Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

In a combined repeated dose toxicity study with reproduction/developmental toxicity screening test in rats according to OECD guideline 422 (GLP-compliant; Braun, 2013) with the read-across substance cerium trinitrate, the NOEL/NOAEL for reproduction toxicity of 330 mg/kg bw/day was derived. However it was based on effects that could be secondary to the chemical stress observed in pregnant females (due to high local irritation observed in the stomach after repeated oral gavage of the compound) rather than primary effects of the test item. A maximal reliability score of 2 (reliable with restrictions) has been assigned because the study is used for read-across purposes in this dossier.

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:
No reliable screening for reproductive / developmental toxicity data with the target substance is available. This endpoint is covered based on data with the source substance cerium trinitrate. Justification for the read across approach is included in section 13.
Reason / purpose:
read-across source
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
bidistilled water
Dose descriptor:
NOAEL
Effect level:
330 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOEL
Effect level:
330 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified
Dose descriptor:
NOAEL
Effect level:
330 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Changes (explained further) at 1000 mg/kg/day observed on day 1 post partum.
Critical effects observed:
not specified
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
330 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Toxicity to reproduction: oral

No study is available with cerium ammonium nitrate. Read-across to the OECD 422 study with cerium trinitrate is proposed. The justification for this read-across is in Section 13 of IUCLID.

Braun (2013) performed a combined repeated dose toxicity study with reproduction/developmental toxicity screening test in RCCHan: WIST (SPF) rats (according to OECD guideline 422). Cerium trinitrate was administered to male rats for 47 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post partum, at dose levels 0, 110, 330 and 1000 mg/kg/day (anhydrous active ingredient). Control animals were dosed with the vehicle (bidistilled water) alone.

The NOAEL for reproduction/developmental toxicity was considered to be 330 mg/kg bw/day, based on changes at 1000 mg/kg/day that included increased total and mean post-implantation loss, decreased mean litter size, increased mean postnatal loss, increased rate of postnatal loss, increased total postnatal loss and decreased group mean pup weights on day 1 post partum. Although such changes could be a secondary effect resulting from chemical stress observed in pregnant females (due to local irritation observed in stomach after repeated oral gavage of the compound), a treatment related effect could not be excluded based on the limited data available from this screening.

Annex IX further testing: extended one generation reproductive toxicity study

A combined repeated dose toxicity study with reproduction/developmental toxicity screening test in the Han Wistar Rat study (OECD 422 guideline) has been performed with the read-across substance cerium trinitrate. The NOEL/NOAEL for reproduction/developmental toxicity was considered to be 330 mg/kg/day

In addition, a prenatal developmental toxicity study was perforemed (according to OECD guideline 414) in rat with cerium ammonium nitrate. No signs of maternal toxicity or adverse effects on embryos or foetuses in any test item treated groups were observed. The NOAEL for maternal toxicity, embryotoxicity, foetotoxicity and teratogenicity was set as at least 1000 mg/kg bw/day. Based on these results, no additional effects are expected in an extended one-generation reproductive toxicity study.

The read-across justification is added in Section 13 of IUCLID.

Effects on developmental toxicity

Description of key information

In a combined repeated dose toxicity study with reproduction/developmental toxicity screening test in rats according to OECD guideline 422 (GLP-compliant; Braun, 2013) with the read-across substance cerium trinitrate, the NOEL/NOAEL for reproduction toxicity of 330 mg/kg bw/day was derived. However it was based on effects that could be secondary to the chemical stress observed in pregnant females (due to high local irritation observed in the stomach after repeated oral gavage of the compound) rather than primary effects of the test item.

