Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1st october 2012 - 14th april 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was conducted according to GLP and in compliance with agreed protocols, with no or minor deviations from standard test guidelines, which do not affect the quality of the relevant results.
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
Remarks:
(No relevant deviation from the standard guideline) GLP compliance
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Details on animals:
Species/strain: Wistar rats, Crl: WI(Han) (Full Barrier)
Source: Charles River, 97633 Sulzfeld, Germany
Sex: male and female; the female animals were non-pregnant and nulliparous.
Age at the start of
the treatment period: males: 10-11 weeks old. females: 10-11 weeks old.
Body weight at the allocation of the animals to the experimental groups: males: 250 - 298 g (mean: 272.80 g, ± 20% = 218.24 – 327.36 g) - females: 162 - 199 g (mean: 183.13 g, ± 20% = 146.50 – 219.75 g)
The animals were derived from a controlled full-barrier maintained breeding system (SPF).

Housing and Feeding Conditions
- Full barrier in an air-conditioned room
- Temperature: 22 3°C
- Relative humidity: 55 10%
- Artificial light, sequence being 12 hours light, 12 hours dark
- Air change: 10 x / hour
- Free access to Altromin 1324 maintenance diet for rats and mice
- Free access to tap water, sulphur acidified to a pH of approximately 2.8 (drinking water, municipal residue control, microbiological controls at regular intervals)
- The animals were kept individually in IVC cages (except during the mating period when one female will be paired with one male), type III H, polysulphone cages on Altromin saw fibre bedding
- Adequate acclimatisation period (at least 5 days) under laboratory conditions

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5 %
Details on exposure:
Prior to the start of the treatment period a detailed clinical observation outside the home cage was made. Before the first administration all animals used for the study were weighed and assigned to the experimental groups with achieving a most homogenous variation in body weight throughout the groups of males and females.



Experimental Groups and Doses
According to the results of the dose range finding study in which no overt toxicological changes were observed at 1000 mg/ kg body weight/ day the following doses: 100 ; 300 and 1000 mg/kg bw were selected for the 3 dose groups (LD = low dose, MD = medium dose, HD = high dose) and 1 control group (C).

The test item and vehicle were administered at a single dose to the animals by oral gavage. The application volume for all groups was 5 mL/kg body weight. For each animal the individual dosing volume was calculated on the basis of the body weight most recently measured on week- based.
Details on mating procedure:
Mating was performed in a ratio of 1:1 (male to female). The vaginal smears of the females were checked every morning after the start of the mating period to confirm the copulation. The day of the vaginal plug and/or sperm was considered as day 0 of gestation.
The cages were arranged in such a way that possible effects due to cage placement were minimised.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dose Formulation Analysis
Each dosing concentration was analyzed for nominal concentration by ICP - optical emission spectroscopy using a validated analytical procedure. Stability and homogeneity of the test item in the vehicle was analyzed for the LD, MD and HD dosing formulation.
Samples for the nominal concentration verification was taken in study week 1 (first week of pre mating period), 3 (first week of mating), 5 (gestation) and 7 (gestation/lactation) of control and all treatment groups.
Samples for homogeneity were taken from the top, middle and bottom of HD, MD, and LD preparation in study week 1 and 5.
Duration of treatment / exposure:
The animals were treated with the test item formulation or vehicle on 7 days per week for a period of 54 days, i.e. during 14 days of pre-mating and maximum 14 days of mating in both males and females, during the gestation period (approximately 21 to 23 days) and up to post-natal day 3 in females.
Males were dosed after the mating period until the minimum total dosing period of 28 days and the rest 5 animals from each group received dose administration for 29 days) was completed.
Frequency of treatment:
Once daily
Remarks:
Doses / Concentrations:
1000 mg/kg/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
300 mg/kg/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
100 mg/kg/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
0 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
10 animals per sex per dose.

Control animals:
yes, concurrent vehicle
Details on study design:
According to the results of the dose range finding study and in consultation with the sponsor three selected doses were tested for the 3 dose groups (LD = low dose, MD = medium dose, HD = high dose) and 1 control group (C).

