, 1991b). A single 24-hour, occluded application of the test item to the intact or abraded skin of six rabbits produced well-defined to severe erythema, and very slight to moderate edema 24 hours after application of the substance. After 72 hours, most abraded sites had well-defined erythema and very slight edema. Most intact sites had decreased to very slight erythema, while edema remained in only three rabbits. Even though yttrium trinitrate powder was considered as moderately irritating using the scoring system applied in the study, based on the raw results it does not meet the criteria for classification as a skin irritant according to Regulation (EC) No 1272/2008.

 

Further, results of a skin sensitisation study in guinea pigs (Salvador, 2015b; GPMT, OECD 406) indicated that yttrium trinitrate induced a slight skin sensitisation response in the guinea pig, since a slight positive reaction was observed in 20% of the test animals after challenge with the test item at a concentration of 5% w/v in corn oil. Before this re-challenge, a challenge with the test item at a concentration of 20% w/v in corn oil resulted in a positive reaction in 75% of the animals in the test group but also in 40% of the control group, indicating that irritation has occurred following dosing with the test item at 20% w/v in corn oil. Nevertheless, based on the results of the re-challenge with 5% w/v test item in corn oil, showing that the incidence of the animals showing a positive reaction was lower than 30%, yttrium trinitrate does not need to be classified as a skin sensitiser, according to Regulation (EC) No 1272/2008.

 

Considering that yttrium trinitrate does not meet the CLP criteria for classification as skin irritant or skin sensitiser, it is not expected that the observed mild irritating and sensitising effects would substantially enhance the expected low dermal absorption.

 

In the absence of measured data on dermal absorption, ECHA guidance (2014) 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 yttrium trinitrate, 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 1% is suggested for risk assessment purposes.

 

Distribution and accumulation

From the above discussion, absorption of yttrium following exposure to yttrium trinitrate 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. Nevertheless, since there are indications for uptake – be it to a limited extent – the available information on distribution and accumulation is discussed below. The focus is on information obtained in studies in which yttrium trinitrate or yttrium compounds with an expected similar behaviour, such as yttrium trichloride, were administered via a relevant pathway for assessment in view of REACH registration (oral, inhalation – no data available for dermal pathway). Nevertheless, since lots of information is available from intravenous and even intraperitoneal studies, the most relevant information from such studies is briefly summarised too. Note that only data obtained with yttrium compounds containing stable yttrium have been included below. Lots of data are available obtained with yttrium radioisotopes or yttrium compounds containing radioisotopes of yttrium but these have not been included because absorption and distribution of these radioisotopes appears to be different.

 

Oral administration

The most relevant study yielding information on distribution and accumulation after oral exposure is the repeated dose toxicity study for yttrium trichloride in rats (Ogawa et al., 1994), which was already mentioned above (partim oral absorption). After 28 days of exposure at the highest dose tested (1000 mg/kg bw/day, as YCl3.6H2O), yttrium was observed to be accumulated in the kidneys at concentrations of ca. 7 µg Y/g dw in males and ca. 8 µg Y/g dw in females. The second highest concentrations were observed in bone (ca. 6 µg Y/g dw in males and females). Concentrations in liver and spleen were negligible compared to those in kidneys and bone (< 1 µg Y/g dw in males and females). As discussed above, the level of accumulation is very low in relation to the daily and total administered dose.

 

Administration via inhalation/intratracheal instillation

The most relevant study in this section was also discussed already above (partim respiratory absorption) (Hirano et al., 1990). In this study, yttrium trichloride was intratracheally instillated in rats (single dose). Pulmonary clearance of the compound was shown to be very slow with a half-life of 168 days. After instillation, yttrium remained predominantly in precipitated form in the lungs and became accumulated in lysosomes of alveolar and interstitial macrophages and basement membranes, explaining the long-term retention of yttrium in the rat lung. There was no indication of significant uptake in the circulatory system, since no accumulation in liver or kidneys was observed.