A prenatal developmental toxicity study according to OECD guideline 414 was performed. Cerium ammonium nitrate was administered daily by oral gavage to pregnant Hannover Wistar rats from gestation days GD6 to GD19. There was no test item-related adverse effect on maternal body weight, body weight gain, maternal corrected body weight and body weight gain, and on food intake in the Low, Mid and high dose groups (100, 300 and 1000 mg/kg bw/day). There were no toxicologically significant differences, or test item related-changes in the examined parameters of the intrauterine development up to and including 1000 mg/kg bw/day. The mean number of viable foetuses in all test item-treated groups as well as their sex distribution were comparable with the control mean. No adverse effect of test item was observed on the mean foetal body weight per litter, although slight, insignificant increase was seen in the High dose group compared to the control. There were no effects of the test item on external, visceral and/or skeletal development of foetuses in the study. No signs of maternal toxicity were noted and there were not oxicological relevant adverse effects on embryos or foetuses in any test item treated groups. The NOAEL for maternal toxicity, embryotoxicity, foetotoxicity and teratogenicity was set as at least 1000 mg/kg bw/day.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
from 2016-12-12 to 2017-05-31
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
2001
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Remarks:
Hannover Wistar (CRL:WI(Han))
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH (Sandhofer Weg 7, D-97633, Sulzfeld, Germany) from SPF colony.
- Age at study initiation: At least 11 weeks old at mating, young adult female rats, nulliparous and non-pregnant
- Weight at study initiation: 195-252 grams; The variation did not exceed +/- 20% of the mean weight.
- Fasting period before study: No data
- Housing: Standard laboratory conditions; Individual housing in Type II polycarbonate cages during mating and gestation period and Type III polycarbonate cages during the acclimatisation period. Lignocel Hygenic Animal Bedding were used in the study. Arbocel crinklets natural nesting material was used in the study. successfully mated animals were housed individually. Deep wood sawdust was used as bedding to allow digging and other normal rodent activities. Nest building material was also added into the cages.
- Diet (e.g. ad libitum): ad libitum, ssniff® SM Autoclavable Complete Diet for Rats and Mice – Breeding and Maintenance”
- Water (e.g. ad libitum): ad libitum, tap water (in water bottles) for human consumption
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.2-25.2°C
- Humidity (%): 10-46 %
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
Distilled water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test item was formulated in the vehicle (distilled water) at the appropriate concentrations according to the dose level and volume. During the formulation process, the pH of each formulation was adjusted using 2M NaOH solution to achieve a pH >= 3.5, to prevent non-specific pH damage to the stomach. The final pH values of the applied dose formulations were measured on each day. Formulations were prepared fresh daily prior to administration to animals (not more than 2 hours before use) to allow their use according to the available stability information. Formulations (yellowish suspensions) were kept protected from light, and were stirred continuously by magnetic stirrer until the end of the treatment.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Distilled water; Based on the available information of a previous rodent study and the results of two DRF studies
- Concentration in vehicle:0, 10, 30, and 100 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg. A constant volume of 10mL/kg body weight was administered to all dose groups, including the controls. The individual volume of the treatment was based on the most recent individual body weight of the animals.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis of test item formulations for concentration and/or homogeneity were performed using a validated ICP/AES method to determine the cerium content. Top, middle and bottom samples were taken from the test item formulations two times during the study (during the first and last week of the treatment). Samples were taken in duplicate (2mL/each), one set to analyse and one set as back-up, if required for any confirmatory analyses. Similarly, duplicate samples were taken from the middle of the vehicle control formulation for concentration measurement (confirmation of absence of cerium content).