Parental animals: Observations and examinations:
Body Weight and Food Consumption
The body weight of all animals were recorded once before the assignment to the experimental groups. on the first day of administration and weekly during the treatment period as well as at the end of the study. During pregnancy, females were weighed on gestation days (GD) 0, 7, 14 and 20 and within 24 hours of parturition (day 0 post-partum) as well as day 4 post-partum along with pups.
Food consumption was measured weekly on the corresponding days of the body weight measurements after the beginning of the dose administration. Food consumption was not measured during the mating period in males and females and the post-mating period in males. The food consumption in males were measured only for two weeks during premating period and not during the postmating period as the number of days during the postmating period are not uniform in all males due to difference in mating.
Other parameters were observed and have been detailled under section 7.5.1 Repeated Dose Toxicity - oral : clinical and functional observations, pathology, histopathology, haematology, clinical biochemistry, blood coagulation, urinalysis.
Oestrous cyclicity (parental animals):
The vaginal smears of the females were checked every morning after the start of the mating period to confirm the copulation. The day of the vaginal plug and/or sperm was considered as day 0 of gestation.
Sperm parameters (parental animals):
At necropsy (one day after the last administration) one epididymis and one testis from males of each group were separated and used for evaluation of sperm parameters. Epididymal sperm motility was evaluated in all male animals using Sperm Analyser. The testicular sperm count could not be measured at the end of the study as the testes stored at -80°C were inadvertently taken out of the freezer before the scheduled measurement.
Litter observations:
The duration of the gestation was recorded and was calculated from day 0 of the pregnancy. Each litter was examined as soon as possible after delivery of the dam to establish the number and sex of pups, stillbirths, live births, runts and the presence of gross abnormalities.
The pre- and post- implantation losses were calculated using number of corpora lutea, number of implantation sites and number of live pups born on PND 0 for each dam. The formula used for the calculation are as follows,
Pre Implantation Loss (%) = (No. of corpora Lutea - No. of implantation site / No. of corpora Lutea) x 100
Post Implantation Loss (%) = (No. of implantation site – No. of live pups / No. of implantation site) x 100
Live pups were counted and sexed and weighed within 24 hours of parturition (day 0 post-partum) and on day 4 post-partum. Live pups were identified by tattooing. In addition to the observations of parent animals, any abnormal behavior of the offspring was recorded.
Postmortem examinations (parental animals):
Gross necropsy
All male animals were sacrificed after the completion of the mating period (minimum dosing period: 28 days) on study day 29 or 30, while female animals were sacrificed on post-natal day 4 (maximum dosing period: 54 days) using an anaesthesia was used. Pups were killed on PND 4 by using high dose of sodium pentobarbitol.
Pups sacrificed on day 4 post-partum were carefully examined externally for gross abnormalities.

Females showing no sign of pregnancy was sacrificed on day 26 after the last day of the mating period.
All animals were subjected to a detailed gross necropsy which includes careful examination of the external surface of the body, all orifices and the cranial, thoracic and abdominal cavities and their contents.
The number of implantation sites and corpora lutea was recorded for each parental female at necropsy.

Organ Weights
The wet weight of the organs of 5 males and 5 females selected from each group was recorded as soon as possible. Paired organs were weighed separately. In addition reproductive organs of all animals were weighed. The enclosed organs were weighed at necropsy:
liver
uterus with cervix
kidneys
thymus
adrenals
thyroid/parathyroid glands
testes
spleen
epididymides
brain
prostate. seminal vesicles and coagulating glands
pituitary gland
ovaries
heart

The following tissues of the same selected animals from each group were preserved in 10 % neutral buffered formalin except eyes, testes and epididymides that were fixed in Modified Davidson’s Fixative for approximately 24 hours before they were transferred to 10% neutral buffered formalin:
brain (cerebrum, cerebellum and pons)
ovaries (females)
spinal cord
uterus with cervix (females)
liver
vagina (females)
kidneys
testes (males)
adrenal glands
epididymides (males)
stomach
prostate and seminal vesicles with coagulating glands as a whole (males)
small and large intestines (including Peyer´s patches)
urinary bladder
thymus
lymphnodes (mesentric and axillary)
Thyroid
peripheral nerve (e.g. sciatic nerve) with skeletal muscle
spleen
bone with bone marrow (sternum)
lung and trachea
pituitary gland
mammary glands
oesophagus
heart
gross lesions

Histopathology
All organs and tissues were evaluated from five selected males and females of the control and high dose group:
Reproductive organs (ovary, uterus, cervix, vagina, testis, epididymis, prostate gland, seminal vesicle and coagulating gland) and macroscopic changes were evaluated in all study animals. For the testes, a detailed qualitative examination was made; taking into account the tubular stages of the spermatogenic cycle for the evaluation of additional hematoxylin-PAS (Periodic Acid Schiff) stained slides.

