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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From July 23, 2013 to January 09, 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report date:
2013

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
No significant deviations to study plan which affected the outcome of the study.
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
Caesium hydroxide monohydrate
Cas Number:
35103-79-8
Molecular formula:
CsOH*H2O
IUPAC Name:
Caesium hydroxide monohydrate
Test material form:
solid

Test animals

Species:
rat
Strain:
other: Hsd.Brl.Han: of Wistar origin
Details on test animals or test system and environmental conditions:
- Source: Charles River (Europe) Laboratories Inc. Toxi-Coop Zrt. 1103 Budapest, Cserkesz u. 90. Hungary
- Age: Females: Young adult and nulliparous females, 11-12 weeks of age at start of the mating period
Males: experienced males used in the developmental DRF study (Study no.: 559.410.3533), 23-24 weeks of age at start of the mating period
- Bodyweight: The group averages of the body weight were as similar as possible on the first day of gestation
- Housing:
Before mating: 1-3 females /cage 1-2 males/cage
Mating: 1 male and 1-3 females / cage
During gestation: 2-3 sperm positive females /cage, if not possible 1 sperm positive female per cage
- Cage type:
Type II polypropylene/polycarbonate
- Bedding:
Lignocel Hygienic Animal Bedding produced by J. Rettenmaier & Söhne GmbH+Co.KG (D-73494 Rosenberg, Holzmühle 1, Germany). Details of bedding quality were reported (Appendix XXIII).
- Light:
12 hours daily, from 6.00 a.m. to 6.00 p.m.
- Temperature:
21-22 °C
- Relative humidity:
40 - 54 %
- Ventilation:
8-12 air exchanges/hour by central air-condition system.
The temperature and relative humidity were checked and recorded once daily during the study. Any deviations were documented.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

The test item was formulated in the vehicle (distilled water) in concentrations of 1, 4, and 15 mg/mL.
Formulations were prepared daily to weekly. Due to the corrosive properties of the test item, the pH value of the formulations was adjusted to pH 7-9 with HCl prior to gavage administration. The suitability of the chosen vehicle for the test item at the intended concentrations was analytically verified up front. A sufficient stability and homogeneity in the chosen vehicle were verified over the range of relevant concentrations at the appropriate frequency of preparation.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical control (concentration, homogeneity) of dosing solutions was performed twice during the treatment period. The Cesiumhydroxidmonohydrat 99.95 concentrations in the samples were found to be 94 – 95 % in comparison to the nominal values.
Details on mating procedure:
The females were paired to males in the mornings for two to four hours (one male: one to three females) until the number of sperm positive females / group achieved at least twenty four. Vaginal smears were prepared from each female, stained with 1 % aqueous methylene blue solution and examined for presence of sperm and for estrus cycle stage.
The day of mating was regarded as day 0 of pregnancy (vaginal plug and/or sperm in the vaginal smear). Sperm positive females were separated and caged in groups of 2 to 3 animals (if not possible one female per cage). Caging of the females individually was avoided except in case of three dams.
Duration of treatment / exposure:
The sperm positive females were treated from gestational day 5 to 19.
Frequency of treatment:
The test item was administered in a single dose by oral gavage (stomach tube) on a 7 days/week basis every day at similar time.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Controls
Dose / conc.:
10 mg/kg bw/day (actual dose received)
Dose / conc.:
40 mg/kg bw/day (actual dose received)
Dose / conc.:
150 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
25 females for the controls, 27 females for the treated groups.
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on the results of a 28 day oral toxicity study

Examinations

Maternal examinations:
CLINICAL EXAMINATIONS
General clinical observations of the females were made once a day from day 0 up to day 19 which were performed after treatment at approximately the same time during the treatment period, considering the peak period of anticipated effects after dosing. Individual observation included the check of behavior and general condition.
Observations for signs of morbidity and mortality were made twice daily, at the beginning of the working period and in the afternoon.

BODYWEIGHT
The body weight of the male animals was not measured.
The body weight of all female rats was measured at least once in the pre-mating period, but was not statistically evaluated. Body weight of sperm positive females was measured on gestation days 0, 3, 5, 8, 11, 14, 17 and 20 (accuracy of 1 g).
The corrected body weight was calculated for day 20 of pregnancy (body weight on day 20 minus the weight of the gravid uterus).

FOOD CONSUMPTION
Food consumption was determined between gestation days 0 to 3, 3 to 5, 5 to 8, 8 to 11, 11 to 14, 14 to 17 and 17 to 20 by weighing the diet at the start of each measurement period and by re-weighing the non-consumed diet at the end of the respective period (accuracy: 1 g).

