Caesium hydroxide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2013-03-01

Reliability:

2 (reliable with restrictions)

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Expert statement

Principles of method if other than guideline:

No guideline followed.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Caesium hydroxide

EC Number:

244-344-1

EC Name:

Caesium hydroxide

Cas Number:

21351-79-1

Molecular formula:

CsHO

IUPAC Name:

caesium hydroxide

Constituent 2

Reference substance name:

Cesium hydroxide

IUPAC Name:

Cesium hydroxide

Test material form:

solid: crystalline

Radiolabelling:

other: not applicable

Test animals

Details on test animals or test system and environmental conditions:

not applicable

Administration / exposure

Details on exposure:

not applicable

Duration and frequency of treatment / exposure:

not applicable

Doses / concentrations

Remarks:

Doses / Concentrations:
not applicable

No. of animals per sex per dose / concentration:

not applicable

Positive control reference chemical:

not applicable

Details on study design:

not applicable

Details on dosing and sampling:

not applicable

Statistics:

not applicable

Results and discussion

Preliminary studies:

not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The inorganic chemical cesium hydroxide (CsOH) appears as a colourless solid at room temperature and has a molecular weight of 149.9128 g/mol. The substance is very soluble in water (the water solubilty of cesium hyroxide monohydrate was determined to be greater than 1000 g/L at 20°C) and, as the substance is an inorganic salt, it has an estimated log Pow of < 0.0. Due to the high melting point of 204°C (determined for cesium hydroxide monohydrate), the vapour pressure is expected to be relatively low at ambient temperature. In an aqueous solution, CsOH dissociates rapidly into the respective cesium (Cs+) and hydroxide (OH-) ions. The present toxicokinetic assessment focused predominantly on the properties of Cs+ ion as OH- will readily react with free H+, thereby causing the formation of H2O.

Oral route:
Upon oral intake, cesium hydroxide will reach the stomach and form the respective Cs+ and OH- ions. For the cesium ion absorption will be 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 molecular weight below 200 g/mol.
With regards with to toxicological data, an acute oral systemic toxicity study conducted with cesium hydroxide monohydrate in rats determined an LD50 value of 1026 mg/kg. Besides local effects on the GI tract also pathologic changes of abdominal organs were observed.
In a 14 day dose range finder study cesium hydroxide monohydrate caused changes in haematology and clinical chemistry parameters. Furthermore, a disturbance in the body weight development was observed.
In a subacute 28 day study 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 does study with cesium hydroxide monohydrate provided further evidence for systemic absorption. Here, high concentrations caused changes in hematology parameters and adverse effects to the male’s reproductive organs. More specifically, atrophic alterations to the testis and epididymides accompanied by a decreased intensity of spermatogenesis and sperm motility
Also according to literature it is accepted that soluble cesium compounds are rapidly absorbed through the walls of the GI tract of humans (Henrichs et al., 1989; Iinuma et al., 1965). Further animal studies on rats and guinea pigs support these findings (Talbot et al., 1993; Stara 1965).
Overall, following oral administration, cesium hydroxide or moreover the respective Cs+ ion will be absorbed within the GI tract and becomes bioavailable.

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 structural analogous 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. These findings support that 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. 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; Stara 1965). Interestingly, 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. Furthermore, according to the results obtained in the aforementioned subchronic 90 day repeated does study it appears that the chemical is able to cross the protective blood testis barrier. Interestingly, in a conducted prenatal developmental toxicity study with cesium hydroxide monohydrate, no pathological changes in the offspring development were observed following oral treatment of pregnant rats. With regards to this study it cannot be concluded that toxicologically relevant amounts were able to cross the placenta.

Details on excretion:

Urinary excretion is the major route of elimination of bioavailabe cesium from the human body. Only a very limited fraction is excreted with the faeces. After an initial relatively fast excretion rate, remaining amounts of the element 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). The element is relatively uniformly eliminated without selectively accumulating in certain tissues (Boecker 1969b).

Metabolite characterisation studies

Details on metabolites:

Due to the physicochemical properties and according to available literature it is not likely that the dissociated cesium ion will undergo further enzymatic biotransformation processes.

Any other information on results incl. tables

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.

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.

