Yttrium oxide (Y2O3), europium-doped

Endpoint summary

Description of key information

A combined repeated dose toxicity study with reproduction/ developmental toxicity screening has been conducted with yttrium oxide according to OECD 422 test guideline using the oral exposure route with wistar rats. No adverse effects were observed and the NOAEL in males and females was considered to be >= 1000 mg/kg/day.  
A publication fully describes a 30 days repeated inhalation study with yttrium oxide in beagle dogs. A systemic NOAEL of > 12.65 mg/m3 was established based on the absence of relevant changes in organ weights, macroscopic observations at necropsy and histopathology at the tested concentration (above 12.65 mg/m3). A local LOAEL of 12.65 mg/m3 is established based on the inflammatory response to dust overload in lungs and bronchial lymph nodes. These results are read across to the registered substance.
No dermal repeated dose toxicity study is available as inhalation exposure is more likely due to the small particle size of the substance. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

The rationale to read across the data is attached in Section 13.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

There were no clinical signs recorded in male and female animals of treated groups that could be directly related to treatment. However, there were few clinical signs namely moving the bedding, nasal discharge (dark or reddish), salivation and piloerection seen occasionally and transiently during the study period in MD or HD group animals. These findings were considered to be due to local effect but not the systemic effect of the test item. These findings were considered not likely to be adverse. In addition, there was alopecia (on hind limb, forelimb, thorax and abdominal region) of few isolated animals of MD or HD groups, which was assumed to be incidental in origin.
During the weekly detailed clinical observation, no significant changes or differences between the groups were found.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

In both males and females, no treatment related changes were noted for body weight and body weight change during the study period. Statistically there were significant increase in body weight change in female HD group during 2nd week of premating period when compared to control. In addition, there was lower mean body weight gain noted between days 1-7 of premating when compared to control without attaining the statistical significance. But, this increase or decrease in weight gain did not correlate with food intake during the same period. Hence, the changes were not considered likely to be adverse. There was decrease in body weight gain noted in female MD and HD groups during lactation period when compared to control. This decrease had no statistical significance and was not likely to be adverse.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

In both males and females, no treatment related changes were noted for treated group when compared to corresponding control. The statistical evaluation of the data revealed no significant changes in food intake in treated group animals when compared to control.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

no effects observed

Description (incidence and severity):

There were no ophthalmoscopic findings in any of the animals of this study.

Haematological findings:

no effects observed

Description (incidence and severity):

No treatment related changes were noted for haematology and blood coagulation parameters measured at the end of treatment period in male and female animals. There were no statistically significant changes noted for haematological and coagulation parameters between the treated and control groups.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

There were no treatment related changes considered for measured clinical biochemistry parameters of male and female treated groups when compared to corresponding control. However, there was statistically significant increase noted for mean potassium value in male MD group. In the absence of dose response pattern no relevance to treatment was considered.

Urinalysis findings:

no effects observed

Description (incidence and severity):

The urinalysis performed in male animals revealed no considerable changes in treated groups when compared to the control.

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

No relevant effects of treatment were observed in any of the parameters of the functional observation battery before and at the end of the treatment period. There were no biologically relevant differences in body temperature between the groups.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

There were no changes considered to be related to treatment noted for organ weight in both males and females when compared to corresponding control. However, there was statistically significant increase in relative weight of left kidney weight in male treated (LD, MD and HD) groups, but not total kidney weight. This change in left kidney weight, in the absence of histological changes was not considered to have toxicological relevance.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

At terminal sacrifice, macroscopic organ findings noted were few, and none of them was considered to be test item related.
Yellow spot(s) at the epididymis were observed without dose relationship in 2/10 control males, 1/10 male of LD group, 3/10 males of MD group and 2/10 males of HD group. They were not considered treatment related as histologically they were confirmed to represent spermatic granuloma, a finding known to occur spontaneously in untreated rats of this strain and age.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Reproductive organs
No test item-related effects were noted on male and female reproductive organs in any of the treatment groups.
Histopathological findings noted in male reproductive organs were few and considered to be spontaneous in nature and unrelated to the test item, comprising multifocal atrophic tubules in the testis of each one male treated at 300 and 1000 mg/kg/day and subsequent epididymal changes in the same animals.
Reproductive organs of most study females showed histomorphological evidence of precedent pregnancy in the uterus. The number of large corpora lutea in the ovary was not essentially different between the groups.
Non pregnant animals showed physiological sexual cycling, and their unsuccessful mating was considered unrelated to the treatment.
Other organs
No test item-related histopathological findings were noted in the other organs evaluated in randomized males and females of the control and high dose group.
Histopathological changes seen at terminal sacrifice were considered to be incidental in origin and/or within the range of expected changes for rats of this age and strain kept under laboratory conditions.

