Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Link to relevant study record(s)

Referenceopen allclose all

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2008-10-01 to 2008-10-13
Reliability:
2 (reliable with restrictions)
Objective of study:
absorption
Qualifier:
according to guideline
Guideline:
other: EMEA, CPMP/ICH/384/95
Deviations:
no
GLP compliance:
no
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 184-196 g
- Acclimation period: at least 5 days
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
HOMOGENEITY AND STABILITY OF TEST MATERIAL: stable (storage in refrigerator)
Duration and frequency of treatment / exposure:
single administration
Remarks:
Doses / Concentrations:
Dose: 1750 mg Cs/kg bw/day
Concentration: 175 mg Cs/mL
No. of animals per sex per dose / concentration:
2 controls, 2 animals per treatment periode (2 treatment periods)
Control animals:
yes, concurrent vehicle
Conclusions:
The plasma level study in rats showed that cesium carbonate was systemically available after single oral administration.
Executive summary:

In this plasma level study (gavage) in the male Wistar rat (non-GLP), cesium carbonate was administered once by oral gavage to four SPF-bred male Wistar rats at a dose level of 1750 mg/kg body weight. Two control animals received a similar dose volume (10 mL/kg body weight) of the vehicle/control item, deionized water.

Blood sampling was performed as terminal bleeding in control animals (no. 1 and 2) prior to the administration start and in test item-treated animals (no 3 and 4) 45 minutes after administration and (in no. 5 and 6) four hours after administration.

Plasma samples were prepared subsequently and send to sponsor’s laboratory for the determination of the cesium amount in the plasma samples. A mean content of 137.5 and 167.5 µg Cs/mL plasma was measured in test item-treated animals 45 minutes and four hours after oral administration, showing that cesium carbonate was systemically available after oral administration.