Formulation samples were kept at room temperature and protected from light (in brown glass containers) until shipment to the Test Site.
Acceptance criteria of the concentration analysis were set according to the analytical method validation, expected to be at 100 +/- 15% of the nominal concentration.
Mean measured concentrations of each dose group were analyzed on 20 December 2016 and on 04 January 2017, as follows:
- 20 December analysis- 10.2 mg/mL (102% of nominal); 29..9 mg/mL (100% of nominal); 106.7 mg/mL (107% of nominal)
- 04 January analysis- 9.8 mg/mL (98% of nominal); 30.4 mg/mL (101% of nominal); 91.6 mg/mL (92% of nominal)
Details on mating procedure:
- The oestrus cycle of female animals was examined shortly before start of pairing.
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1 male, 1 female
- Length of cohabitation: Approximately 2 hours in the morning, daily, until at least 24 sperm-positive females/group are obtained
- Proof of pregnancy: After the daily mating period, a vaginal smear was prepared and stained with 1% aqueous methylene blue solution. The smear was examined with a light microscope; the presence of a vaginal plug or sperm was considered as evidence of copulation (referred to as gestation day 0, GD0). Sperm positive females were seperated and caged individually.
Duration of treatment / exposure:
from gestation day 6 to gestation day 19
Frequency of treatment:
7 days/week, daily administration, approx at similar times
Duration of test:
20 days from confirmed mating until necropsy
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Vehicle control group, group 1, 0 mg/mL
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
Low dose group, group 2, 10 mg/mL
Dose / conc.:
300 mg/kg bw/day (nominal)
Remarks:
Mid dose group, group 3, 30 mg/mL
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
High dose group, group 4, 100 mg/mL
No. of animals per sex per dose:
24 mated females per dose group, 4 dose groups
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:The dose levels were set based on available information of the chemical nature and characteristics of the test item and on available results of an acute toxicity study, a Dose Range Finding (DRF) study in non-pregnant Hannover Wistar rats and a DRF study in pregnant Hannover Wistar rats
- In the acute oral toxicity study according to OECD guideline 420, the test item was considered to be classified as category 4 with LD50 between 300 and 2000 mg/kg according to CLP Regulation.
- In the non-pregnant DRF, signs of toxicity have been observed at 1000 mg/kg bw/day dose level (transient piloerection, reduced body weight, food consumption and reduced water consumption), but these effects appeared to be restricted to the first few days of treatment. At necropsy, adverse local signs of irritation were observed on the gastric glandular mucosa. Due to the transient nature of effects, 1000 mg/kg bw/day was also selected as the highest dose in the follow-up DRF study in pregnant animals. As no significant toxicity was observed in pregnant rats up to the highest dose level tested, 1000 mg/kg bw/day was selected as high dose for this OECD 414 study.
Based on this information, the doses of 100, 300 and 1000 mg/kg bw/day were deemed suitable for the purpose of the study.
- Rationale for animal assignment (if not random): The sperm-positive, assumed pregnant females were allocated to each experimental group (on each mating day) in such a way that the group average of the body weight was as similar as possible. Females paired with the same male were allocated to different groups on the same mating day.
- Justification of the strain: The rat is regarded as a suitable rodent species for reproduction studies and the test guideline states it is the preferred rodent species. The Hannover Wistar rat was selected due to the experience of the Test Facility with this strain in teratology studies.
- Route of administration: The oral route is a potential route of human exposure to the test item and it was considered suitable to provide the exposure required for this developmental toxicology study.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily (at the beginning and end of each working day); only one general clinical observation in the afternoon on days when detailed clinical observation is made in the morning. When signs of toxicity were noted in a certain animal, this animal was observed more frequently.
- Parameters:
- signs of morbidity and mortality
- pertinent behavioural changes

