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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2012-07-23 to 2013-01-09
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP and guideline compliant. An experimental study was performed with a structural analogous read-across substance. Please refer to IUCLID section 13 for read-across justification.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2013

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: solid
Details on test material:
Please refer to section "Confidential details on test material" below.

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (Europe) Laboratories Inc., Toxi-Coop Zrt., Cserkesz u. 90., 1103 Budapest, Hungary
- Age at study initiation (start of mating): adult (males), 11-12 weeks old (females)
- Weight at study initiation: The group averages of the body weight were as similar as possible on the first day of gestation.
- Fasting period before study: no
- Housing: 1-2 males/cage and 1-3 females/cage before mating, 1 male and 1-3 female(s)/cage during mating, 2-3 or 1 sperm positive female(s)/cage during gestation; in type II polypropylene/polycarbonate cages.
- Diet: ssniff® SM R/M-Z+H "Autoclavable complete feed for rats and mice – breeding and maintenance" (ssniff Spezialdiäten GmbH, 59494 Soest, Germany), ad libitum.
- Water: tap water from municipal supply, from 500 mL bottles, ad libitum.
- Acclimation period: 96 days (males), 26 days (females)

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C
- Humidity: 30 - 70 %
- Air changes: 8 - 12 air exchanges/hour by central air-condition system.
- Photoperiod: 12 hours dark / 12 hours light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test item was formulated in the vehicle water. 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.

VEHICLE
- Concentration in vehicle: 1, 4 or 15 mg/mL
- Amount of vehicle: dose volume of 10 mL/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Formulations were prepared in the formulation laboratory of the test facility daily to weekly. 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 (Toxi-Coop Study no.: 559.198.2751) analytical control (concentration, homogeneity) of dosing solutions was performed in the Laboratory of Toxi-Coop Zrt. twice during the treatment period. The cesium hydroxide monohydrate concentrations in the samples were found to be 94 – 95 % in comparison to the nominal values.
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1/1-3
- Length of cohabitation: 2-4 hours
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
Days 5-19 of gestation
Frequency of treatment:
Once per day
Duration of test:
15 treatment days
Doses / concentrations
Remarks:
Doses / Concentrations:
10, 40 and 150 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
At least 24 sperm positive females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose setting was based on the results of a dose range finding prenatal developmental toxicity study (study number: 559.410.3533), under consideration of the results of a 14-day repeated dose oral gavage dose range finding toxicity study in rats (study number 559.400.2734) and a 28-day repeated dose oral gavage toxicity study in rats (study number 559.407.2735).

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily (mortality), once daily (clinical signs of systemic toxicity)

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: On gestation days 0, 3, 5, 8, 11, 14, 17 and 20

FOOD CONSUMPTION: Yes
- Time schedule for examinations: Between gestation days 0-3, 3-5, 5-8, 8-11, 11-14, 14-17 and 17-20
- Food consumption determined and mean daily diet consumption calculated as g food/kg bw/day: Yes

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: General macroscopical examination for gross lesions

OTHER:
- All sperm positive animals were examined for vaginal bleeding on days 13 and/or 14 of the gestation phase.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination.
Examinations included:
- Gravid uterus weight
- Number of corpora lutea
- Number of implantations
- Number of early resorptions
- Number of late resorptions
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 (all animals assigned for soft tissue examinations)
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 intergroup differences. If a significance was the result of the Bartlett’s test, the Kruskal-Wallis analysis of variance was used and the intergroup comparisons were performed using the Mann-Whitney U-test.
Indices:
Percent pre-implantation loss, post-implantation loss, sex distribution.
Percent external, visceral and skeletal abnormalities.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
There were no significant differences indicated in the body weight and body weight gain of the dams in the 10 and 40 mg/kg bw/day dose groups.
There was a statistically significantly lower body weight gain indicated in the 150 mg/kg bw/day dose group in the last three days of the study (p<0.01, -20%) and if the whole in-life phase was evaluated (p<0.05, -10%). A statically significant reduction in the corrected body weight gain was observed in the 40 mg/kg bw/day dose group (p<0.01, -17%) and in the 150 mg/kg bw/day dose group (p<0.05, -14%), which corresponded with a lower food consumption and was attributed to an effect of the test item.