No clinical signs were noted during acclimatization period. No clinical signs were noted in control animals no 1 and 2 and in test item-treated animals no 3 and 4 at treatment day. Whereas in test item-treated animals no 5 and 6 weakened condition, hunched posture, ruffled fur and bradypnea was noted approximately one hour after administration of the test item until the end of treatment period (four hours after administration). Body weights ranged from 223 to 235 g at treatment day.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
06 August, 2015 to 01 April, 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Objective of study:
other: It was the intention of this toxicokinetic study to relate plasma and blood levels of Cs to the systemic general and male reproductive toxicity of Cs. This will enable the extrapolation of the toxicity produced by CsCl to other Cs salts.
Principles of method if other than guideline:
Four groups of Han Wistar rats received cesium chloride (CsCl) at doses of 0, 13, 38 and 127 mg CsCl/kg bw/day (equivalent to 0, 10, 30 and 100 mg Cs/kg bw/day) for 13 weeks, followed by an 8-week recovery period. A further treated group received CsCl at 253 mg CsCl/kg bw/day (equivalent to 200 mg Cs/kg bw/day) for a reduced treatment period of 9 weeks because of excessive toxicity, followed by an approximate 12-week recovery period. During the study, toxicokinetics, clinical condition, body weight, food consumption, blood pH and pCO2 investigations were undertaken. Additional blood and plasma samples from an associated toxicology study, obtained following a 12 and 16 week recovery period from animals that received 127 mg CsCl/kg bw/day (equivalent to 100 mg Cs/kg bw/day), were analysed for cesium as part of this study.
GLP compliance:
yes (incl. QA statement)
Radiolabelling:
no
Species:
rat
Strain:
other: RccHan™;WIST
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS Limited (formally Harlan (UK) Ltd)
- Females (if applicable) nulliparous and non-pregnant: [yes]
- Age of the main study and recovery animals at start of
treatment: 41 to 47 days.
- Weight range of the main study and recovery animals at the start of treatment: Males: 114 to 173 g, Females: 115 to 145 g
- Housing: Polycarbonate cages with a stainless steel mesh lid, changed at appropriate intervals. Five of the same sex per cage, unless reduced by mortality. Bedding: Wood based bedding which was changed at appropriate intervals each week
- Diet (e.g. ad libitum): Teklad 2014C Diet. Non-restricted (removed overnight before blood sampling for hematology or blood chemistry and during the period of urine collection).
- Water (e.g. ad libitum): Potable water from the public supply via polycarbonate
bottles with sipper tubes. Bottles were changed at appropriate intervals.
- Acclimation period: 12 days before commencement of treatment.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 40-70%
- Photoperiod (hrs dark / hrs light): 12:12
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Oral, by gavage, using a suitably graduated syringe and a rubber catheter inserted via the mouth.
Volume dose: 10 mL/kg body weight.
Individual dose volume: Calculated from the most recently recorded scheduled
body weight.
Control (Group 1): Vehicle at the same volume dose as the treated groups.
Frequency: Once daily at approximately the same time each day.
Duration and frequency of treatment / exposure:
- Exposure: 90 days
- Recoverty period: 16 weeks
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Controls
Dose / conc.:
13 mg/kg bw/day (actual dose received)
Remarks:
Equivalent to 10 mg Cs/kg bw/day
Dose / conc.:
38 mg/kg bw/day (actual dose received)
Remarks:
Equivalent to 30 mg Cs/kg bw/day
Dose / conc.:
127 mg/kg bw/day (actual dose received)
Remarks:
Equivalent to 100 mg Cs/kg bw/day
Dose / conc.:
253 mg/kg bw/day (actual dose received)
Remarks:
Equivalent to 200 mg Cs/kg bw/day
No. of animals per sex per dose / concentration:
5
Control animals:
yes
Positive control reference chemical:
No
Details on study design:
- Dose selection rationale: The doses used in this study (0, 13, 38, 127 and 253 mg CsCl/kg/day which correspond with 0, 10, 30 100 and 200 mg Cs/kg/day) were selected based on the findings of an ora
l gavage 90 day toxicity study of CsOH.H2O in the rat and an oral gavage reproduction/developmental screening study (56 days of treatment) of CsNO3 in the rat.
- Post-exposure recovery period in satellite groups: The recovery periods were initially intended to be 4 or 8 weeks duration. These were extended when the severity of effect on spermatogenesis and lack of recovery seen after 4 weeks recovery for animals at the high dose indicated a longer period of recovery would be needed.
Details on dosing and sampling:
During the study, toxicokinetics, clinical condition, body weight, food consumption, blood pH and pCO2 investigations were undertaken. Additional blood and plasma samples from an associated toxicology study, obtained following a 12 and 16 week recovery period from animals that received 127 mg CsCl/kg bw/day (equivalent to 100 mg Cs/kg bw/day), were analysed for cesium as part of this study.
Statistics:
Summary statistics (e.g. means and standard deviations) presented in this report were calculated from computer-stored individual raw data. Group mean values and standard deviations were frequently calculated using a greater number of decimal places than presented in the appendices. It is, therefore, not always possible to derive exact group values from the data presented in the appendices.
Metabolites identified:
no

Toxicokinetics


Cesium concentrations increased proportionally with dose in both plasma and blood samples over the 13-week study period, and showed a dose dependent reduction over the 4 to 16 week recovery period. The mean plasma concentrations of cesium achieved in the rat after daily treatment for 90 days (duration of treatment was just not enough to achieve steady state plasma concentrations) were 11.3 (0.08 mM), 36.5 (0.27 mM) and 87.7 µg Cs/mL (0.65 mM) for dose groups receiving 10, 30 and 100 mg Cs/kg bw/day, respectively.


Concentrations in plasma and blood increased proportionally to dose. Cesium concentrations in the blood were 3 to 5x those in plasma. Cesium concentrations increased in both plasma and blood samples over the 13 week treatment period. Cesium concentrations on Day 91 were, for blood, up to 27x higher, and in plasma, up to 7x higher than Day 1 values, at 2 hours after dosing, indicating significant accumulation.


Following cessation of treatment, there was a dose-dependent reduction in cesium concentrations. For animals receiving the lowest concentration of 10 mg Cs/kg bw/day, concentrations were below LOQ in plasma by Day 120 (after 4 weeks of recovery), and in blood by Day 151 (after 8 weeks of recovery). For animals which received 30, 100 or 200 mg Cs/kg bw/day, quantifiable levels of cesium were still present in the blood and plasma at the end of the respective recovery periods tested (8, 16 or 12 weeks at 30, 100 or 200 mg Cs/kg bw/day, respectively).