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed at the highest dose tested.

Key result

Critical effects observed:

no

Conclusions:

Repeated dose administration of yttrium oxide to the male (minimum 28 days) and female (maximum 54 days) Wistar rats at dosages of 100, 300 and 1000 mg/kg body weight revealed neither mortalities nor findings of toxicological relevance in male and female animals. There were no toxicologically relevant findings noted for reproductive and developmental parameters (NOAEL = 1000 mg/kg bw/day). This result is read across to yttrium oxide, europium-doped.

Based on the data generated from this “Combined Repeated Dose Oral Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test with Yttrium Oxide, the no observed adverse effect level (NOAEL) for systemic and reproductive and developmental toxicity is considered to be 1000 mg/kg body weight.

No classification for repeat-dose toxicity is warranted based on the absence of toxicologically relevant effects in this study, according to the criteria of Annex VI Directive 67/748/EEC or the 1272/2008 regulation -CLP).

Executive summary:

There was no mortality noted in treated (at 100, 300 and 1000 mg/kg bw/day) and control groups during the study period (at least 28 days for males and 54 days for females). During the weekly detailed clinical observation, no significant changes or differences between the groups were found. There were no ophthalmoscopic findings in any of the animals of this study. Weight increase or decrease had no statistical significance and was not likely to be adverse. The statistical evaluation of food consumption revealed no significant changes in food intake in treated group animals when compared to control. There were no statistically significant changes noted nor for haematological and coagulation parameters nor for clinical biochemistry parameters of male and female treated groups when compared to corresponding control. The urinalysis performed in male animals revealed no considerable changes in treated groups when compared to the control.

There were no changes considered to be related to treatment noted for organ weight in both males and females when compared to corresponding control. However, there was statistically significant increase in relative weight of left kidney weight in male treated (LD, MD and HD) groups, but not total kidney weight. This change in left kidney weight, in the absence of histological changes was not considered to have toxicological relevance. At terminal sacrifice, macroscopic organ findings noted were few, and none of them was considered to be test item related. No test item-related histopathological findings were noted in the other organs evaluated in randomized males and females of the control and high dose group. Based on these results the NOAEL was established at 1000 mg/kg bw/day. This result is read across to yttrium oxide, europium-doped.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available study is performed according to OECD test guidelines and GLP principles (Klimisch 1 study).

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

The rationale to read across the data is attached in Section 13.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Description (incidence and severity):

no mortality

Mortality:

no mortality observed

Description (incidence):

no mortality

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

No effect on plasma volume & hemoglobin concentration. Significant increase of white blood cells & decrease of the erythrocyte volume which should indicate Y2O3 was being transported from the lungs to other tissues, having negative erythropoiesis effect.

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Description (incidence and severity):

Lungs exposed dogs were reddish gray and were firmer than the lungs of the controls. Bronchial lymph nodes in exposed dogs were enlarged 8 - 10 times; other body lymph nodes were normal in size. With regards to gross appearance, other organs were normal.

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Details on results:

Histologic examination showed no effect on: heart, liver, spleen, mesenteric lymph nodes, testis or ovaries, kidneys, adrenal gland, and bone marrow.
Thoraxic radiography showed subtle changes which are consistent with the slightly increased density at the hilus of the lung. Possibly the enlarged bronchial lymph nodes which contained numerous dustladen macrophages contributed to the slight increase in density.

Blood lactate concentration:
This parameter was obtained by subtracting a normal value before the exposure and after 30 days of exposure for the same dog.
Normal value was determined as the average of results for 4 determinations (2 made during the week before exposure and 2 during the weeks after exposure began).
The mean of the difference was + 5.00 mg/100 mL of blood. This difference was tested as relevant according to the Student’s test (p = 0.05). It was assumed that, with repeated treadmill exercise under conditions of no exposure, post exercise blood lactate concentration would decrease. This decrease was demonstrated by Yoder and al.
A variance analysis showed no significant difference due to replication of test or sex of dog.

