Registration Dossier

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2013-03-01

Reliability:

2 (reliable with restrictions)

Principles of method if other than guideline:

No guideline followed.

Radiolabelling:

other: not applicable

Details on test animals or test system and environmental conditions:

not applicable

Details on exposure:

not applicable

Duration and frequency of treatment / exposure:

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

Preliminary studies:

not applicable

Details on absorption:

The inorganic chemical cesium nitrate (CsNO3) appears as solid white crystals at room temperature and has a molecular weight of 194.9104 g/mol. The substance is very soluble in water (239.5 g/L at 0°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 401°C, the vapour pressure is expected to be very low at ambient temperature. In an aqueous solution, CsNO3 dissociates rapidly into the respective cesium (Cs+) and nitrate (NO3-) ions.

Oral route:
Upon oral intake, cesium nitrate will reach the stomach and form the respective Cs+ and NO3- ions. Based on the reduced molecular weight of the nitrate ion absorption through the walls of the gastrointestinal (Gl) tract 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 weight below 200 g/mol.
With regards with to toxicological data, the conducted acute oral systemic toxicity study with cesium nitrate in rats determined an LD50 value in the range of 300 and 2000 mg/kg. However, local effects on the GI tract potentially causing systemic toxicity were observed.
Interestingly, in a 14 day dose range finder study the related analogue substance 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 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 does 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 male’s reproductive organs. More specifically, atrophic alterations to the testis and epididymides accompanied by a decreased intensity of spermatogenesis and sperm motility
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; Iinuma et al., 1965). Further animal studies on rats and guinea pigs support these findings (Talbot et al.,1993; Stara ,1965).
Studies with rats showed that ingested nitrate can readily cross the epithelium of the upper small intestine while only little (if any) absorption in the stomach and the large intestine takes place (Witter and Balish, 1979).
Overall, following oral administration, cesium nitrate and moreover the two respective ions will be well absorbed within the GI tract and become 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.
Consequently, an acute systemic dermal toxicity testing performed with cesium nitrate on rats did not reveal that toxicological relevant amounts were absorbed into the systemic circulation. Here, no systemic effects were observed and the LD50 was determined to be greater than 2000 mg/kg bw (limit dose).
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.
Following absorption, the nitrate ion is distributed within the human body via the blood stream. Subsequently, a considerable portion of the ion is selectively transported to the salivary glands and probably to other exocrine glands including the mammary glands (Bartholomew and Hill, 1984; Spiegelhalder et al., 1976).

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).
The vast majority of the systemically available nitrate will be readily excreted unchanged through urine while considerable amount can also be excreted by exocrine glands via sweat and breast milk (Bartholomew and Hill, 1984; Green et al., 1981; Spiegelhalder et al., 1976). Due to the fast excretion bioaccumulation is not assumed.

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.
The most important metabolite of nitrate is nitrite. The reduction of nitrate to nitrite appears predominately in the oral cavity via microorganisms contained in the saliva (Eisenbrand et al., 1980; Spiegelhalder et al., 1976). Further nitrate transformation is mediated by bacteria present in the GI tract where besides nitrite also carcinogenic nitrosamine compounds can be formed (Vermeer et al., 1998). Moreover, within body cells nitrate is enzymatically converted to nitrite by eukaryotic nitrate reductases. The formed nitrite in turn can cause the oxidation of oxyhaemoglobin to methaemoglobin.

References

Bartholomew, B., Hill, MJ. (1984). The pharmacology of dietary nitrate and the origin of urinary nitrate. Food and Chemical. Toxicology 22: 789-795.

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.

Eisenbrand, G., Spiegelhalder. B., Preussmann, R. (1980). Nitrate and nitrite in saliva. Oncology, 37: 227-231.

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.

Green, LC., Ruiz-De-Luzuriaga, K., Wagner, DA., Rand, W., Istfan, N., Young, VR., Tannenbaum, SR. (1981) Nitrate biosynthesis in man. Proceedings of the National Academy of Sciences USA, 78: 7764-7768.

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.

Spiegelhalder, B., Eisenbrand, G., Preussmann, R. (1976) Influence of dietary nitrate on nitrite content of human saliva: Possible relevance to in vivo formation of N-nitroso compounds. Food and Cosmetics Toxicology., 14: 545-548.