 


Clinical observations


Treatment at doses up to 100 mg Cs/kg bw/day was generally well-tolerated. Treatment at 200 mg Cs/kg bw/day was stopped in Week 9 because of excessive toxicity. Irritable and vocal behaviour was observed for animals receiving 30 or 100 mg Cs/kg bw/day from Week 8. A high incidence of encrustations on the lower jaw, and/or muzzle was apparent for animals given 100 or 200 mg Cs/kg bw/day. The incidence of encrustations decreased as the recovery phase progressed, though animals previously treated at 100 or 200 mg Cs/kg bw/day were recorded as being irritable and vocal during the recovery period.


No animals died or were killed prematurely.


 


Body weight and food consumption


Body weight gain for animals receiving 100 or 200 Cs/kg bw/day and food consumption for animals receiving 200 mg Cs/kg bw/day was lower than that of the controls throughout the treatment period with recovery being demonstrated after cessation of treatment.


 


Blood pH and pCO2


Venous blood pH was generally higher than that of the controls and venous blood pCO2 values were consistently lower than those of the controls, from 24 hours after dosing on Day 1 until the end of the study for animals which received 100 or 200 mg Cs/kg bw/day. These changes were also apparent on Day 91 for animals receiving 10 or 30 mg Cs/kg bw/day and on Day 151 for animals receiving 30 mg Cs/kg bw/day.

Conclusions:
Oral administration of cesium chloride (CsCl), to Han Wistar rats for 13 weeks at doses of 13, 38 and 127 mg CsCl/kg bw/day (equivalent to 10, 30 and 100 mg Cs/kg bw/day) was generally well-tolerated. Treatment at 253 mg CsCl/kg bw/day (equivalent to 200 mg Cs/kg bw/day) was stopped in Week 9 because of excessive toxicity. Cs plasma and blood concentrations increased roughly dose proportionally between 10 and 200 mg Cs/kg bw/day during treatment. Following cessation of treatment there was a dose dependent reduction in cesium concentrations, though quantifiable levels were still present in the blood and plasma at the end of the respective recovery periods tested (8, 16 or 12 weeks
at 30, 100 or 200 mg Cs/kg bw/day, respectively). Although venous blood pH was generally higher than that of the concurrent controls and venous blood pCO2 values were consistently lower than those of the concurrent controls
throughout the treatment period for animals which received 100 or 200 mg Cs/kg bw/day and at the end of the treatment period (Day 91) for animals receiving 10 or 30 mg Cs/kg bw/day, they were considered not to be representative of a clear metabolic alkalosis.
Executive summary:

A study was conducted to assess the toxicokinetics of cesium (Cs), blood pH and pCO2 during 13-weeks of oral gavage in Han Wistar rats followed by an 8-week recovery period. It was the intention of this toxicokinetic study to relate plasma and blood levels of Cs to the systemic general and male reproductive toxicity of Cs. This should enable the extrapolation of the toxicity produced by CsCl to other Cs salts. Four groups of 5 rats received cesium chloride (CsCl) at doses of 0, 13, 38 and 127 mg CsCl/kg bw/day (equivalent to 0, 10, 30 and 100 mg Cs/kg bw/day) for 13 weeks, followed by an 8-week recovery period. A further treated group received CsCl at 253 mg CsCl/kg bw/day (equivalent to 200 mg Cs/kg bw/day) for a reduced treatment period of 9 weeks because of excessive toxicity, followed by an approximate 12-week recovery period. During the study, toxicokinetics, clinical condition, body weight, food consumption, blood pH and pCO2 investigations were undertaken. Additional blood and plasma samples from an associated toxicology study, obtained following a 12 and 16 week recovery period from animals that received 127 mg CsCl/kg bw/day (equivalent to 100 mg Cs/kg bw/day), were analysed for cesium as part of this study.


Cesium concentrations increased proportionally with dose in both plasma and blood samples over the 13-week study period and showed a dose dependent reduction over the 4 to 16 week recovery period. Absorption of Cs can be regarded as fast. Quantifiable plasma concentrations were already reached 2 hours after dosing of 100 and 200 mg Cs/kg bw/d. The mean plasma concentrations of cesium achieved in the rat after daily treatment for 90 days (duration of treatment was just not enough to achieve steady state plasma concentrations) were 11.3 (0.08 mM), 36.5 (0.27 mM) and 87.7 µg Cs/mL (0.65 mM) for dose groups receiving 10, 30 and 100 mg Cs/kg bw/day, respectively. Cesium concentrations in the blood were 3 to 5x those in plasma after 4 weeks of treatment. After cessation of exposure, Cs plasma and blood concentrations decreased slowly with a terminal apparent elimination half-life of 37-46 days.


