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Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
13.93 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
GLP and guideline study.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Short description of key information:
A study on toxicity to reproduction with cesium sulphate is not available. A 90-day study with the structural analogous substance cesium hydroxide monohydrate and cesium chloride revealed effects on male reproductive organs and the sperm motility and morphology. In this particular case a two-generation reproduction toxicity study according to OECD guideline 416 provides no further gain of knowledge. Consequently, the endpoint is waived for cesium sulphate.

Based on these results cesium sulphate was classified as toxic to reproduction, category 2 according to regulation (EG) No. 1272/2008 (CLP). Cesium sulfate is also classified as STOT RE2 "may cause damage to multiple organs (kidneys, adrenals) through repeated or prolonged exposure.
In addition, the preparation of a dossier for harmonised classification and labelling according to article 36 of the regulation (EG) No. 1272/2008 (CLP) is in progress.
For the detailed mechanistic clarification of the new findings refer to section 13 of IUCLID "classification rationale for repro 2" for further details.

Justification for selection of Effect on fertility via oral route:
Based on the result of the subchronic repeated dose oral toxicity study (see IULCID section 7.5.1)

Effects on developmental toxicity

Description of key information
No developmental toxicity study with cesium sulphate is available. Consequently, read-across with the structural analogous read-across substance cesium hydroxide monohydrate was performed. In a developmental toxicity study with cesium hydroxide monohydrate according to OECD guideline 414 no developmental toxicity was observed.
There are no studies on cesium sulphate to cover the endpoint "Developmental toxicity / Teratogenicitiy" via respiratory or dermal route.
Link to relevant study records
Reference
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.
Reason / purpose:
reference to other study
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
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
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
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).
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.
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.
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
Key result
Dose descriptor:
NOAEL
Effect level:
10.8 mg/kg bw/day (nominal)
Based on:
other: calculated for cesium sulphate
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
161.6 mg/kg bw/day (nominal)
Based on:
other: calculated for cesium sulphate
Basis for effect level:
other: developmental toxicity
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.
Dose descriptor:
NOAEL
Effect level:
ca. 150 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
CsOH
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in postnatal survival
external malformations
skeletal malformations
visceral malformations
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 161.6 mg/kg bw/day
Based on:
other: cesium sulfate (MM 361.87)
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in postnatal survival
external malformations
skeletal malformations
visceral malformations
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
A prenatal development toxicity study with cesium sulphate 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 sulphate: NOAEL for maternal toxicity 10.8 mg/kg bw/day.
Cesium sulphate: NOAEL for developmental toxicity 161.6 mg/kg bw/day.
Executive summary:

A prenatal development toxicity study with cesium sulphate 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 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 sulphate: NOAEL for maternal toxicity 10.8 mg/kg bw/day.

Cesium sulphate: NOAEL for developmental toxicity 161.6 mg/kg bw/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
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

A prenatal development toxicity study with cesium sulphate 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 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 sulphate: NOAEL for maternal toxicity 10.8 mg/kg bw/day.

Cesium sulphate: NOAEL for developmental toxicity 161.6 mg/kg bw/day.


Justification for selection of Effect on developmental toxicity: via oral route:
GLP and guideline compliant study with the structural analogous read-across substance cesium hydroxide monohydrate. Please refer to IUCLID section 13 for read-across justification.

Justification for classification or non-classification

Based on the result of the subchronic repeated dose oral toxicity study (see IULCID section 7.5.1) cesium hydroxide monohydrate causes interference with the male reproductive system (testis, epididymis, spermatogenesis). Therefore also cesium sulphate is classified as Repr. 2 (H361f) according to Regulation (EC) No 1272/2008.

Based on the results of a developmental toxicity study with the structural analogous substance cesium hydroxide monohydrate cesium sulphate is not subject to classification as reproductive toxic according to the criteria EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No 1272/2008.