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.

Vermeer IT., Pachen DM., Dallinga JW., Kleinjans JC., van Maanen JM. (1998) Volatile N-nitrosamine formation after intake of nitrate at the ADI level in combination with an amine-rich diet. Environmental Health Perspective 106 459–463.

Witter JP., Balish E. (1979). Distribution and metabolism of ingested NO3- and NO2- in germfree and conventional-flora rats. Applied Environmental Microbiology., 38: 861-869.

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:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Based on the physicochemical properties and according to findings reported in scientific literature, cesium nitrate, 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.
Within the body nitrate will be partially converted to nitrite followed by excretion via the kidney with the urine.
Based on the physicochemical properties and according to scientific literature the cesium and nitrate ions will not bioaccumulate within specific body tissues.

Executive summary:

The inorganic chemical cesium nitrate (CsNO3) appears as solid white crystals at room temperature and has a molecular weight of 194.9104 g/mol. The substance is very soluble in water (239.5 g/L at 0°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 401°C, the vapour pressure is expected to be very low at ambient temperature. In an aqueous solution, CsNO3 dissociates rapidly into the respective cesium (Cs+) and nitrate (NO3-) ions.

Absorption

Oral route:

Upon oral intake, cesium nitrate will reach the stomach and form the respective Cs+ and NO3- ions. Based on the reduced molecular weight of the nitrate ion absorption through the walls of the gastrointestinal (Gl) tract 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 weight below 200 g/mol. With regards with to toxicological data, the conducted acute oral systemic toxicity study with cesium nitrate in rats determined an LD50 value in the range of 300 and 2000 mg/kg. However, local effects on the GI tract potentially causing systemic toxicity were observed. Interestingly, in a 14 day dose range finder study the related analogue substance 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 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 does 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 male’s reproductive organs. More specifically, atrophic alterations to the testis and epididymides accompanied by a decreased intensity of spermatogenesis and sperm motility 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; Iinuma et al., 1965). Further animal studies on rats and guinea pigs support these findings (Talbot et al.,1993; Stara ,1965). Studies with rats showed that ingested nitrate can readily cross the epithelium of the upper small intestine while only little (if any) absorption in the stomach and the large intestine takes place (Witter and Balish, 1979). Overall, following oral administration, cesium nitrate and moreover the two respective ions will be well absorbed within the GI tract and become 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. Consequently, an acute systemic dermal toxicity testing performed with cesium nitrate on rats did not reveal that toxicological relevant amounts were absorbed into the systemic circulation. Here, no systemic effects were observed and the LD50 was determined to be greater than 2000 mg/kg bw (limit dose). 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. Following absorption, the nitrate ion is distributed within the human body via the blood stream. Subsequently, a considerable portion of the ion is selectively transported to the salivary glands and probably to other exocrine glands including the mammary glands (Bartholomew and Hill, 1984; Spiegelhalder et al., 1976).

Metabolism

Due to the physicochemical properties and according to available literature it is not likely that cesium will undergo further enzymatic biotransformation processes. The most important metabolite of nitrate is nitrite. The reduction of nitrate to nitrite appears predominately in the oral cavity via microorganisms contained in the saliva (Eisenbrand et al., 1980; Spiegelhalder et al., 1976). Further nitrate transformation is mediated by bacteria present in the GI tract where besides nitrite also carcinogenic nitrosamine compounds can be formed (Vermeer et al., 1998). Moreover, within body cells nitrate is enzymatically converted to nitrite by eukaryotic nitrate reductases. The formed nitrite in turn can cause the oxidation of oxyhaemoglobin to methaemoglobin.

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). The vast majority of the systemically available nitrate will be readily excreted unchanged through urine while considerable amount can also be excreted by exocrine glands via sweat and breast milk (Bartholomew and Hill, 1984; Green et al., 1981; Spiegelhalder et al., 1976). Due to the fast excretion bioaccumulation is not assumed.

Summary

Based on the physicochemical properties and according to findings reported in scientific literature, cesium nitrate, 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. Within the body nitrate will be partially converted to nitrite followed by excretion via the kidney with the urine. Based on the physicochemical properties and according to scientific literature the cesium and nitrate ions will not bioaccumulate within specific body tissues.