Caesium fluoride

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

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.

Reference 2

Endpoint:

basic toxicokinetics, other

Type of information:

other: Statement

Adequacy of study:

key study

Study period:

2021-03-22

Reliability:

2 (reliable with restrictions)

Qualifier:

according to guideline

Guideline:

other: Statement according to ECHA Guidance 2017, chapter R.7c

Details on absorption:

Oral route:

Upon oral intake, cesium carbonate will form the respective Cs+ and F- ions once solved in gastrointestinal tract (GIT) fluids. Based on the small molecular weight and their charged state both ions absorption through the walls of the GIT is likely to occur via passive diffusion. Moreover, 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 molecular weights below 200 g/mol.
The above assumptions are supported by in vivo data, when administering CsF or other cesium or fluoride salts to rats via the oral route.
In an acute oral toxicity study with cesium fluoride the LD50 value in rats was determined to be between 300 and 2000 mg/kg bw. The toxicokinetic study with the source substance CsCl showed a fast uptake considering the rapid Cs+ appearance in plasma within 2 hours after dosing (Webley, 2016). 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).
Sodium fluoride is legally classified as acutely toxic Cat. 3, while sodium cation being a physiologically ubiquitous occurring ion may be excluded as affective moiety. Susheela et al. 1982 demonstrated systemically available fluoride in rabbits after various periods of repeated oral administration of 10 mg NaF/kg bw/d. In this study, fluoride content proportionate to administration duration was observed indicating no restriction in absorption or other kinetic processes for the F- ion. Formation of non-ionized hydrofluoric acid is favored due to the low pH in the stomach, which is better absorbed than the fluoride ion (Carlson et al. 1960; Taves and Guy, 1979).
Taken together, it can be concluded that both ions resulting from dissociation of the CsF salt are rapidly and well absorbed upon ingestion. In the presence of food systemic absorption rates can vary (Moore and Comar, 1962; Trautner and Einwag, 1989).


Inhalation route:

Considering the very low vapour pressure, the resulting low volatility and the fact that the chemical exists as a crystalline solid at room temperature with particle sizes well above 100 µm it is unlikely 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 its respective ions, being charged, 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 and became systemically available. In line with this are the findings of acute systemic dermal toxicity tests performed with the source substances cesium nitrate and cesium iodide on rats, which did not indicate absorption of toxicological relevant amounts as there were no systemic effects were observed and the LD50 was determined to be greater than 2000 mg/kg bw (limit dose). The same applies for sodium fluoride also revealing an acute dermal LD50 of >2000 mg/kg bw/d.
Taken together, these findings support that very limited absorption into the systemic circulation is expected for both ions after dermal application of CsF.

Details on distribution in tissues:

Once absorbed, 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.

There are data available in the literature demonstrating systemic distribution of fluoride ion after oral or i.v. administration (Susheela et al. 1982; Whitford et al. 1991). In summary, fluoride was readily detected in plasma and is thus well distributed by the blood stream. A preference to accumulate in calcified tissues such as bones and teeth is reported. While accumulation in soft tissue, i. e. edible parts, appears to be less relevant. Therefore, in terms of biomagnification there is no concern. The EU RAR (2001) notes that the lowest fluoride levels are found in herbivores, with higher levels in omnivores and highest levels in predators, scavengers and pollinators; the findings indicate a moderate degree of biomagnification. Vertebrate species store most of the fluoride in the bones and (to a lesser extent) the teeth; elevated levels of fluoride in the bones and teeth have been shown in animals from polluted areas. Sloof et al (1989) conclude that the limited data indicate that fluoride biomagnification in the aquatic environment is of little significance. Fluoride accumulates in aquatic organisms predominantly in the exoskeleton of crustacea and in the skeleton of fish; no accumulation was reported for edible tissues.

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 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). 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).
Whitford et al. (1991) investigated excretion kinetics of fluoride after intravenous administration in five species (dog, cat, rat, rabbit and hamster) after IV administration, while major quantitative differences in plasma clearance efficiency were reported among the species while plasma, renal and extra-renal (calcified tissue) values of the young adult dog, when factored for body weight, resemble those of the young adult human most closely.