The food consumption of the dams was reduced slightly but statistically significantly in the mid dose group (40 mg/kg bw/day) between days 11 to 14 (p<0.01 without a dose response, -8%), 14 to 17 (p<0.05, -7%) and 17 to 20 (p<0.01, -12%). In the high dose group (150 mg/kg bw/day) the food consumption was reduced as well slightly but statistically significant from day 14 up to necropsy (p<0.01, -8 to -10%) if compared to the control. The reduction in the food consumption associated with a lower body weight gain in the 150 mg/kg bw/day dose group and with a reduced corrected body weight gain in the 40 and 150 mg/kg bw/day dose group.
A slight reduction in the food consumption (p<0.05, -8%) of the dams observed between days 17 to 20 in the 10 mg/kg bw/day dose group did not result in changes in the body weight parameters and was regarded to be incidental.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
7.9 mg/kg bw/day (nominal)
Based on:
other: calculated for cesium
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
118.7 mg/kg bw/day (nominal)
Based on:
other: calculated for cesium
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
15.5 mg/kg bw/day (nominal)
Based on:
other: calculated for cesium iodide
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
232.1 mg/kg bw/day (nominal)
Based on:
other: calculated for cesium iodide
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There was no effect related to the administration of the test item 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 item 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.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
A prenatal development toxicity study with cesium iodide is not available. Consequently, read-across was applied using study results from cesium hydroxide monohydrate.
Based on the observations the No Observed Adverse Effect Level (NOAEL) for cesium hydroxide monohydrate was determined as follows:
NOAEL maternal toxicity: 10 mg/kg bw/day
NOAEL developmental toxicity: 150 mg/kg bw/day

Conclusively, the calculated NOAEL for cesium and cesium nitrate were determined as follows:
Cesium: NOAEL for maternal toxicity 7.9 mg/kg bw/day.
Cesium: NOAEL for developmental toxicity 118.72 mg/kg bw/day.
Cesium iodide: NOAEL for maternal toxicity 15.5 mg/kg bw/day.
Cesium iodide: NOAEL for developmental toxicity 232.1 mg/kg bw/day.
Executive summary:

A prenatal development toxicity study with cesium iodide is not available. Consequently, read-across was applied using study results from cesium hydroxide monohydrate.

Groups of 27 sperm- positive female Wistar rats were treated with the test item by oral administration daily at three dose levels of 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 resorption, 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. In total, there were 18, 20, 22 and 23 evaluated litters in the control, 10, 40 and 150 mg/kg bw/day groups, respectively. Oral treatment of pregnant rats from gestation days 5 to 19 (i.e. the day before Caesarean section) with the test item did not cause death, clinical signs or macroscopical alterations at necropsy at the dose levels of 10, 40 and 150 mg/kg bw/day. The test item did not reveal any adverse effect on the pregnancy of the dams, the pre-implantation loss, the intrauterine mortality of the conceptuses, the number of viable fetuses and their sex distribution. The development of fetuses evaluated at external, visceral and skeletal examination and determined by the fetal body weight was undisturbed. The test item caused no fetal malformation at the dose levels of 10, 40 and 150 mg/kg bw/day. The reduced food consumption from day 14 onwards and the lower corrected body weight gain of the dams at the dose levels of 40 and 150 mg/kg bw/day as well as the reduced body weight gain in the last three days of the in- life phase of the dams in the 150 mg/kg bw/day dose group were attributed to the treatment with the test item.

Based on these observations the No Observed Adverse Effect Level (NOAEL) was determined to be 10 mg/kg bw/day for maternal toxicity and 150 mg/kg bw/day for developmental toxicity.

Conclusively, the calculated NOAEL for cesium and cesium iodide were determined to be:

Cesium: NOAEL for maternal toxicity 7.9 mg/kg bw/day.

Cesium: NOAEL for developmental toxicity 118.72 mg/kg bw/day.

Cesium iodide: NOAEL for maternal toxicity 15.5 mg/kg bw/day.

Cesium iodide: NOAEL for developmental toxicity 232.1 mg/kg bw/day.