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: on all animals at the onset of treatment (GD6), then at least weekly. On necropsy days, detailed clinical observations were made only once.
- Parameters:
- signs of toxicity like changes in skin, fur, eyes, mucous membranes, occurence of secretions and excretions, and autonomic activity (eg lachrymation, piloerection, pupil zize, unusual repiratory pattern), changes in gait, posture and response to handling as well as the presence of clonic and tonic movements, stereotypies (eg excessive grooming, repetitive circling), bizarre behaviour (eg self-mutilation, walking backwards), tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma
- on GD13 and/or 14, the sperm-positive females were examined for the presence of vaginal bleeding or 'placental sign' (intrauterine extravasation of blood as an early sign of pregnancy in rat, which is considered to confirm implantation)

BODY WEIGHT: Yes
- Time schedule for examinations: Body weight of each animal will be recorded with precision of ±1 g at least on GD 0, 3, 6, 8, 10, 12, 14, 16, 18 and 20.
- Corrected body weight was calculated: body weight on GD 20 minus weight of the gravid uterus

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food was weighed with precision of ±1 g at least on GD0, 3, 6, 8, 10, 12, 14, 16, 18 and 20. Food consumption was calculated for each interval, including GD0-6, GD6-20 and GD0-20.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Before expected delivery, on GD 20, Caesarean section was performed on each treated dam. Sodium pentobarbital administered by intraperitoneal injection, followed by exsanguination was used for euthanasia.
Females showing signs of premature delivery prior to scheduled necropsy were euthanized and subjected to a thorough macroscopic examination.
- Gross pathology: the dams' viscera were examined macroscopically for any strucutural abnormalities or pathological changes. All the gross findings were retained in 10% buffered formalin solution (or modified Davidson fixative, in case of the eyes) for possible future evaluation
- Histopathology: no histopathology evaluation was performed, unless deemed necessary and depending on the effects observed.
Ovaries and uterine content:
The ovaries and uterus were removed and the pregnancy status was ascertained
Examinations included:
- Gravid uterus weight: Yes, including cervix; not from animals found dead during the study. The uterus was examined for early and late embryonic or foetal deths and for the number of live foetuses
- Number of corpora lutea: Yes, in each ovary
- Number of implantations: Yes, in each uterine horn
- Number of early resorptions: Yes, degree of resorption was described in order to estimate the relative time of death of the conceptus
- Number of late resorptions: Yes, degree of resorption was described in order to estimate the relative time of death of the conceptus
- Other:
- Placentas were examined macroscopically
- Uteri that appeared non-gravid were further examined to confirm the non-pregnant status
- Classified according to time of death: preimplantation loss, postimplantation loss, early and late embryonic loss as well as foetal death.
Fetal examinations:
- External examinations: Yes: all per litter; plus an additional examination of the great arteries
- Soft tissue examinations: Yes, half of the litter
- the abdominal and thoracic region was opened and the thymus and great arteries were freshly examined by means of a dissecting microscope. The rest of the body was fixed in Sanomya mixture then after fination the body was micro-dissected by means of a dissecting microscope.
- Skeletal examinations: Yes, half of the litter
- the abdominal region was opened and the viscera and skin of foetuses were removed and the cadaver was fiwed in alcian-blue - acetic acid - ethanol mixture. After fixation in isopropanol the skeletons were stained by KOH-Alizarin red-S method and examined by means of a dissecting microscope.
- Head examinations: Yes, half of the litter
- the heads were examined by Wilson's free-hand razor blade method
- Each foetus was weighed individually (accuracy +/-0.01 g)
- The gender of the foetuses was determined according to appearance of the anogenital distance
- All abnormalities (external, soft tissue and skeletal formations, and variatons) found during the foetal examinations were recorded; photographic records were made additionally
Statistics:
- SAS v9.2 software package in case of Provantis v9.2
- normality and heterogeneity of variance between groups: checked by Shapiro-Wilk and Levene tests using the most appropriate data format (log-trasnformed when justified)
- where both tests showed no significant heterogeneity: Anova/Ancova (one-way analysis of variance) test
- if obtained result was positive, Dunnett's (Multiple range) test to assess the significance of inter-group differences; identifying differences of <0.05 or <0.01 as appropriate. This parameteric analysis was the better option when the normality and heterogeneity assumptions implicit in the tests were adequate.
- If Shapiro-Wilk or Levene tests showed significance: non-parameteric analysis. A Kruskal-Wallis analysis of variance was used after Rank Transformation
- if there was a positive result: inter-group comparisons using Dunn test; identifying differences of <0.05 or <0.01 as appropriate
- SPSS PC+4.0 program package (for data tabulated in Excel), the heterogeneity of variance between groups was checked by Bartlett's test
- no significant heterogeneity detected: one-way analysis of variance (ANOVA)
-if obtained result significant: duncan's Multiple Range test to assess the significance of inter-group differences
- significance heterogeneity : normal distribution of data examine dby Kolmogorow-Smirnow test
- in case of not normal distribution: non-paramteric method of Kruskal-wallis One-Way analysis of variance
- if positive result: inter-group comparisons using Mann-Whitney U-test
- the Chi-squared test was used for comparing group incidences against the controls
Indices:
Necropsy data:
- preimplantation loss (%, group mean): (number of corpora lutea - number of implantations)/number of corpora lutea x 100
- postimplantation loss (%, group mean): (number of implantations - number of live foetuses)/number of implantations x 100
Foetal data