Postmortem examinations (offspring):
Pups were killed on PND 4 by using high dose of sodium pentobarbitol.
Pups sacrificed on day 4 post-partum were carefully examined externally for gross abnormalities.
Statistics:
Evaluation of Results and Statistical Analysis
The findings of this study were evaluated in terms of the observed effects, the necropsy and the microscopic findings.
Parameters like body weight gain and food consumption were calculated for each animal as the difference in weight measured from one week to the next. Mean body weights are also presented as figures. The relative organ weights were calculated in relation to the body weight (measured at necropsy) and are presented as percentage.
A statistical assessment of the results of the body weight. food consumption, parameters of haematology, blood coagulation and clinical biochemistry, absolute and relative organ weights and reproductive and development parameters were performed by comparing values of dosed with control animals of the main groups using a one-way ANOVA and a post-hoc Dunnett Test (a normal distribution was assumed based on the in vivo data). These statistics were performed with GraphPad Prism 5.01 software (p<0.05 was considered as statistically significant).
Reproductive indices:
Copulation index, fertility index and delivery index was calculated for each group. The calculations were made using the formula as below,
Copulation Index (%) = (No. of rats copulated / No.of pairs) X 100
Fertility Index (%) = (No. of females pregnant / No. of females copulated) X 100
Offspring viability indices:
Delivery Index (%) = (No. of dams with live newborns / No. of pregnant dams) X 100
Clinical signs:
no effects observed
Description (incidence and severity):
(see "Details on results".)
Body weight and weight changes:
no effects observed
Description (incidence and severity):
(see "Details on results".)
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
(see "Details on results".)
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
(see "Details on results".)
Other effects:
no effects observed
Description (incidence and severity):
Test substance intake: (see "Details on results".)
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
(see "Details on results".)
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
(see "Details on results".)
Reproductive performance:
no effects observed
Description (incidence and severity):
(see "Details on results".)
Clinical Observation:
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 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 hindlimb, 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.
There were no ophthalmoscopic findings in any of the animals of this study.

Functional Observation:
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.

Body Weight development:
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.
One female from medium dose did not show the evidence of mating through vaginal smear. However, animal was pregnant and littered. Hence, the body weight data measured during the gestation period is excluded as the precise GD 0 was not clear for this animal.

Pre- and Post-Natal Data (Tables 2 and 3):
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.

Sperm analysis (table 1):
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.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: copulation index (%), fertility index (%), delivery index (%) and viability index (%), Successful mating resulted 100% pregnancy rates,
Clinical signs:
no effects observed
Description (incidence and severity):
(see "Details on results".)
Mortality / viability:
no mortality observed
Description (incidence and severity):
(see "Details on results".)
Body weight and weight changes:
no effects observed
Description (incidence and severity):
(see "Details on results".)
Sexual maturation:
no effects observed
Description (incidence and severity):
(see "Details on results".)
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
(see "Details on results".)
Gross pathological findings:
no effects observed
Description (incidence and severity):
(see "Details on results".)
Histopathological findings:
no effects observed
Description (incidence and severity):
(see "Details on results".)
Pup Survival Data (table 5)
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 (%).