Stara JF. (1965) Tissue distribution and excretion of cesium-137 in the guinea pig after administration by three different routes. Health Physics 11:1195-1202.

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.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Based on the physical-chemical properties and according to findings reported in scientific literature, cesium hydroxide monohydrate and hence, cesium hydroxide anhydrous, or moreover the Cs+ 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 cesium ion will circulate within the blood stream and is distributed to the whole body. According to scientific literature the ion will be predominately excreted via the urine in its unchanged form.
Based on the physicochemical properties and according to scientific literature the cesium ions will not bioaccumulate within specific body tissues.

Executive summary:

The inorganic chemical cesium hydroxide (CsOH) appears as a colourless solid at room temperature and has a molecular weight of 149.9128 g/mol. The substance is very soluble in water (the water solubilty of cesium hydroxide monohydrate was determined to be greater than 1000 g/L at 20°C) and, as the substance is an inorganic salt, it has an estimated log Pow of less than 0.0. Due to the high melting point of 204°C (determined for cesium hydroxide monohydrate), the vapour pressure is expected to be relatively low at ambient temperature. In an aqueous solution, CsOH dissociates rapidly into the respective cesium (Cs+) and hydroxide (OH-) ions.

The present toxicokinetic assessment focused predominantly on the properties of Cs+ ion as OH- will readily react with free H+, thereby causing the formation of H2O.

Absorption

Oral route:

Upon oral intake, cesium hydroxide will reach the stomach and form the respective Cs+ and OH- ions. For the cesium ion absorption will be 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 molecular weight below 200 g/mol. With regards with to toxicological data, an acute oral systemic toxicity study conducted with cesium hydroxide monohydrate in rats determined an LD50 value of 1026 mg/kg. Besides local effects on the GI tract also pathologic changes of abdominal organs were observed. In a 14 day dose range finder study cesium hydroxide monohydrate caused changes in haematology and clinical chemistry parameters. Furthermore, a disturbance in the body weight development was observed. In a subacute 28 day study 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 does study with cesium hydroxide monohydrate provided further evidence for systemic absorption. Here, high concentrations caused changes in haematology parameters and adverse effects to the male’s reproductive organs. More specifically, atrophic alterations to the testis and epididymides accompanied by a decreased intensity of spermatogenesis and sperm motility Also according to literature it is accepted that soluble cesium compounds are rapidly absorbed through the walls of the GI tract of humans (Henrichs et al., 1989; Iinuma et al., 1965). Further animal studies on rats and guinea pigs support these findings (Talbot et al.,1993; Stara 1965). Overall, following oral administration, cesium hydroxide or moreover the respective Cs+ ion will be absorbed within the GI tract and becomes bioavailable.

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 structural analogous 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. These findings support that 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. 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; Stara 1965). Interestingly, 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. Furthermore, according to the results obtained in the aforementioned subchronic 90 day repeated does study it appears that the chemical is able to cross the protective blood testis barrier. Interestingly, in a conducted prenatal developmental toxicity study with cesium hydroxide monohydrate, no pathological changes in the offspring development were observed following oral treatment of pregnant rats. With regards to this study it cannot be concluded that toxicologically relevant amounts were able to cross the placenta.

Metabolism

Due to the physicochemical properties and according to available literature it is not likely that the dissociated cesium ion will undergo further enzymatic biotransformation processes.

Excretion

Urinary excretion is the major route of elimination of bioavailable cesium from the human body. Only a very limited fraction is excreted with the faeces. After an initial relatively fast excretion rate, remaining amounts of the element 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). The element is relatively uniformly eliminated without selectively accumulating in certain tissues (Boecker 1969b).

Conclusion

Based on the physical-chemical properties and according to findings reported in scientific literature, cesium hydroxide monohydrate and hence, cesium hydroxide anhydrous, or moreover the Cs+ 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 cesium ion will circulate within the blood stream and is distributed to the whole body. According to scientific literature the ion will be predominately excreted via the urine in its unchanged form. Based on the physicochemical properties and according to scientific literature the cesium ions will not bioaccumulate within specific body tissues.

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.

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.

Stara JF. (1965) Tissue distribution and excretion of cesium-137 in the guinea pig after administration by three different routes. Health Physics 11:1195-1202.

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.