- sex distribution (%, group mean): (number of male (female) foetuses)/number of foetuses x 100
- external abnormalities/litter (%, group mean): (number of foetuses with abnormality)/number of foetuses x 100
- visceral abnormalities/litter (%, group mean): (number of foetuses with abnormality)/number of foetuses x 100
- skeletal abnormalities/litter (%, group mean): (number of foetuses with abnormality)/number of foetuses x 100
Historical control data:
No data
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
- No test item-related effects or systemic clinical signs were noted in the treated animals of the Low (100 mg/kg bw/day), Mid (300 mg/kg bw/day) or High (1000 mg/kg bw/day) dose groups.
- Noisy respiration was recorded for a High dose animal (4504) for one day; thin fur / alopecia on some areas was recorded for some animals (1502, 1506 and 1518 in the Control group; 2510 and 2517 in the Low dose group; 3504 and 3507 in the Mid dose group; 4507 and 4515 in the High dose group) on some days, but those findings were not considered as a test item related effect.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No mortality was recorded for any animals in the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No test item related effect on body weight was observed in the Low, Mid or High dose groups when compared to control. No toxicologically significant changes were observed in the mean body weights of the Low, Mid or high dose groups when compared to controls. Similarly, no statistically significant or biologically relevant differences were seen in the body weight gain, corrected body weight gain or net body weight gain values during the treatment period (GD 6-20) or entire study (GD 0-20) compared to the control value
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
No biologically relevant changes were observed in the mean daily food consumption of dams in the Low, Mid and High dose groups (100, 300 and 1000 mg/kg bw/day, respectively) compared to the control value.
The food consumption of the Low, Mid and High dose groups was comparable with the Control group. Actually, in some periods slight increase in the daily mean food consumption was detected (the difference was not larger than 5.1% in any cases). There was no statistical significance and dose dependency, furthermore based on the absolute values, these facts were considered not test item-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment-related observations were recorded for any evaluated animals in the study. Fur thinning or alopecia was detected for some animals at necropsy, these are with correlation in the findings recorded during the in-life phase. However, these facts were considered as biologically not relevant findings and not related to the test item administration.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Details on results:
No further data
Number of abortions:
not specified
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
- Number of females with <+ 5 implantation sites: 1 in control group, 0 in Low, Mid and High dose group
- there was no statistically significant difference in foetal death in any test item treated group compared to the control
- the mean number of corpora lutea was comparable with the control in all test item treated groups.
- no effect was observed in preimplantation loss of the test item treated groups when compared to the control
- However, the slightly lower number of implantation (and later the consequently lower number of viable foetuses) in the Mid dose group gained statistical significance compared to the control. Based on the lack of dose response (the observed values in the Low dose and High dose groups showed results similar to control levels), these facts were considered not related to the test item administration.
- the early and the late embryonic loss did not differ significantly from the control in the test item treated groups. There was no statistically significant difference in the postimplantation loss between the test item treated and control groups
Total litter losses by resorption:
not specified
Description (incidence and severity):
Number of corpora lutea (mean): control: 11.65, low dose: 11.68, mid dose: 10.63, high dose:11.33
Early or late resorptions:
not specified
Dead fetuses:
no effects observed
Description (incidence and severity):
- The total intrauterine mortality was comparable with the control; no statistically significant differences were observed
- There was no statistically significant difference in the number of dead foetuses in any test item treated group compared to the control
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
- 96 (24 in each group) were mated in the study
- the number of confirmed pregnant, evaluated dams was 23 in the control group, 22 in the Low dose group , 24 in the Mid dose group and 24 in the High dose group.
Other effects:
no effects observed
Description (incidence and severity):
Evaluation of placentas: No abnormalities were observed on the placentas of any animals in the Control, Low, Mid or High dose groups
Details on maternal toxic effects:
No further data
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: absence of significant toxic effects
Remarks on result:
not determinable due to absence of adverse toxic effects
Abnormalities:
no effects observed
Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
- The mean weight of foetuses per litter in the Low and Mid groups did not differ significantly from the control mean value. In the High dose group, statistically significant increase (p<0.01) was seen in this parameter as well as in the mean foetal weight, but based on the biological relevance this fact was considered as a non-adverse test item related effect.
- The total number of retarded foetuses (runts) as well as the number of affected litters was lower in all test item treated groups than in the Control group, indicating no effect on this parameter
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Reduction in number of live offspring:
not specified
Changes in sex ratio:
no effects observed
Description (incidence and severity):
There was no toxicologically significant difference in the sex distribution of foetuses between the control and treated groups
Changes in litter size and weights:
not specified
Description (incidence and severity):