 

Intravenous administration

Hirano et al. (1993) demonstrated that after a single intravenous injection of rats with yttrium trichloride at a dose of 1 mg Y/animal, blood yttrium content decreased rapidly within 3 h. After 7 h, 75% of the administered yttrium was accumulated in the liver, 20% in spleen, and less important amounts in the lungs and kidneys. Thereafter, the half-life of yttrium in the liver was about 144 days. Lung yttrium content increased up to 92 days post-injection. Yttrium accumulated in the kidneys represented about 0.5% of the injected dose throughout the experiment at a dose of 1 mg Y/animal. Dose-related changes in yttrium distribution at 1 h post-injection were also reported in this publication. The single administered doses were 0.1, 0.5, 1, 1.5 or 2 mg Y/rat. Percentages in lung and spleen were not significantly different up to 1 mg Y/rat but were significantly increased at 2 mg Y/rat. The percentage of yttrium in the liver was increased with dose from 0.5 to 2 mg Y/rat, whereas the percentage of yttrium in the blood and kidney were decreased over the same doses. For instance, 70-80% of injected yttrium remained in the blood at 1 h post-injection from 0.1 to 0.5 mg Y/rat, however, the percentage of blood yttrium was decreased sharply with dose above 0.5 mg Y/rat. Most blood yttrium (> 98.5%) was distributed to plasma at doses from 0.1 to 1 mg Y/rat, whereas only 30% of blood yttrium was present in plasma at 2 mg Y/rat. HPLC-ICP results revealed that most yttrium in blood plasma was found in colloidal material. The colloidal form of yttrium in blood plasma was taken up rapidly mainly by the liver and spleen. TEM-XMA results indicated that yttrium was insolubilised in granular lysosomal inclusions of phagocytic cells in the liver and spleen, as was also observed in rat lungs after intratracheal instillation of yttrium trichloride (see above, Hirano et al, 1990). Yttrium also triggered acute hypercalcemia in the blood plasma, restoring to normal levels with increasing time post-injection. This again confirms the interaction between yttrium and calcium, which was also reported above (section on oral absorption). The initial hypercalcemia was ascribed to the fact that part of the physiologically regulated calcium was transformed in colloidal material, which can be assumed not to be available for physiological regulation, resulting in compensation through resorption from the bone. The observed increase in calcium concentrations in liver (10-fold compared to control at 100 h post-injection) and spleen (100-fold compared to control at 100 h post-injection), mainly due to deposition of calcium in colloidal material from the blood plasma, consequently cause the decrease to normal calcium concentrations in blood plasma over time. Increases of calcium content in spleen and liver, but also in lungs, were also observed after single intravenous injection of yttrium trichloride in rats or yttrium in male mice (Nakamura et al., 1993, 1997; Shinohara and Chiba, 1990).

 

Nakamura et al. (1997) intravenously administered 5 or 10 mg Y/kg (using yttrium trichloride) in rats (single dose) and investigated distribution to liver, spleen, bone, lung, and kidney. 68-72% of the administered dose was distributed to the liver after 1 day. For blood and the other organs investigated, the % of the administered dose remaining in blood or distributed to the organ under consideration 1 day post-injection differed depending on the administered dose (5 / 10 mg Y/kg):

- Spleen: 4.4 / 16%

- Bone: 15 / 9%

- Lung: 0.73 / 2.3%

- Kidney: 0.56 / 0.32%

- Blood: 9.2 / 0.61%

 

Intraperitoneal administration

One study (MacDonald et al., 1952) was identified, in which yttrium trichloride was administered intraperitoneally (60 mg/kg bw) in male rats every 2 days, with the maximal number of injections amounting to 83 in a single animal. Yttrium content in ashed liver, kidney, spleen, and lungs ranged from 1000 to 10000 ppm. Although total dosages as large as 936 mg were administered, the amount of yttrium in bone ash never exceeded 330 ppm. For comparison, for bone-seekers such as strontium, uptake is much greater, by about 100-fold. There was no linear increase with dose. When the bone was burdened with 150-200 ppm yttrium (observed already when ca. 50 mg was injected), further accumulation became more difficult.