A highly positive increase occurred in 3 dogs, 1 from each experiment which indicated that some alteration had occurred in their ability to transfer, transport or utilize oxygen. Toward the end of the experiment, it became difficult to these dogs to complete their 10-minute exercise period. It was observed that certain dogs respond to treadmill exercising quite favorably, whereas others are more reluctant to increase work output. In an ideal situation only dogs responding favorably should be selected and subjected to a greater work task.

Erythrocyte volume:The overall mean of the difference was 3.9 mL/kg of body weight and was only significant at the 0.10 level. No difference was observed regarding replication or sex. The mean of this difference was negative. One might assume that with increased tissue demands for oxygen an increase in erythrocyte volume might occur. It is possible that enough yttrium oxide was being transported from the lungs to other tissues to have an inhibiting effect upon erythropoiesis. One might have observed a more significant decrease in erythrocyte volume if the period of exposure and exercise had been extended.

Plasma volume and hemoglobin concentration: the mean of the differences were not significant.

Leukocyte count: The overall mean of the difference is 2.333 lecuocytes/cm3 of blood. This was significant increase (p = 0.01) indicating an active response of the body to remove foreign material. Regarding the absence of difference observed in white blood cell counts by Davison if mice and guinea pigs were exposed to dust aerosols of neodymium, this result could be a peculiarity of species response or effect of yttrium oxide (combined with treadmill exercise).
A slightly significant decrease in circulating monocytes was seen at the end of the exposure period. This was significant at the 0.10 level.
No significant change in distribution of other white blood cell types was detected.

Necropsy results:
Lungs of exposed dogs were reddish grey instead of pink. Bronchial lymph nodes in exposed dogs were enlarges 8 to 10 times but other body lymph nodes were normal in size. With regards to gross appearance, all other organs were normal.

Results of histologic examination:
Many cellular elements were within the alveoli of lungs of exposed dogs. The most apparent histologic change occurring as a result of 30 day’s exposure to yttrium oxide was the presence of many macrophages and leukocytes in the alveoli. According to Hatch & gross, these alveolar macrophages or “dust cells” are desquamated alveolar cells. The extreme hypertrophy of alveolar epithelial cells prior to desquamation is shown.
The leukocytes were mainly neutrophils. Many had elongated nuclei and were probably in the process of diapedesis. Seemingly, a leukotactic substance was attracting many leucocytes to the lungs and this was reflected by the increased leukocyte count.
Examination of the lungs indicated no connective tissue increase.

Results of examination of bronchial lymph nodes from exposed dogs indicated the presence of many dust-laden macrophages. These macrophages were seen after 30 days of exposure.
The same result of the macrophages increase was observed by Davison in mice tracheobronchial lymph nodes after 100-day’s exposure to neodymium oxide and in guinea pigs after a 50-day’s exposure to neodymium oxide.
This experiment indicated that the lymphatics of the dog seem quite efficient in removing the contaminant from the lungs to the bronchial lymph nodes.

Radiographic examination: slight increase of the lung density probably due to the increase of dust-laden macrophages.

Key result

Dose descriptor:

NOAEC

Remarks:

systemic

Effect level:

>= 12.65 mg/m³ air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no systemic effects observed

Key result

Dose descriptor:

LOAEC

Remarks:

local

Effect level:

12.65 mg/m³ air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: local effect: inflammatory response to dust overload in lungs and bronchial lymph nodes

Key result

Critical effects observed:

no

Conclusions:

In a subacute repeated dose inhalation study with yttrium oxide, no relevant systemic effects were observed, exposing dogs 30 days to 12.65 mg/m3. An overall systemic NOAEL was established to be >= 12.65 mg/m3, based on the absence of change in hematology, organ weights, macroscopic observations at necropsy and histopathology at the tested concentration. A local LOAEL of 12.65 mg/m3 could be derived based on the inflammatory response to dust overload in lungs and bronchial lymph nodes. This result is read across to Yttrium oxide, europium-doped.