Treatment at doses up to 100 mg Cs/kg bw/day was generally well-tolerated. Treatment at 200 mg Cs/kg bw/day was stopped in Week 9 because of excessive toxicity. Irritable and vocal behaviour was observed for animals receiving 30 or 100 mg Cs/kg bw/day from Week 8. A high incidence of encrustations on the lower jaw, and/or muzzle was apparent for animals given 100 or 200 mg Cs/kg bw/day. The incidence of encrustations decreased as the recovery phase progressed, though animals previously treated at 100 or 200 mg Cs/kg bw/day were recorded as being irritable and vocal during the recovery period. No animals died or were killed prematurely. Body weight gain for animals receiving 100 or 200 Cs/kg bw/day and food consumption for animals receiving 200 mg Cs/kg bw/day was lower than that of the controls throughout the treatment period with recovery being demonstrated after cessation of treatment. Venous blood pH was generally higher than that of the controls and venous blood pCO2 values were consistently lower than those of the controls, from 24 h after dosing on Day 1 until the end of the study for animals which received 100 or 200 mg Cs/kg bw/day. These changes were also apparent on Day 91 for animals receiving 10 or 30 mg Cs/kg bw/day and on Day 151 for animals receiving 30 mg Cs/kg bw/day. However, this was not considered to be representative of a clear metabolic alkalosis.

