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Effects on fertility

Description of key information

A combined repeated dose oral toxicity study with a reproduction/ developmental toxicity screening performed with substance analogue Yttrium Oxide is available. Based on this study, the no observed adverse effect level (NOAEL) for systemic and reproductive and developmental toxicity is considered to be >=1000 mg/kg body weight. No adverse effects on fertility were observed. This result is read across to yttrium oxide, europium doped.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
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, non-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
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):
For details see 7.5.1.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
For details see 7.5.1.
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:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
For details see 7.5.1.
Other effects:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
There were no treatment related changes noted for epididymal sperm motility (Motile Count %, Static Count % and Rapid Count %) measured in all animals of treated and control groups. The statistical analysis of epididymal sperm motility indicated no statistical significant difference between the treated and control groups.
Reproductive performance:
no effects observed
Description (incidence and severity):
No treatment related changes were noted for number of corpora lutea, number of implantation sites, number of live pups born on PND 0 and percentage of pre and post implantation loss in treated groups when compared to control. The statistical evaluation of data revealed no significant differences between the values of treated and control groups.
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 seen at highest test dose
Key result
Critical effects observed:
no
Clinical signs:
no effects observed
Description (incidence and severity):
No treatment related changes were noted for survival of the pups from PND 0 to PND 4 in treated groups when compared to control.
Mortality / viability:
no mortality observed
Description (incidence and severity):
One pup each in Control, LD and MD groups found dead or missing between PND 0 and 4. The missing pup was assumed to be cannibalized by the dam, this observation was considered to be incidental. No treatment related changes were considered for viability index (%).
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment related gross external findings were observed in any of the treated groups. However, there were few isolated findings noted in pups namely dry skin, dark spot on/ or dark abdomen, dark snout in control group; dark spot on forelimb and thoracic back, dark snout in LD group; dry skin in MD and HD groups. These findings were considered to be incidental in origin.
Histopathological findings:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects seen at highest dose tested
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Conclusions:
Repeated dose administration of Yttrium Oxide to male (minimum 28 days) and female (maximum 54 days) Wistar rats following OECD guideline 422 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 also no toxicologically relevant findings noted for reproductive and developmental parameters.

Based on these data, the no observed adverse effect level (NOAEL) for systemic and reproductive and developmental toxicity is considered to be 1000 mg/kg body weight/day. The NOEL for reproductive performance (mating and fertility) was considered to be 1000 mg/kg/day and the NOEL for toxic effects on progeny was 1000 mg/kg/day. This result is read across to Yttrium oxide, europium-doped.
Executive summary:

A repeated dose study was performed according to OECD guideline 422 with Yttrium Oxide. Male (minimum 28 days) and female (maximum 54 days) Wistar rats were dosed at dosages of 100, 300 and 1000 mg/kg body weight/day. 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.

No test item-related effects were noted on male and female reproductive organs in any of the treatment groups. The statistical analysis of epididymal sperm motility indicated no statistical significant difference between the treated and control groups. No treatment related changes were noted for the precoital interval and duration of gestation in treated groups when compared to control. All pregnancies resulted in normal births.

There were no treatment related changes noted for copulation index (%), fertility index (%), delivery index (%) and viability index (%) in treated groups when compared to corresponding control group.

Successful mating resulted 100% pregnancy rates in C and HD groups and 90% pregnancy rates in LD and MD groups. Histologically, they showed physiological sexual cycling, and their unsuccessful mating was considered unrelated to the treatment. The statistical evaluation of pre and post-natal data revealed no significant differences between the values of treated and control groups. No treatment related no significant changes were noted for survival of the pups and for viability index (%).

Based on these data, the no observed adverse effect level (NOAEL) for systemic and reproductive and developmental toxicity is considered to be >=1000 mg/kg body weight/day. The NOEL for reproductive performance (mating and fertility) was considered to be 1000 mg/kg/day and the NOEL for toxic effects on progeny was 1000 mg/kg/day. This result is read across to Yttrium oxide, europium-doped.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Klimisch 1 study (performed with substance analogue).
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No study with yttrium oxide, europium doped is available. However, a study with yttrium oxide is present. The justification for this analogue approach is described in a report (see section 13 of IUCLID).

An OECD 422 study according to GLP principles was performed with rats. Yttrium oxide was administered daily by oral gavage to male and female Wistar rats,7 days per week with a maximum exposure of 54 days in total for females (at least 14 days of pre-mating, maximum 14 days of mating, 22 days of gestation and 4 days of post-partum) and minimum 28 days for males., at dose-levels of 100, 300 or 1000 mg/kg/day. There were no adverse effects of treatment on tested Wistar rats at any dose-level on mortality, clinical signs and biochemistry, body weight or food consumption. There were no effects in any group on mating, fertility or delivery and no treatment-related effects on the mean numbers of corpora lutea, implantations or pups. There were no effects on mean pup body weight or survival. There were no treatment-related organ weights and macroscopic changes in rats treated even at 1000 mg/kg/day. There were no treatment related changes noted for copulation index (%), fertility index (%), delivery index (%) and viability index (%) in treated groups when compared to corresponding control group. Successful mating resulted 100% pregnancy rates in C and HD groups and 90% pregnancy rates in LD and MD groups. One female of LD group and one female of MD group were found not to be pregnant at terminal sacrifice. Histologically, they showed physiological sexual cycling, and their unsuccessful mating was considered unrelated to the treatment. Based on this the NOAEL for systemic and reproductive and developmental toxicity is considered to be >= 1000 mg/kg body weight.