Details on metabolites:

Enzymatic biotransformation processes are not relevant for alkali-earth metal ions like cesium. There are no indications that fluoride undergoes any metabolism in terms of conjugation in the organism.

References

ECHA (2017) Guidance on information requirements and chemical safety assessment, Chapter R.7c.: Endpoint specific guidance.

 

Bawden, J.W., Deaton, T.G., and Crenshaw, M.A. (1987). The short-term uptake and retention of fluoride in developing enamel and bone. J. Dent. Res. 66, 1587-1590.

 

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.

 

Carlson, CH., Armstrong, W.D., and Singer, L. (1960). Distribution and excretion of radiofluoride in the human. Proc. Soc. Exp. Biol. Med. 104, 235-239.

 

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.

 

Eanes, E.D., and Reddi, A.H. (1979). The effect of fluoride on bone mineral apatite. Metab. Bone Dis. Rel. Res. 2, 3-10.

 

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.

 

Ghosh A, Sharma A, Talukder G. (1993) Effects of cesium on cellular systems. Biol. Trace Elem. Res. 38, 165-203.

 

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.

 

Leggett RW, Williams LR, Melo DR, Lipsztein JL (2003) A physiologically based biokinetic model for cesium in the human body. Sci. Total Environ. 317, 235-55.

 

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.

 

Melnikov P, Zanoni LZ (2010) Clinical effects of cesium intake. Biol. Trace Elem. Res. 135, 1-9.

 

Moore W Jr, Comar CL (1962) Absorption of caesium 137 from the gastro-intestinal tract of the rat. Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 5, 247-54.

 

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.

 

Rääf CL (2006) Human metabolism of caesium. NKS-120. Nordisk Kernesikkerhedsforskning, Roskilde (Denmark) ISBN 87-7893-181-9.

 

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.

 

Threefoot SA, Burch GE, Ray CT (1955) The biologic decay rates and excretion of radiocesium, Cs134, with evaluation as a tracer of potassium in dogs. J. Lab. Clin. Med. 45, 313-22.

 

Susheela, AK,and Das, T.K. (1988). Chronic fluoride toxicity: A scanning electron microscopic study of duodenal mucosa. Clin Toxicol. 26, 467-476.

 

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.

 

Taves, D.R., and Guy, W.S. (1979). Distribution of fluoride among body compartments. In Continuing Evaluation of the Use of Fluorides (E. Johansen, D.R. Taves, and T.O. Olsen, Eds.), pp. 159-186. Westview Press, Boulder, CO.

 

Trautner, IC, and Einwag, J. (1989). Influence of milk and food on fluoride bioavailability from NaF and Na2FPO3 in man. J. Dent. Res. 68,72-77.

 

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.

 

Conclusions:

Based on the physicochemical properties and according to scientific literature bioaccumulation criteria are not fulfilled for cesium fluoride.

Executive summary:

Based on the physical-chemical properties, a toxicokinetic study with cesium chloride and according to findings reported in scientific literature, cesium fluoride and moreover its two respective ions which are immediately formed 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 both ions will be predominately excreted via the urine in unchanged form, i.e. no metabolic transformation of conjugation takes place.

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 fluoride and moreover its two respective ions which are immediately formed 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 both ions will be predominately excreted via the urine in unchanged form, i.e. no metabolic transformation of conjugation takes place. Based on the physicochemical properties and according to scientific literature bioaccumulation criteria are not fulfilled for both ions. For cesium 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 fluoride (CsF) appears as white crystalline powder at room temperature and has a molecular weight of 152 g/mol. The substance is very soluble in water (>1000 g/L at 15-20 °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 above 400°C, the vapour pressure is expected to be very low at ambient temperature. In an aqueous solution, CsF dissociates rapidly into the cesium (Cs⁺) cation and fluoride (F^-) anion.

The toxicokinetic assessment focuses on both ions as they exhibit different toxicological events.