Executive summary:

An inhalation study was was performed with dogs exposed to yttrium oxide for 6 hours/day, 5 days/week for 6 weeks. The exposure lasted 30 days (180 exposure hours in total) and treadmill exercise was given for 10 minutes a day throughout the experiment. Post-exercise value of blood lactate concentration was determined 2 times a week and erythrocyte volume, plasma volume, hemoglobin concentration and leukocyte count were determined before the start and at the end of the exposure period. Thoracic radiographs were done before the exposure to determine freedom from lung lesions and subsequent fitness for treadmill exercise. Histologic examination was done on dogs after exposure period. Aerosol concentration, distribution and particle size have been determined. At necropsy, lungs of the exposed dogs were found to be reddish grey and were firmer than the lungs of the controls. Bronchial lymph nodes in exposed dogs were enlarged 8 - 10 times compared to controls; other body lymph nodes were normal in size. With regards to gross appearance, other organs were normal. Histopathological examination did not reveal any effects on heart, liver, spleen, mesenteric lymph nodes, testis or ovaries, kidneys, adrenal gland and bone marrow. Thoracic radiographs of each dogs were made before and at the end of the exposure period to determine freedom of lung lesions and subsequent fitness for treadmill exercise. No relevant effects were found. Significant increase of white blood cells, dust-laden macrophages in the bronchial lymph nodes & decrease of the erythrocyte volume indicated Y2O3 was being transported from the lungs to other tissues, having negative effect on erythropoiesis. The observed effects were rather consistent with a species-specific phenomenon of "lung overload" inflammatory response in the rat following inhalation of poorly soluble particles of low toxicity and resulting "portal-of-entry" effects, with a limited relevance to the human occupational situation given the levels of exposure. This resulted in overall systemic NOAEL of >= 12.65 mg/m³, based on the absence of change in organ weights, macroscopic observations at necropsy and histopathology at the tested concentration. The increased leucocyte counts in exposed dogs was considered to be secondary to the local effects. A local LOAEL of 12.65 mg/m³was derived based on the inflammatory response to dust overload in lungs and bronchial lymph nodes.

This value can be read-across to yttrium oxide, europium doped based on the chemical similarity with yttrium oxide, which is expected to result in similar behaviour in the lungs.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

subacute

Species:

dog

Quality of whole database:

The operational conditions, control and results are fully described in the publication (Klimisch 2 study).

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

The rationale to read across the data is attached in Section 13.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Description (incidence and severity):

no mortality

Mortality:

no mortality observed

Description (incidence):

no mortality

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

No effect on plasma volume & hemoglobin concentration. Significant increase of white blood cells & decrease of the erythrocyte volume which should indicate Y2O3 was being transported from the lungs to other tissues, having negative erythropoiesis effect.

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Description (incidence and severity):

Lungs exposed dogs were reddish gray and were firmer than the lungs of the controls. Bronchial lymph nodes in exposed dogs were enlarged 8 - 10 times; other body lymph nodes were normal in size. With regards to gross appearance, other organs were normal.

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Details on results:

Histologic examination showed no effect on: heart, liver, spleen, mesenteric lymph nodes, testis or ovaries, kidneys, adrenal gland, and bone marrow.
Thoraxic radiography showed subtle changes which are consistent with the slightly increased density at the hilus of the lung. Possibly the enlarged bronchial lymph nodes which contained numerous dustladen macrophages contributed to the slight increase in density.

Blood lactate concentration:
This parameter was obtained by subtracting a normal value before the exposure and after 30 days of exposure for the same dog.
Normal value was determined as the average of results for 4 determinations (2 made during the week before exposure and 2 during the weeks after exposure began).
The mean of the difference was + 5.00 mg/100 mL of blood. This difference was tested as relevant according to the Student’s test (p = 0.05). It was assumed that, with repeated treadmill exercise under conditions of no exposure, post exercise blood lactate concentration would decrease. This decrease was demonstrated by Yoder and al.
A variance analysis showed no significant difference due to replication of test or sex of dog.

A highly positive increase occurred in 3 dogs, 1 from each experiment which indicated that some alteration had occurred in their ability to transfer, transport or utilize oxygen. Toward the end of the experiment, it became difficult to these dogs to complete their 10-minute exercise period. It was observed that certain dogs respond to treadmill exercising quite favorably, whereas others are more reluctant to increase work output. In an ideal situation only dogs responding favorably should be selected and subjected to a greater work task.

Erythrocyte volume:The overall mean of the difference was 3.9 mL/kg of body weight and was only significant at the 0.10 level. No difference was observed regarding replication or sex. The mean of this difference was negative. One might assume that with increased tissue demands for oxygen an increase in erythrocyte volume might occur. It is possible that enough yttrium oxide was being transported from the lungs to other tissues to have an inhibiting effect upon erythropoiesis. One might have observed a more significant decrease in erythrocyte volume if the period of exposure and exercise had been extended.