Pup External Findings
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.
Dose descriptor:
NOEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: no significant changes were noted for survival of the pups and for viability index (%)
Reproductive effects observed:
not specified

Table 1 :Mean Epididymal Sperm Motility

Group

Motile Count [%]

Static Count [%]

Rapid [%]

C

 

 

 

 

Mean

75.10

24.90

55.80

SD

3.80

3.80

3.97

N

10

10

10

LD

 

 

 

 

Mean

76.30

23.70

57.45

SD

3.73

3.73

5.23

N

10

10

10

 

 

 

 

MD

 

 

 

 

Mean

72.44

27.56

54.67

SD

7.93

7.93

6.45

N

9

9

9

HD

 

 

 

 

Mean

72.70

27.30

54.90

SD

8.22

8.22

7.59

N

10

10

10

 Table 2 : Mean Precoital Interval and Duration of Gestation

Group

Precoital Interval (Days)

Duration of Gestation (Days)

C

 

 

 

Mean

2.20

22.20

SD

1.03

0.63

N

10

10

LD

 

 

 

Mean

2.67

22.33

SD

1.32

0.50

N

9

9

MD

 

 

 

Mean

3.63

22.38

SD

3.54

0.52

N

8

8

HD

 

 

 

Mean

2.40

21.90

SD

1.96

0.32

N

10

10

Table 3 :Pre- and Post-Natal Data

Group

No. Corpora Lutea (CL)

No. Implantation Sites (IS)

No. Live Pups on PND 0

No. Live Pups on PND 4

Pre Implantation Loss (%)

Post Implantation Loss (%)

C

 

 

 

 

 

 

 

Mean

12.50

11.60

10.90

10.80

6.64

7.24

SD

3.37

3.06

3.18

3.46

5.03

8.87

N

10

10

10

10

10

10

LD

 

 

 

 

 

 

 

Mean

12.44

11.11

11.00

10.89

10.71

1.01

SD

1.88

2.09

2.12

2.03

10.26

3.03

N

9

9

9

9

9

9

MD

 

 

 

 

 

 

 

Mean

13.33

11.78

11.11

11.11

9.73

5.65

SD

3.24

1.72

1.76

1.76

10.90

6.29

N

9

9

9

9

9

9

HD

 

 

 

 

 

 

 

Mean

12.80

12.10

11.50

11.40

4.77

4.92

SD

2.10

1.60

1.72

1.65

7.20

7.23

N

10

10

10

10

10

10

Pe Implantation Loss (%) = (No. of corpora Lutea - No. of implantation site / No. of corpora Lutea) x 100

Post-Implantation Loss (%) = (No. of implantation site – No. of live pups / No. of implantation site) x 100

Table 4 :Mean Reproductive Indices

Parameters

C

LD

MD

HD

Copulation Index (%)

100

100

100

100

Fertility Index (%)

100

90

90

100

Delivery Index(%)

100

100

100

100

Viability Index (%)

 

 

 

 

 

Mean

95

99

100

97

SD

10.5

2.50

0.0

8.0

N

10

9

9

10

 

Copulation Index (%) = (No. of rats copulated / No. of pairs) x 100

Fertility Index (%) = (No. of females pregnant / No. of females copulated) x 100

Delivery Index (%) = (No. of dams with live newborns / No. of pregnant dams) x 100

Conclusions:
In conclusion, the repeated dose administration of the 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 also no toxicologically relevant findings noted for reproductive and developmental parameters.

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 both male and female animals for systemic toxicity was considered to be 1000 mg/ kg body weight/ day. The no observed effect level (NOEL) for the reproductive and developmental toxicity was considered to be 1000 mg/kg body weight/day.
Executive summary:

The aim of this study was to assess the possible effects of Yttrium Oxide on male and female fertility and embryofetal development including the oral toxicity of Yttrium Oxide after repeated dose administration by oral gavage. This study was performed according to OECD guideline 422 and in compliance with GLP.

The test item was administered daily by oral gavage in graduated doses to 3 groups of test animals, one dose level per group for a treatment period maximum of 54 days in females and minimum 28 days in males. Animals of control group were handled identically as the dose groups but received same dose volume of the vehicle (aqueous carboxymethyl cellulose solution 0.5% w/w) used in this study. The 4 groups comprised 10 male and 10 female Wistar rats.