Endpoint:
basic toxicokinetics, other
Type of information:
other: Statement
Adequacy of study:
key study
Study period:
2015-05-18
Reliability:
2 (reliable with restrictions)
Qualifier:
according to guideline
Guideline:
other: Statement according to ECHA Guidance 2008, chapter R.7c
Details on absorption:
Upon oral intake, cesium carbonate will reach the stomach and dissociate in the respective ions. For the cesium ion absorption is facilitated by transport through potassium channels and activation of the sodium pump (Cecchi et al., 1987; Edwards 1982). Another common route of absorption, namely crossing of the gut epithelial by passing through aqueous pores or through membranes by bulk transport of water, is also likely due to the ions’ good water solubility and their atomic weight below 200 g/mol.
With regards to toxicological data, the conducted acute oral systemic toxicity study with cesium carbonate in rats determined an LD50 value of 2333 mg/kg bw. In a 14-day dose range finder study the related analogue substance cesium hydroxide monohydrate caused changes in hematology and clinical chemistry parameters. Furthermore, a disturbance in the body weight development was observed. In a subacute 28-day study the analogue cesium hydroxide monohydrate caused a slight depression in the body weight development and changes in serum potassium levels for male animals. Moreover, changes in serum potassium and creatinine concentrations and reduced kidney weights were noted for the female animals. The results obtained from a subchronic 90-day repeated dose study with the analogue substance cesium hydroxide monohydrate provided further evidence for systemic absorption. Here, high concentrations caused changes in hematology parameters and adverse effects to the kidneys, adrenals and male reproductive organs. More specifically, atrophic alterations to the testis and epididymides accompanied by a decreased intensity of spermatogenesis and sperm motility. The toxicokinetic study with CsCl showed a fast uptake considering the rapid Cs+ appearance in plasma within 2 hours after dosing. Cs+ concentrations increased in both plasma and blood samples over the 13 week treatment period.
According to literature it is generally accepted that soluble cesium compounds are rapidly absorbed through the walls of the GI tract of humans (Henrichs et al., 1989; Linuma et al., 1965). Further animal studies on rats and guinea pigs support these findings (Talbot et al.,1993). Overall, following oral administration, cesium carbonate will be well absorbed, within the GI tract, after dissociation and become bioavailable.
In the presence of food systemic absorption rates can vary (Moore and Comar, 1962).
Considering the very low vapour pressure, the resulting low volatility and the fact that the chemical exist as a crystalline solid at room temperature with particle sizes well above 100 µm it is unlike that the substance will be inhaled either in vapour form or as dust particles under use conditions.
The physicochemical properties of the parent substance and the respective ions do not favour dermal absorption. The ionic nature of the inorganic salt will hinder dermal uptake. Pendic and Milivojevic (1966) conducted a dermal absorption study on the source substance cesium chloride (CsCl) in rats. In this study it was determined that only a minor fraction (approximately 3 %) of radiolabeled CsCl applied to a skin surface of several cm² was absorbed within 6 hours into the systemic circulation. Hence, very limited absorption into the systemic circulation is expected after dermal application.
Details on distribution in tissues:
Once absorbed into the blood stream, the cesium ion is readily distributed throughout the body independent of the administration route. The rat study by Webley (2016) showed a 3- to 5-fold higher Cs+ concentration in the whole blood then in plasma. Within the body, the cesium cation behaves in a similar manner as the potassium cation (Rundo 1964; Rundo et al., 1963). In order to gain entrance to the interior part of body cells, both alkali metals compete with each other for the transport through potassium channels and activation of the sodium pump (Cecchi et al., 1987; Edwards 1982). Miller (1964) evaluated the distribution profile of cesium while examining two workers who were accidentally exposed to the radioactive form of this element (137Cs) via the inhalation route. This study showed that cesium was quite uniformly distributed to the whole body (head, chest, upper abdomen, lower abdomen, thighs, legs, and feet). Furthermore, it was shown that bioaccumulation to a particular body tissue is unlikely. The described uniform distribution within the whole body was also observed in several animal studies (Furchner et al., 1964; Boecker 1969a and 1969b). A biokinetic model published by Leggett et al. in 2003 confirmed that cesium, once in the body, will distribute systemically, with higher concentrations in the kidneys, skeletal muscles, liver and erythrocytes. This was confirmed by several animal studies (Threefoot et al., 1955; Moore and Comar, 1962; Iinuma et al., 1965; Ghosh et al., 1993; ATSDR, 2004; Melnikov and Zanoni, 2010). The distribution to multiple compartments is also supported by the toxicokinetic study with CsCl (Webley, 2016). A study conducted by Vandecasteele et al., (1989) with adult sheep showed that cesium was able two cross the placenta and, furthermore, was detectable in the breast milk.
Details on excretion:
Urinary excretion is the major route of elimination of bioavailable cesium from the human body. Only a very limited fraction is excreted with faeces. After an initial relatively fast excretion rate, remaining amounts of cesium are eliminated in a rather slow manner from the human body with average half times often exceeding 12 weeks, depending on age, sex and route of administration (Henrichs et al.,1989 Richmond et al., 1962). Iinuma et al. (1965) and Rääf (2006) reported that the elimination half life will not exceed 100 days for men and 75 days for women. An elimination half life between 37 and 46 days was determined in the study with Wistar rats (Webley, 2016). The element is relatively uniformly eliminated without selectively accumulating in certain tissues (Boecker 1969b).
Details on metabolites:
Due to the physicochemical properties and according to available literature it is not likely that cesium will undergo further enzymatic biotransformation processes.

References


Boecker BB. (1969a) Comparison of 137Cs metabolism in the beagle dog following inhalation and intravenous injection. Health Physics 16(6):785-788.


 


Boecker BB. (1969b) The metabolism of 137Cs inhaled as 137CsCl by the beagle dog. Proceedings of the Society Experimental Biology and Medicine 130(3):966-971.


 


Webley LJ (2016) CsCl: Toxicokinetic study by oral administration to Wistar rats for 13 weeks followed by an 8 week recovery period; Envigo CRS Limited, UK; Report Number: BFG0002; Sponsor: Cabot Corporation


 


Harlan Laboratories (2008) Plasma Level Study (Gavage) in the Male Wistar Rat (non-GLP); Harlan Laboratories Ltd., Switzerland; Report Number: C17936; Sponsor: Rockwood Lithium GmbH


 


Cecchi X., Wolff D., Alvarez O., Latorre, R. (1987) Mechanisms of Cs+ blockade in a Ca2+ -activated K+ channel from smooth muscle. Biophysical Journal 52:707-716.


 


ECHA (2008) Guidance on information requirements and chemical safety assessment, Chapter R.7c.: Endpoint specific guidance.


 


Edwards C. (1982) The selectivity of ion channels in nerve and muscle. Neuroscience 7:1335-1366.