Plasma volume and hemoglobin concentration: the mean of the differences were not significant.

Leukocyte count: The overall mean of the difference is 2.333 lecuocytes/cm3 of blood. This was significant increase (p = 0.01) indicating an active response of the body to remove foreign material. Regarding the absence of difference observed in white blood cell counts by Davison if mice and guinea pigs were exposed to dust aerosols of neodymium, this result could be a peculiarity of species response or effect of yttrium oxide (combined with treadmill exercise).
A slightly significant decrease in circulating monocytes was seen at the end of the exposure period. This was significant at the 0.10 level.
No significant change in distribution of other white blood cell types was detected.

Necropsy results:
Lungs of exposed dogs were reddish grey instead of pink. Bronchial lymph nodes in exposed dogs were enlarges 8 to 10 times but other body lymph nodes were normal in size. With regards to gross appearance, all other organs were normal.

Results of histologic examination:
Many cellular elements were within the alveoli of lungs of exposed dogs. The most apparent histologic change occurring as a result of 30 day’s exposure to yttrium oxide was the presence of many macrophages and leukocytes in the alveoli. According to Hatch & gross, these alveolar macrophages or “dust cells” are desquamated alveolar cells. The extreme hypertrophy of alveolar epithelial cells prior to desquamation is shown.
The leukocytes were mainly neutrophils. Many had elongated nuclei and were probably in the process of diapedesis. Seemingly, a leukotactic substance was attracting many leucocytes to the lungs and this was reflected by the increased leukocyte count.
Examination of the lungs indicated no connective tissue increase.

Results of examination of bronchial lymph nodes from exposed dogs indicated the presence of many dust-laden macrophages. These macrophages were seen after 30 days of exposure.
The same result of the macrophages increase was observed by Davison in mice tracheobronchial lymph nodes after 100-day’s exposure to neodymium oxide and in guinea pigs after a 50-day’s exposure to neodymium oxide.
This experiment indicated that the lymphatics of the dog seem quite efficient in removing the contaminant from the lungs to the bronchial lymph nodes.

Radiographic examination: slight increase of the lung density probably due to the increase of dust-laden macrophages.

Key result

Dose descriptor:

NOAEC

Remarks:

systemic

Effect level:

>= 12.65 mg/m³ air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no systemic effects observed

Key result

Dose descriptor:

LOAEC

Remarks:

local

Effect level:

12.65 mg/m³ air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: local effect: inflammatory response to dust overload in lungs and bronchial lymph nodes

Key result

Critical effects observed:

no

Conclusions:

In a subacute repeated dose inhalation study with yttrium oxide, no relevant systemic effects were observed, exposing dogs 30 days to 12.65 mg/m3. An overall systemic NOAEL was established to be >= 12.65 mg/m3, based on the absence of change in hematology, organ weights, macroscopic observations at necropsy and histopathology at the tested concentration. A local LOAEL of 12.65 mg/m3 could be derived based on the inflammatory response to dust overload in lungs and bronchial lymph nodes. This result is read across to Yttrium oxide, europium-doped.

Executive summary:

An inhalation study was was performed with dogs exposed to yttrium oxide for 6 hours/day, 5 days/week for 6 weeks. The exposure lasted 30 days (180 exposure hours in total) and treadmill exercise was given for 10 minutes a day throughout the experiment. Post-exercise value of blood lactate concentration was determined 2 times a week and erythrocyte volume, plasma volume, hemoglobin concentration and leukocyte count were determined before the start and at the end of the exposure period. Thoracic radiographs were done before the exposure to determine freedom from lung lesions and subsequent fitness for treadmill exercise. Histologic examination was done on dogs after exposure period. Aerosol concentration, distribution and particle size have been determined. At necropsy, lungs of the exposed dogs were found to be reddish grey and were firmer than the lungs of the controls. Bronchial lymph nodes in exposed dogs were enlarged 8 - 10 times compared to controls; other body lymph nodes were normal in size. With regards to gross appearance, other organs were normal. Histopathological examination did not reveal any effects on heart, liver, spleen, mesenteric lymph nodes, testis or ovaries, kidneys, adrenal gland and bone marrow. Thoracic radiographs of each dogs were made before and at the end of the exposure period to determine freedom of lung lesions and subsequent fitness for treadmill exercise. No relevant effects were found. Significant increase of white blood cells, dust-laden macrophages in the bronchial lymph nodes & decrease of the erythrocyte volume indicated Y2O3 was being transported from the lungs to other tissues, having negative effect on erythropoiesis. The observed effects were rather consistent with a species-specific phenomenon of "lung overload" inflammatory response in the rat following inhalation of poorly soluble particles of low toxicity and resulting "portal-of-entry" effects, with a limited relevance to the human occupational situation given the levels of exposure. This resulted in overall systemic NOAEL of >= 12.65 mg/m³, based on the absence of change in organ weights, macroscopic observations at necropsy and histopathology at the tested concentration. The increased leucocyte counts in exposed dogs was considered to be secondary to the local effects. A local LOAEL of 12.65 mg/m³was derived based on the inflammatory response to dust overload in lungs and bronchial lymph nodes.