The mean weight of foetuses per litter in the Low and Mid groups did not differ significantly from the control mean value . In the High dose group, statistically significant increase (p<0.01) was seen in this parameter as well as in the mean foetal weight, but based on the biological relevance this fact was considered as a non-adverse test item related effect.
Changes in postnatal survival:
no effects observed
Description (incidence and severity):
- The total number of retarded foetuses (runts) as well as the number of affected litters was lower in all test item treated groups than in the Control group, indicating no effect on this parameter
External malformations:
no effects observed
Description (incidence and severity):
No external malformation was recorded in the study.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
All the skeletal findings correspond with the concurrent historical control or the concurrent study control data, or were considered to be incidnetla findigns without dose response.
- Based on the skeletal findings the number of malformed/variant/intact foetuses were comparable with the control in the Low, Mid and High dose groups.
- There was no malformation recorded except of one foetus with split vertebra in the Low dose group. Based on the lack of dose response and isolated occurence, this observation was considered as an incidental background finding, unrelated to treatment.
- In case of several variations (incomplete ossification of skull (3 or more bones), bipartite ossification of the vertebra, unossified or incompletely ossified pubis and incomplete ossification of the tarsal bones), the foetal or litter based incidence in the test item treated groups was comparable with the current study control or historical control values. Therefore, they were considered as biologically not relevant findings and not related to the test item treatment
- Incomplete ossification of hyoid body was observed only in two foetuses of the control group; thus these were considered as irrelevant findings from the study point fo view
- some of the observed variations (large fontanelle or wide frontal-parietal suture on the skull, interrupted ossification of ribs) were considered incidental findings based on the isolated occurrence (recorded only for one or two foetuses), these were not related to the treatment
- the incidence of dumbbell shaped vertebra was higher in the low dose group than in the current study control value or the relevant HC data, however, there was no dose response (the Mid and High dose groups showed this variation in a similar manner to the Control group). The difference was statistically not significant; thus it was considered not being treatment related
- in case of ossified sternebra (3 or less), the foetal or litter based incidence in the High dose group was higher than the current study control or historical control data. This finding is considered to be related to retarded ossification, a common foetal finding associated with individual retarded development. Two of the four affected foetuses in the High dose group had retarded body weight, similarly both affected foetuses in the control group had retarded body weight). Therefore, the facts were considered findings secondary to incidental individual foetuses with retarded development (runts), not related to the test item treatment.
- In case of dumbbell or asymmetric ossification of 2 or more vertebras, increased incidence was observed in the Low and high dose groups, when compared to the Control group or the historical control data. No statistical significance was detected, and there was no dose response (the calculated incidence in the Mid dose group was lower than in the control group). Furthermore, the observed litter based frequencies (31.8% in the Low dose group and 29.2% in the High dose group) were similar to the high end of the historical control range (29.6%). Based on these data, the observed values were considered not related to the test item treatment.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
- No visceral malformations were recorded in the study. All of the other visceral findings (variations) are consistent in general nature and incidence with the study concurrent control data or the existing historical control data, therefore considered as incidental findings.
- Based on the visceral findings the number of malformed/variant/intact foetuses were comparable with the control in the Low, Mid and High dose groups.
- no visceral malformations were recorded in any animal of the study.
- In case of thymic cord variations, the foetal or litter based incidence in the test item treated groups was comparable with the historical control range. Therefore, they were considered as biologically not relevant findigns and not related to the test item treatment.
- In case of renal papilla variation, recorded only in the high dose group, the calculated incidence was slightly higher than the relevant historical control mean value and within the normal range. But based on the low absolute values (only one litter was affected) and the lack of statistical significance, it was considered as incidental finding, unrelated to test administration.
- In case of short branchiocephalic trunk variation, increased incidences were observed in the Mid and High dose groups compared to the control values (the incidence in the Low dose group was similar to the control values). However, there was no dose response and the calculated litter based incidences (12.5% in the Mid dose group and 8.3% in the High dose group) correlated with the frequencies seen in the historical control database (range of 6.5-21.7%), thus they were considered as not being treatment related.
- Similarly, the calculated incidence for convoluted ureter variation seen in the high dose group was higher than in the current study control value. However, the litter based incidence (8.3%) correlated with the frequencies seen in the historical control database (range of 1.1-9.1%), thus it was considered not being a test item related effect.
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
No further data
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: absence of significant adverse effects
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
based on summary report - to be confirmed
Abnormalities:
no effects observed
Developmental effects observed:
no