 


Furchner JE., Trafton GA., Richmond CR. (1964) Distribution of cesium137 after chronic exposure in dogs and mice. Proceedings of the Society Experimental Biology and Medicine 116:375-378.


 


Henrichs K., Paretzke HG., Voigt G,. Berg D (1989) Measurements of Cs absorption and retention in man. Health Physics 57(4):571-578.


 


Iinuma T., Nagai T., Ishihara T. (1965) Cesium turnover in man following single administration of 132Cs: Whole body retention and excretion pattern. Journal of Radiation Research 6:73-81.


 


Marquardt H., Schäfer S. (2004) Toxicology. Academic Press, San Diego, USA, 2nd Edition. Miller CE. (1964) Retention and distribution of 137Cs after accidental inhalation. Health Physics 10:10651070. Mutschler E., Schäfer-Korting M. (2001). Arzneimittelwirkungen. Lehrbuch der Pharmakologioe und Toxikologie. Wissenschaftliche. Verlagsgesellschaft Stuttgart.


 


Pendic B., Milivojevic K. (1966) Contamination interne au 137Cs par voie transcutanée et effet des moyens de décontamination et de protection sur la résorption transcutanée de ce radionuclide. Health Physics 12:1829-1830.


 


Richmond CR., Furchner JE., Langham WH. (1962) Long-term retention of radiocesium by man. Health Physics 8:201-205.


 


Rundo J. (1964) A survey of the metabolism of caesium in man. British Journal of Radiology 37:108-114.


 


Rundo J., Mason JI., Newton D., Taylor BT. (1963) Biological half-life of caesium in man in acute chronic exposure. Nature 200:188-189.


 


U.S. Department of Health and Human Services (2004) toxicological profile for cesium, Public Health Service Agency for Toxic Substances and Disease Registry, Atlanta, Georgia.


 


Vandecasteele CM, Van Hees M., Culot JP., Vankerkorn J. (1989) Radiocaesium metabolism in pregnant ewes and their progeny. Science of the Total Environment 85:213-223.


 


Talbot RJ, Newton D, Segal MG. (1993) Gastrointestinal absorption by rats of 137Cs and 90Sr from U3O8 fuel particles: Implications for radiation doses to man after a nuclear accident. Radiation Protection Dosimetry 50(1):39-43.

Conclusions:
Based on the physical-chemical properties and according to findings reported in scientific literature, cesium carbonate, and moreover its two respective ions which immediately form in aqueous solutions, will be absorbed via the GI tract and become systemically available. Uptake into the systemic circulation following dermal exposure is very limited due to the ionic nature of the inorganic salt. Based on the low vapour pressure and the particle size, it is unlikely that relevant amounts of the substance will become systemically bioavailable via the lungs. After becoming bioavailable, it is assumed that the ions will circulate within the blood stream and are distributed to the whole body. According to scientific literature the cesium ion will be predominately excreted via the urine in its unchanged form. Based on the physicochemical properties and according to scientific literature cesium ions will not bioaccumulate within specific body tissues.
Executive summary:

In accordance with the Guidance on Information Requirements and Chemical Safety Assessment, chapter R.7c the profile on basic toxicokinetics of cesium carbonate was derived from physico-chemical data as well as from toxicological data of cesium carbonate and structurally related cesium salts.


 


Taken together, due to a plasma level study in male rats, its physico-chemical properties and the observed systemic toxicity at least at high concentrations of cesium compounds cesium carbonate more precisely the cesium ion will be well absorbed within the GI tract and become bioavailable following oral administration. This estimation is confirmed by literature data.


 


Based on its physico-chemical properties and absence of toxicity in acute dermal toxicity studies very limited absorption into the systemic circulation is expected after dermal application. Literature data support this estimation.


 


Considering the physico-chemical properties it is unlike that the substance will be respirated either in vapour form or as dust particles under use conditions.


 


Due to the physico-chemical properties cesium ions are readily distributed throughout the body. This is confirmed by the presence of target organs in subacute and subchronic studies of analogous cesium compounds and literature data.


 


Based on the physico-chemical properties and according to available literature it is not likely that cesium carbonate will undergo further enzymatic biotransformation processes or will reveal an accumulation potential.