Summarising the information discussed above:

- There is a difference in distribution depending on the exposure pathway followed in the study. After repeated oral administration of yttrium trichloride, the highest concentrations of yttrium were found in kidney, immediately followed by bone, whereas yttrium concentrations in liver and spleen were negligible (Ogawa et al., 1994). No accumulation in liver and kidney was observed after intratracheal installation of a single dose of yttrium trichloride (Hirano et al., 1990), indicating that there was no significant transfer to the circulatory system. Contrary to what was observed after oral exposure, yttrium was predominantly distributed to the liver, followed by spleen, after intravenous injection of yttrium trichloride (Hirano et al., 1993; Nakamura et al., 1997). Nakamura et al. (1997) also found yttrium in bone at similar concentrations as in spleen. However, the study of MacDonald et al. (1952), in which yttrium trichloride was administered intraperitoneally, demonstrated that yttrium should not be considered as a bone-seeker (such as strontium and lead), since yttrium accumulated in bone at levels ca. 100-fold less than these elements.

- In the intravenous studies, yttrium was shown to disappear quickly from the blood (in general scarcely detected after 4 hours) but can be retained in organs for a long time. Also after intratracheal instillation (Hirano et al., 1990), a long retention time in the lungs was reported.

- Both after intravenous injection (Hirano et al., 1993) and intratracheal instillation (Hirano et al., 1990) of yttrium trichloride, yttrium ended up in granular lysosomal inclusions in phagocytic cells: in the lungs after intratracheal instillation, and in liver and spleen after intravenous injection. There are indications for association with phosphorus and other elements (Sr, S, Fe, Ca) in the lysosomes (Hirano et al., 1993).

In conclusion, based on all available information on distribution, although absorption of yttrium is expected to be extremely low after exposure to yttrium trinitrate via relevant pathways, bioaccumulation of the very small bioavailable fraction cannot be totally excluded. However, considering the limited bioavailability for uptake after oral, inhalation, and dermal exposure, the rather low accumulated levels observed in test animals after oral exposure or intratracheal instillation, as well as the additional fact that the assessment of bioaccumulation potential of yttrium in aquatic organisms indicates that yttrium has a low potential for bioaccumulation and that bioaccumulation decreases when ascending the food chain, it can be safely concluded that yttrium, following exposure to yttrium trinitrate, has a low accumulation potential in humans.

 

Metabolism

As an element yttrium 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 yttrium trinitrate was demonstrated not to be mutagenic in vitro, both in the presence and absence of metabolic activation. As discussed above, several studies (Hirano et al., 1990, 1993) have observed that yttrium, after exposure to yttrium trichloride, is concentrated in granular inclusions in lysosomes of phagocytic cells (in the lungs after intratracheal instillation, in liver and spleen after intravenous injection), where it may be associated with other elements. This can be considered as a detoxification mechanism. No other information relevant for this section has been identified.

 

Excretion

Although no information could be found on yttrium trinitrate, several studies are available evaluating the excretion of yttrium after oral or intravenous administration of yttrium trichloride in rats.

Nakamura et al. (1991a) administered oral doses of 100 and 1000 mg YCl3/kg bw to rats and observed 92-98% excretion via the faeces within 4 days in the 100 mg/kg dose group and 94-98% within 7 days in the 1000 mg/kg dose group. This finding confirms the expectation that yttrium, after oral administration of a water-soluble yttrium compound such as yttrium trichloride (but also yttrium trinitrate), is rather unavailable for uptake in the small intestine, as discussed above.

After intravenous administration of 10 mg YCl3/kg bw, 5-18% of the administered yttrium was found to be excreted via the faeces within 7 days, whereas no yttrium was detected in urine (Nakamura et al., 1991b). This is in agreement with abovementioned findings (Hirano et al., 1993) that yttrium-containing colloids are formed in the blood after intravenous administration of yttrium trichloride, which are then deposited in liver and spleen, where they are included in lysosomes of phagocytic cells. From there, gradual release, e.g., to the gut, may occur, resulting in excretion via the faeces.

 

Finally, a urinary excretion rate of 0.216% was measured in 24-h urine samples after oral administration of 116.7 mg yttrium trichloride in male rats (Hayashi et al., 2006; Kitamura et al., 2012). The low urinary elimination rate was considered due to retention of yttrium in the reticuloendothelial phagocytic clearance system (as already described above) and overflow of administered yttrium into urine.


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