This value can be read-across to yttrium oxide, europium doped based on the chemical similarity with yttrium oxide, which is expected to result in similar behaviour in the lungs.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

12.65 mg/m³

Study duration:

subacute

Species:

dog

Quality of whole database:

The operational conditions, control and results are fully described in the publication.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No study with yttrium oxide, europium doped is available. However, several studies with yttrium oxide are present. The justification for this analogue approach is described in a report (see section 13 of IUCLID) and at the beginning of chapter 1.4 of the CSR.

Oral exposure:

An OECD422 oral repeated dose study has been performed exposing 10 rats/sex to 0, 100, 300, and 1000 mg/kg bw of yttrium oxide via gavage. There was no mortality noted in treated and control groups during the study period (at least 28 days for males and 54 days for females). During the weekly detailed clinical observation, no significant changes or differences between the groups were found. There were no ophthalmoscopic findings in any of the animals of this study. Weight increase or decrease had no statistical significance and was not likely to be adverse. The statistical evaluation of food consumption revealed no significant changes in food intake in treated group animals when compared to control.

There were no statistically significant changes noted for haematological and coagulation parameters, for clinical biochemistry parameters and for functional observation parameters of male and female treated groups when compared to corresponding control. The urinalysis performed in male animals revealed no considerable changes in treated groups when compared to the control. There were no changes considered to be related to treatment noted for organ weight in both males and females when compared to corresponding control. However, there was statistically significant increase in relative weight of left kidney weight in male treated (LD, MD and HD) groups, but not total kidney weight. This change in left kidney weight, in the absence of histological changes was not considered to have toxicological relevance. At terminal sacrifice, macroscopic organ findings noted were few, and none of them was considered to be test item related. No test item-related histopathological findings were noted in the other organs evaluated in randomized males and females of the control and high dose group.

Inhalation exposure:

A publication, with a reliability of 2 according to Klimisch scoring system, described a 30 days repetead inhalation study with dogs, exposed to 12.65 mg/m3 yttrium oxide. It fully describes the experimental conditions and the results. The study showed no relevant effect on gross pathology, histopathology: no effect on heart, liver, spleen, mesenteric lymph nodes, testis or ovaries, kidneys, adrenal gland and bone morrow, thoracic radiographs of each dogs were made before and at the end of the exposure period. Lungs of exposed dogs were reddish gray and were firmer than the lungs of the controls. Bronchial lymph nodes in exposed dogs were enlarged 8 - 10 times; other body lymph nodes were normal in size. With regards to gross appearance, other organs were normal. Only significant increase of white blood cells, dust-laden macrophages in the bronchial lymph nodes & decrease of the erythrocyte volume which should indicate yttrium oxide was being transported from the lungs to other tissues, having negative erythropoiesis effect. The observed effects were rather consistent with a species-specific phenomenon of "lung overload" inflammatory response in the rat following inhalation of poorly soluble particles of low toxicity and resulting "portal-of-entry" effects (local LOAEC is 12.65 mg/m3, systemic NOAEL is >=12.65 mg/m3), with a limited relevance to the human occupational situation given the levels of exposure. Therefore no classification is warranted for this endpoint.

Justification for classification or non-classification

Based on the availabe data yttrium oxide, europium doped is not classified for repeated dose toxicity according to CLP Regulation (EC) No. 1272/2008 including its amendments.