 


Considering the physico-chemical properties and the available literature cesium ions from the uptake of cesium carbonate are mainly urinary excreted.


 


All species formed from carbonate by hydrolysis naturally occur in the human body. Thus, the toxicological relevance of carbonate linked to the uptake of cesium carbonate is regarded as very low.

Description of key information

Based on the physical-chemical properties, a toxicokinetic study with Cesium chloride and according to findings reported in scientific literature, cesium carbonate, and moreover its two respective ions which immediately form in aqueous solutions, will be well absorbed via the GI tract and become systemically available. Uptake into the systemic circulation following dermal exposure is very limited due to the ionic nature of the inorganic salt. Based on the low vapour pressure and the particle size, it is unlikely that relevant amounts of the substance will become available for absorption via the lungs. After becoming bioavailable, it is assumed that the ions circulate within the blood stream and are distributed to the whole body. According to scientific literature the cesium ion will be predominantely excreted via the urine in its unchanged form. Based on the physicochemical properties and according to scientific literature cesium ions will not bioaccumulate within specific body tissues. This was also confirmed in the toxicokinetic study with Cesium Chloride (Webley, 2016).

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

A toxicokinetic study in rats is available with the source substance CsCl (Webley, 2016). The purpose of this study was to assess the toxicokinetics of Cesium (Cs+), blood pH and pCO2 in a 13-week oral gavage study in Han Wistar rats followed by an 8-week recovery period. It was the intention of this toxicokinetic study to relate plasma and blood levels of Cs+ to the systemic general and male reproductive toxicity of Cs+. This will enable the extrapolation of the toxicity produced by CsCl to other Cs+ salts. The results of the study confirm the toxicokinetic assessment based on physicochemical properties of the substances (ECHA 2017c) and other existing and published toxicological data.


 


The inorganic chemical cesium carbonate (Cs2CO3) appears as solid white crystals at room temperature and has a molecular weight of 325.81 g/mol. The substance is very soluble in water (>1000 g/L at 15-20 °C). Due to the high melting point of above 400°C, the vapour pressure is expected to be very low at ambient temperature. In an aqueous solution, Cs2CO3 dissociates rapidly into the cesium (Cs+) cation and the respective anions, in this case the hydroxide and hydrogen carbonate ion. With decreasing pH carbon dioxide is formed.


The toxicokinetic assessment focuses mainly on the cesium ion as it is the toxicologically relevant species. The available anion carbonate is considered as non-toxic. The low toxicological concern is proven by the fact that carbonate is a natural constituent of man as part of the so-called carbon cycle. The buffer system carbonic acid/hydrogen carbonate/carbonate plays an important role in maintaining a constant pH in blood plasma. For more information please refer to the counterion file published by Eurometaux and presented in the read across statement in IUCLID section 13.


 


 


Absorption


 


Oral route:


Upon oral intake, cesium carbonate will reach the stomach and dissociate in the respective ions. For the cesium ion absorption is facilitated by transport through potassium channels and activation of the sodium pump (Cecchi et al., 1987; Edwards 1982). Another common route of absorption, namely crossing of the gut epithelial by passing through aqueous pores or through membranes by bulk transport of water, is also likely due to the ions’ good water solubility and their atomic weight below 200 g/mol.


The available plasma level study with cesium carbonate in vivo supports the above assumptions. Cesium carbonate was administered once by oral gavage to four SPF-bred male Wistar rats at a dose level of 1750 mg/kg body weight. A mean content of 137.5 and 167.5 µg Cs/mL plasma was measured in test item-treated animals 45 minutes and four hours after oral administration, showing that cesium carbonate was systemically available after oral administration (Harlan, 2008).


With regards to toxicological data, the conducted acute oral systemic toxicity study with cesium carbonate in rats determined an LD50 value of 2333 mg/kg bw. In a 14-day dose range finder study the related analogue substance cesium hydroxide monohydrate caused changes in hematology and clinical chemistry parameters. Furthermore, a disturbance in the body weight development was observed. In a subacute 28-day study the analogue cesium hydroxide monohydrate caused a slight depression in the body weight development and changes in serum potassium levels for male animals. Moreover, changes in serum potassium and creatinine concentrations and reduced kidney weights were noted for the female animals. The results obtained from a subchronic 90-day repeated dose study with the analogue substance cesium hydroxide monohydrate provided further evidence for systemic absorption. Here, high concentrations caused changes in hematology parameters and adverse effects to the kidneys, adrenals and male reproductive organs. More specifically, atrophic alterations to the testis and epididymides accompanied by a decreased intensity of spermatogenesis and sperm motility. The toxicokinetic study with CsCl showed a fast uptake considering the rapid Cs+ appearance in plasma within 2 hours after dosing. Cs+ concentrations increased in both plasma and blood samples over the 13 week treatment period.