The following doses were evaluated:

Control (C): 0 mg/kg body weight/ day

Low Dose (LD): 100 mg/kg body weight/ day

Medium Dose (MD): 300 mg/kg body weight/ day

High Dose (HD): 1000 mg/kg body weight/ day

The test item formulation was prepared freshly on each day of administration. The test item was suspended in 0.5% aqueous carboxymethyl cellulose and administered daily during 14 days of pre-mating and maximum 14 days of mating in both male and female animals, during the gestation period and up to post-natal day 3 in females. Males were dosed for minimum of 28 days. Dose volumes were adjusted individually based on weekly body weight measurements. The administration volume was 5 mL/kg body weight.

The statistical analysis of epididymal sperm motility indicated no statistical significant difference between the treated and control groups.

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.

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 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 both male and female animals for systemic toxicity was considered to be 1000 mg/ kg body weight/ day. The no observed effect level (NOEL) for the reproductive and developmental toxicity was considered to be 1000 mg/kg body weight/day.

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:
Test was performed according to an international guideline and according to GLP.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

A Combined Repeated Dose Oral Toxicity Study with the Reproduction / Developmental Toxicity Screening Test in Wistar Rats with Yttrium Oxide was performed according to an international guideline OCDE n°422 and according to GLP (Klimisch 1) and thus considered as the key study.

The test item, yttrium oxide 99.9 %, was administered daily by oral gavage to groups of 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.

The enclosed examinations were done:

Body weight and food consumption on each group.

Concerning parents, testicular sperm counts and sperm motility on males were assessed as well as the estrous cyclicity of females. Litter examination was done as follow: number and sex of pumps, stillbirths, liv births, runts and presence of gross abnomalies.

The enclosed reproductive and offspring viability indices were assessed:

Copulation index, fertility index and delivery index was calculated for each group. The calculations were made using the formula as below,
Copulation Index (%) = (No. of rats copulated / No.of pairs) X 100
Fertility Index (%) = (No. of females pregnant / No. of females copulated) X 100

Delivery Index (%) = (No. of dams with live newborns / No. of pregnant dams) X 100

Other parameters were also assessed and described in section 7.5.1: clinical and functional observations, pathology, histopathology, haematology, clinical biochemistry, blood coagulation, urinalysis.

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 effect on organ weights and no 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 to 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 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.

As the OECD 422, on the screening Reproduction/Developmental Toxicity Screening Test, stated that the NOEL for reproductive and developmental toxic effects on parents and progeny by oral route was 1000 mg/kg/day. This result means that the yttrium oxide does not show any toxicological effect on parents. Consequently, in accordance with section 1 of REACH Annex XI, the two-generation reproductive toxicity study according to OECD 416 (required in section 8.7.3 of Annex IX) does not need to be conducted as the study does not appear to be scientifically necessary.


Short description of key information:
No adverse effects on fertility were observed in an OECD 422 screening reproductive / developmental toxicity study on wistar rats.

Justification for selection of Effect on fertility via oral route:
The only available study was performed according to the GLP and to an international guideline 422: Combined Repeated Dose Oral Toxicity Study with the Reproduction / Developmental Toxicity Screening Test in Wistar Rats with Yttrium Oxide.

Effects on developmental toxicity

Description of key information
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/day.
Moreover, this route of exposure for reproductive toxicity can be considered as the worst route of exposure, considering that dermal exposure is unlikely (yttrium oxide is below the solubility limit to allow the dermal absorption and showed no local effects) and that acute test by inhalation and subchronic test by inhalation also showed no toxicity.
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:
Test was performed according to an international guideline and according to GLP.
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

According to the absence of adverse effects and the results obtained on developmental toxicity in an OECD 422 screening reproductive / developmental toxicity study on rat, no further testing is proposed for this endpoint.


Justification for selection of Effect on developmental toxicity: via oral route:
The only available study was performed according to the GLP and to an international guideline OECD 422: a combined repeated dose with reproduction/developmental toxicity screening

Toxicity to reproduction: other studies

Additional information

The repeated dose administration of the 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/day 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 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 both male and female animals for systemic toxicity was considered to be 1000 mg/ kg body weight/ day.

The no observed effect level (NOEL) for the reproductive and developmental toxicity was considered to be 1000 mg/kg body weight/day.

Justification for classification or non-classification

As no adverse effects on fertility and on progeny were observed according to the results of the OECD 422 study, for concentrations up to 1000 mg/kg bw, no classification is required according to the 1272/2088/EC regulation.