PLACENTAL SIGNS
All sperm positive animals were examined for vaginal bleeding (placental sign of gestation) on the 13th gestational day. If negative on day 13, the examination was repeated on day 14 of gestation.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
- Head examinations: Yes: [half per litter]
Statistics:
The statistical evaluation of data was performed with the program package SPSS PC+4.0.
The homogeneity of variance between groups was checked by Bartlett’s homogeneity of variance test.
Where no significant heterogeneity was detected a one-way analysis of variance (ANOVA) was carried out. If the obtained result was significant Duncan’s Multiple Range test was used to access the significance of inter-group differences. If a significance was the result of the Bartlett’s test, the Kruskal-Wallis analysis of variance was used and the inter-group comparisons were performed using Mann-Whitney U-test.
Historical control data:
Yes

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
There were no clinical signs or treatment related necropsy findings recorded for the dams.
Mortality:
no mortality observed
Description (incidence):
None of the pregnant females died in the course of the study before scheduled necropsy.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A statistically significant reduction in the food consumption was to see in the mid and high dose group (40 and 150 mg/kg bw/day) from gestational day 14 up to necropsy if compared to the control. This reduction in the food consumption was observed in association with a statistically significantly lower body weight gain in the high dose group noted during the last three days of the study and during the whole in-life phase. Corrected body weight gain in the mid and high dose groups was also statistically significantly reduced. These findings were attributed to an effect of the test substance.
The slightly reduced food consumption of the dams which was statistically significant in the mid dose group (40 mg/kg bw/day) between days 11 to 14 (without a dose response) and the slightly lower food consumption of the dams in the low dose group (10 mg/kg bw/day) associated with no changes in the body weight parameters and were considered to be incidental.
There were no significant differences in the body weight and body weight gain of the dams in the low and mid dose groups (0 and 40 mg/kg bw/day).
Food consumption and compound intake (if feeding study):
effects observed, treatment-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:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Maternal developmental toxicity

Number of abortions:
not examined
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
There was no effect related to the administration of the test substance in the preimplantation loss, intrauterine mortality of the conceptuses, the number of implantations, viable fetuses and their sex distribution.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
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 examined
Changes in number of pregnant:
not examined
Other effects:
not examined

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
Remarks on result:
other:
Remarks:
equivalent to 12 mg cesium formate monohydrate/kg bw/day

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects
Remarks on result:
other:
Remarks:
equivalent to 175 mg cesium formate monohydrate/kg bw/day

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Under the study conditions, the NOAEL for maternal toxicity was determined to be 10 mg/kg bw/day (equivalent to 12 mg cesium formate monohydrate/kg bw/day) and the NOAEL for developmental toxicity was 150 mg/kg bw/day (equivalent to 175 mg cesium formate monohydrate/kg bw/day).
Executive summary:

A study was conducted to determine the prenatal developmental toxicity of the read across substance cesium hydroxide monohydrate 99.95 according to OECD Guideline 414, in compliance with GLP. Groups of 27 sperm-positive female Hsd. Brl. Han: WISTAR rats were treated with the test substance by oral administration daily at 10, 40 and 150 mg/kg bw/day from Day 5 up to and including Day 19 post coitum. A control group of 25 sperm positive females was included and the animals were given the vehicle distilled water. The treatment volume was 10 mL/kg bw. During the study, mortality was checked for and clinical observations were performed. Body weight and food consumption of the dams were also recorded. The day when sperm was detected in the vaginal smear was regarded as Day 0 of gestation. A Caesarean section and gross pathology were performed on Gestational Day 20. The number of implantations, early and late resorptions, live and dead fetuses in each uterine horn and the number of corpora lutea were recorded. Each fetus was weighed and examined for sex and gross external abnormalities. The placentas were weighed and examined externally. About half of each litter was preserved for visceral examination and the other half of the litters were preserved for skeletal evaluation. At visceral examination the bodies were micro dissected by means of a dissecting microscope. The heads were examined by Wilson's free-hand razor blade method. After cartilage-bone staining the skeletons were examined by means of a dissecting microscope. All abnormalities found during the fetal examinations were recorded.None of the pregnant females died in the course of the study before scheduled necropsy. There were no clinical signs or treatment related necropsy findings recorded for the dams. A statistically significant reduction in the food consumption was seen at 40 and 150 mg/kg bw/day from Gestational Day 14 up to necropsy compared to the control. This reduction in the food consumption was observed in association with a statistically significantly lower body weight gain in the high dose group noted during the last three days of the study and during the whole in-life phase. Corrected body weight gain in the mid and high dose groups was also statistically significantly reduced. These findings were attributed to an effect of the test substance. The slightly reduced food consumption of the dams which was statistically significant at 40 mg/kg bw/day between Days 11 to 14 (without a dose response) and the slightly lower food consumption of the dams at 10 mg/kg bw/day associated with no changes in the body weight parameters and were considered to be incidental. There were no significant differences in the body weight and body weight gain of the dams at 0 and 40 mg/kg bw/day.There was no effect related to the administration of the test substance in the preimplantation loss, intrauterine mortality of the conceptuses, the number of implantations, viable fetuses and their sex distribution. The mean fetal weight, placental and relative placental weight were similar across the control and test substance treated groups. The distribution of external, visceral and skeletal variations was homogenous among the experimental groups. There were no malformations found during external and visceral evaluation of the fetuses and there were no significant differences in the skeletal malformations if compared to the control. Under the study conditions, the NOAEL for maternal toxicity was determined to be 10 mg/kg bw/day (equivalent to 12 mg cesium formate monohydrate/kg bw/day) and the NOAEL for developmental toxicity was 150 mg/kg bw/day (equivalent to 175 mg cesium formate monohydrate/kg bw/day) (Toxi-COOP, 2013).