According to literature it is generally accepted that soluble cesium compounds are rapidly absorbed through the walls of the GI tract of humans (Henrichs et al., 1989; Linuma et al., 1965). Further animal studies on rats and guinea pigs support these findings (Talbot et al.,1993). Overall, following oral administration, cesium carbonate will be well absorbed, within the GI tract, after dissociation and become bioavailable.


In the presence of food systemic absorption rates can vary (Moore and Comar, 1962).


 


Inhalation route:


 


Considering the very low vapour pressure, the resulting low volatility and the fact that the chemical exist as a crystalline solid at room temperature with particle sizes well above 100 µm it is unlike that the substance will be inhaled either in vapour form or as dust particles under use conditions.


 


 


Dermal route:


 


The physicochemical properties of the parent substance and the respective ions do not favour dermal absorption. The ionic nature of the inorganic salt will hinder dermal uptake. Pendic and Milivojevic (1966) conducted a dermal absorption study on the source substance cesium chloride (CsCl) in rats. In this study it was determined that only a minor fraction (approximately 3 %) of radiolabeled CsCl applied to a skin surface of several cm² was absorbed within 6 hours into the systemic circulation. Hence, very limited absorption into the systemic circulation is expected after dermal application.


 


 


Distribution


 


Once absorbed into the blood stream, the cesium ion is readily distributed throughout the body independent of the administration route. The rat study by Webley (2016) showed a 3- to 5-fold higher Cs+ concentration in the whole blood then in plasma. Within the body, the cesium cation behaves in a similar manner as the potassium cation (Rundo 1964; Rundo et al., 1963). In order to gain entrance to the interior part of body cells, both alkali metals compete with each other for the transport through potassium channels and activation of the sodium pump (Cecchi et al., 1987; Edwards 1982). Miller (1964) evaluated the distribution profile of cesium while examining two workers who were accidentally exposed to the radioactive form of this element (137Cs) via the inhalation route. This study showed that cesium was quite uniformly distributed to the whole body (head, chest, upper abdomen, lower abdomen, thighs, legs, and feet). Furthermore, it was shown that bioaccumulation to a particular body tissue is unlikely. The described uniform distribution within the whole body was also observed in several animal studies (Furchner et al., 1964; Boecker 1969a and 1969b). A biokinetic model published by Leggett et al. in 2003 confirmed that cesium, once in the body, will distribute systemically, with higher concentrations in the kidneys, skeletal muscles, liver and erythrocytes. This was confirmed by several animal studies (Threefoot et al., 1955; Moore and Comar, 1962; Iinuma et al., 1965; Ghosh et al., 1993; ATSDR, 2004; Melnikov and Zanoni, 2010). The distribution to multiple compartments is also supported by the toxicokinetic study with CsCl (Webley, 2016). A study conducted by Vandecasteele et al., (1989) with adult sheep showed that cesium was able two cross the placenta and, furthermore, was detectable in the breast milk.


 


Metabolism


 


Enzymatic biotransformation processes are not relevant for alkali-earth metal ions like cesium.


 


Excretion


 


Urinary excretion is the major route of elimination of bioavailable cesium from the human body. Only a very limited fraction is excreted with faeces. After an initial relatively fast excretion rate, remaining amounts of cesium are eliminated in a rather slow manner from the human body with average half times often exceeding 12 weeks, depending on age, sex and route of administration (Henrichs et al.,1989 Richmond et al., 1962). Iinuma et al. (1965) and Rääf (2006) reported that the elimination half life will not exceed 100 days for men and 75 days for women. An elimination half life between 37 and 46 days was determined in the study with Wistar rats (Webley, 2016). The element is relatively uniformly eliminated without selectively accumulating in certain tissues (Boecker 1969b).