Formulation analysis:

All test item formulations were within the range of 92-107% of the nominal concentration and were found to be homogenous. No test item (cerium) was detected in the vehicle control samples. Based on these results, test item formulations were considered suitable for the study purposes.

Conclusions:
Based on the observations made in the dams and their foetuses, no signs of maternal toxicity were noted and there were no toxicologically relevant adverse effect on embryos or foetuses in any test item treated groups. The following no-observed-adverse-effect (NOAEL) levels were derived:
- NOAELmaternal toxicity: at least 1000 mg/kg bw/day
- NOAELembryotoxicity: at least 1000 mg/kg bw/day
- NOAELfoetotoxicity: at least 1000 mg/kg bw/day
- NOAELteratogenecity: at least 1000 mg/kg bw/day
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
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

Four studies are available:

- OECD422:

No study is available with cerium ammonium nitrate. Read-across to the OECD 422 study with cerium trinitrate is proposed. The justification for this read-across is in Section 13 of IUCLID. Braun (2013) performed a combined repeated dose toxicity study with reproduction/developmental toxicity screening test in RCCHan: WIST (SPF) rats (according to OECD guideline 422). Cerium trinitrate was administered to male rats for 47 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post partum, at dose levels 0, 110, 330 and 1000 mg/kg/day (anhydrous active ingredient). Control animalswere dosed with the vehicle (bidistilled water) alone. The NOAEL for reproduction/developmental toxicity was considered to be 330 mg/kg bw/day, based on changes at 1000 mg/kg/day that included increased total and mean post-implantation loss, decreased mean litter size, increased mean postnatal loss, increased rate of postnatal loss, increased total postnatal loss and decreased group mean pup weights on day 1 post partum. Although such changes could be a secondary effect resulting from chemical stress observed in pregnant females (due to local irritation observed in stomach after repeated oral gavage of the compound), a treatment related effect could not be excluded based on the limited data available from this screening.

- DRF non-pregnant animals: In preparation of the OECD414 study, cerium ammonium nitrate was administered by oral gavage to Wistar non-pregnant female rats for 14 consecutive days at dose levels of 100 or 300 mg/kg bw/day in distilled water. There were adverse effects noted. Test item treatment resulted in transient piloerection and significantly lower body weight, food and water consumption in the High dose group (1000 mg/kg bw/day). These effects were apparently restricted to the first few days of treatment. At necropsy, adverse local signs of irritation were seen on the gastric glandular mucosa. Based on these results, dose levels of 500, 750 and 1000 mg/kg bw/day were proposed for the dose range finding study in pregnant animals.

- DRF pregnant animals: In preparation of the OECD414 study, cerium ammonium nitrate was administered via oral gavage to pregnant Hannover Wistar rats at dose levels of 500, 750 and 1000 mg/kg bw/day, daily from gestation day 6 to gestation day 19. No signs of maternal toxicity, embryotoxicity or foetotoxicity were observed in any test item treated dose groups (up to and including 1000 mg/kg bw/day). Based on these results, the dose levels proposed for the OECD 414 study were 100, 300 and 1000 mg/kg bw/day, at a dose volume of 10 mL/kg usign distilled water as vehicle.

- OECD 414: A prenatal developmental toxicity study according to OECD guideline 414 was performed. Cerium ammonium nitrate was administered daily by oral gavage to pregnant Hannover Wistar rats from gestation days GD6 to GD19. There was no test item-related adverse effect on maternal body weight, body weight gain, maternal corrected body weight and body weight gain, and on food intake in the Low, Mid and high dose groups (100, 300 and 1000 mg/kg bw/day). There were no toxicologically significant differences, or test item related-changes in the examined parameters of the intrauterine development up to and including 1000 mg/kg bw/day. The mean number of viable foetuses in all test item-treated groups as well as their sex distribution were comparable with the control mean. No adverse effect of test item was observed on the mean foetal body weight per litter, although slight, insignificant increase was seen in the High dose group compared to the control. There were no effects of the test item on external, visceral and/or skeletal development of foetuses in the study. No signs of maternal toxicity were noted and there were not oxicological relevant adverse effects on embryos or foetuses in any test item treated groups. The NOAEL for maternal toxicity, embryotoxicity, foetotoxicity and teratogenicity was set as at least 1000 mg/kg bw/day.

Toxicity to reproduction: other studies

Description of key information

No other studies are available

Justification for classification or non-classification

On the basis of the available information, cerium ammonium nitrate is considered not to be classified as reproductive toxicant according to CLP regulation.