 

 

Absorption

 

Oral route:

Upon oral intake, cesium carbonate will form the respective Cs⁺ and F^- ions once solved in gastrointestinal tract (GIT) fluids. Based on the small molecular weight and their charged state both ions absorption through the walls of the GIT is likely to occur via passive diffusion. Moreover, 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 molecular weights below 200 g/mol.

The above assumptions are supported by in vivo data, when administering CsF or other cesium or fluoride salts to rats via the oral route.

In an acute oral toxicity study with cesium fluoride the LD50 value in rats was determined to be between 300 and 2000 mg/kg bw. The toxicokinetic study with the source substance CsCl showed a fast uptake considering the rapid Cs⁺ appearance in plasma within 2 hours after dosing (Webley, 2016). 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).

Sodium fluoride is legally classified as acutely toxic Cat. 3, while sodium cation being a physiologically ubiquitous occurring ion may be excluded as affective moiety. Susheela et al. 1988 demonstrated systemically available fluoride in rabbits after various periods of repeated oral administration of 10 mg NaF/kg bw/d. In this study, fluoride content proportionate to administration duration was observed indicating no restriction in absorption or other kinetic processes for the F^- ion. Formation of non-ionized hydrofluoric acid is favored due to the low pH in the stomach, which is better absorbed than the fluoride ion (Carlson et al. 1960; Taves and Guy, 1979).

Taken together, it can be concluded that both ions resulting from dissociation of the CsF salt are rapidly and well absorbed upon ingestion. In the presence of food systemic absorption rates can vary (Moore and Comar, 1962; Trautner and Einwag, 1989).

 

Inhalation route:

Considering the very low vapour pressure, the resulting low volatility and the fact that the chemical exists as a crystalline solid at room temperature with particle sizes well above 100 µm it is unlikely 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 its respective ions, being charged, 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 and became systemically available. In line with this are the findings of acute systemic dermal toxicity tests performed with the source substances cesium nitrate and cesium iodide on rats, which did not indicate absorption of toxicological relevant amounts as there were no systemic effects were observed and the LD50 was determined to be greater than 2000 mg/kg bw (limit dose). The same applies for sodium fluoride also revealing an acute dermal LD50 of >2000 mg/kg bw/d.

Taken together, these findings support that very limited absorption into the systemic circulation is expected for both ions after dermal application of CsF.

 

Distribution

Once absorbed, 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.

 

There are data available in the literature demonstrating systemic distribution of fluoride ion after oral or i.v. administration (Susheela et al. 1988; Whitford et al. 1991). In summary, fluoride was readily detected in plasma and is thus well distributed by the blood stream. A preference to accumulate in calcified tissues such as bones and teeth is reported. While accumulation in soft tissue, i. e. edible parts, appears to be less relevant. Therefore, in terms of biomagnification there is no concern. The EU RAR (2001) notes that the lowest fluoride levels are found in herbivores, with higher levels in omnivores and highest levels in predators, scavengers and pollinators; the findings indicate a moderate degree of biomagnification. Vertebrate species store most of the fluoride in the bones and (to a lesser extent) the teeth; elevated levels of fluoride in the bones and teeth have been shown in animals from polluted areas. Sloof et al (1989) conclude that the limited data indicate that fluoride biomagnification in the aquatic environment is of little significance. Fluoride accumulates in aquatic organisms predominantly in the exoskeleton of crustacea and in the skeleton of fish; no accumulation was reported for edible tissues.

 

Metabolism

Enzymatic biotransformation processes are not relevant for alkali-earth metal ions like cesium. There are no indications that fluoride undergoes any metabolism in terms of conjugation in the organism.

 

 

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). 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).

Whitford et al. (1991) investigated excretion kinetics of fluoride after intravenous administration in five species (dog, cat, rat, rabbit and hamster) after IV administration, while major quantitative differences in plasma clearance efficiency were reported among the species while plasma, renal and extra-renal (calcified tissue) values of the young adult dog, when factored for body weight, resemble those of the young adult human most closely.