Effects on developmental toxicity

Description of key information
A combined repeated dose oral toxicity study with a reproduction/ developmental toxicity screening performed with substance analogue Yttrium Oxide is available. Based on this study, the no observed adverse effect level (NOAEL) for systemic and reproductive and developmental toxicity is considered to be >=1000 mg/kg body weight. This result is read across to yttrium oxide, europium doped.
    
    
    
    
    

A combined repeated dose oral toxicity study with a reproduction/ developmental toxicity screening performed with substance analogue Yttrium Oxide is available. Based on this study, the no observed adverse effect level (NOAEL) for systemic and reproductive and developmental toxicity is considered to be 1000 mg/kg body weight. This result is read across to yttrium oxide, europium doped.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Remarks:
screening study
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, non-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.
Ophthalmological findings:
no effects observed
Description (incidence and severity):
There were no ophthalmoscopic findings in any of the animals of this study.
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.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
No treatment related changes were noted for number of corpora lutea, number of implantation sites, number of live pups born on PND 0 and percentage of pre and post implantation loss in treated groups when compared to control. The statistical evaluation of data revealed no significant differences between the values of treated and control groups.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Abnormalities:
no effects observed
Description (incidence and severity):
No treatment related changes were noted for survival of the pups from PND 0 to PND 4 in treated groups when compared to control. However, there was 1 pup each in Control (Pup no. 3; animal 50), LD (Pup no. 12, animal 58) and MD (Pup no. 9, animal 70) groups found dead or missing between PND 0 and 4. The missing pup was assumed to be cannibalized by dam, which was considered to be incidental. No treatment related changes were considered for viability index (%).
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment related gross external findings were observed in any of the treated groups. However, there were few isolated findings noted in pups namely dry skin, dark spot on/ or dark abdomen, dark snout in control group; dark spot on forelimb and thoracic back, dark snout in LD group; dry skin in MD and HD groups. These findings were considered to be incidental in origin.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects seen at highest dose tested
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Repeated dose administration of Yttrium Oxide to male (minimum 28 days) and female (maximum 54 days) Wistar rats following OECD guideline 422 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 also no toxicologically relevant findings noted for reproductive and developmental parameters.

Based on these data, the no observed adverse effect level (NOAEL) for systemic and reproductive and developmental toxicity is considered to be 1000 mg/kg body weight/day. The NOEL for reproductive performance (mating and fertility) was considered to be 1000 mg/kg/day and the NOEL for toxic effects on progeny was 1000 mg/kg/day. This result is read across to Yttrium oxide, europium-doped.
Executive summary:

A repeated dose study was performed according to OECD guideline 422 with Yttrium Oxide. Male (minimum 28 days) and female (maximum 54 days) Wistar rats were dosed at dosages of 100, 300 and 1000 mg/kg body weight/day. 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.

No test item-related effects were noted on male and female reproductive organs in any of the treatment groups. The statistical analysis of epididymal sperm motility indicated no statistical significant difference between the treated and control groups. No treatment related changes were noted for the precoital interval and duration of gestation in treated groups when compared to control. All pregnancies resulted in normal births.

There were no treatment related changes noted for copulation index (%), fertility index (%), delivery index (%) and viability index (%) in treated groups when compared to corresponding control group.

Successful mating resulted 100% pregnancy rates in C and HD groups and 90% pregnancy rates in LD and MD groups. Histologically, they showed physiological sexual cycling, and their unsuccessful mating was considered unrelated to the treatment. The statistical evaluation of pre and post-natal data revealed no significant differences between the values of treated and control groups. No treatment related no significant changes were noted for survival of the pups and for viability index (%).

Based on these data, the no observed adverse effect level (NOAEL) for systemic and reproductive and developmental toxicity is considered to be >=1000 mg/kg body weight/day. The NOEL for reproductive performance (mating and fertility) was considered to be 1000 mg/kg/day and the NOEL for toxic effects on progeny was 1000 mg/kg/day. This result is read across to Yttrium oxide, europium-doped.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Klimisch 1 study (performed with substance analogue)
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

No study with yttrium oxide, europium doped is available. However, a study with yttrium oxide is present. The justification for this analogue approach is described in a report (see section 13 of IUCLID).

An OECD 422 study according to GLP principles was performed with rats. Yttrium oxide was administered daily by oral gavage to male and female Wistar rats,7 days per week with a maximum exposure of 54 days in total for females (at least 14 days of pre-mating, maximum 14 days of mating, 22 days of gestation and 4 days of post-partum) and minimum 28 days for males., at dose-levels of 100, 300 or 1000 mg/kg/day.There were no adverse effects of treatment on tested Wistar rats at any dose-level on mortality, clinical signs and biochemistry, body weight or food consumption.There were no effects in any group on mating, fertility or delivery and no treatment-related effects on the mean numbers of corpora lutea, implantations or pups. There were no effects on mean pup body weight or survival. There were no treatment-related organ weights and macroscopic changes in rats treated even at 1000 mg/kg/day.There were no treatment related changes noted for copulation index (%), fertility index (%), delivery index (%) and viability index (%) in treated groups when compared to corresponding control group. Successful mating resulted 100% pregnancy rates in C and HD groups and 90% pregnancy rates in LD and MD groups. One female of LD group and one female of MD group were found not to be pregnant at terminal sacrifice. Histologically, they showed physiological sexual cycling, and their unsuccessful mating was considered unrelated to the treatment.Based on this the NOAEL for systemic and reproductive and developmental toxicity is considered to be >= 1000 mg/kg body weight.

Justification for classification or non-classification

Based on the available information, yttrium oxide, europium doped does not have to be classified for reproduction toxicity according to CLP Regulation (EC) No. 1272/2008 including its amendments.

Additional information