Caesium fluoride

Endpoint summary

Description of key information

Based on the two 90 d studies with the structural analogues cesium hydroxide hydrate and cesium chloride as well as a 2 year study with sodium fluoride the following effects levels were determined:

NOAEL (CsOH): 25 mg/kg bw/day for male and female animals (equivalent to 19.8 mg Cs/kg bw/day)

NOAEL (CsCL): 13 mg CsCl/kg bw/day (equivalent to 10 mg Cs/kg bw/day)

LOAEL (NaF): 3.75 mg/kg bw/d (equivalent to 1.7 mg F/kg bw/d)

No effects were observed up to 19.8 mg Cs+/kg bw/d. The lowest observed adverse effect level was 1.7 mg F/kg bw/d. Re-calculation results in a NOAEL of 22.6 mg/kg bw/d and a LOAEL of 13.9 mg/kg bw/d for cesium fluoride. The LOAEL derived from sodium fluoride will be taken as key value for risk assessment.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

Please refer to read-across justification attached to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

LOAEL

Remarks:

NaF

Effect level:

25 ppm

Sex:

male/female

Basis for effect level:

other: Alterations of the teeth were observed in the incisors and were more frequent in males than females at concentrations of 25, 100 and 175 ppm.

Remarks on result:

other: corresponds to ca. 3.75 mg/kg bw/d

Critical effects observed:

no

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

Please refer to read-across justification attached to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

19.8 mg/kg bw/day (actual dose received)

Based on:

other: calculated for Cs

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

haematology

sperm measures

Remarks on result:

other: based on CsOH monohydrate

Dose descriptor:

NOAEL

Effect level:

22.6 mg/kg bw/day (actual dose received)

Based on:

other: calculated for CsF

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

haematology

sperm measures

Remarks on result:

other: Based on CsOH monohydrate

Dose descriptor:

NOAEL

Effect level:

10.3 mg/kg bw/day (actual dose received)

Based on:

other: calculated for Cs

Sex:

male/female

Basis for effect level:

sperm measures

Remarks on result:

other: Based on CsCl

Key result

Dose descriptor:

NOAEL

Effect level:

11.8 mg/kg bw/day (actual dose received)

Based on:

other: calculated for CsF

Sex:

male/female

Basis for effect level:

sperm measures

Remarks on result:

other: Based on CsCl

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

34.4 mg/kg bw/day (actual dose received)

System:

male reproductive system

Organ:

other: sperm cell number and morphology

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

13.9 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

WoE of read-across from GLP and guideline compliant studies

System:

male reproductive system

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

There is no repeated dose toxicity study for cesium fluoride available. Consequently, data from the structural analogous substances cesium hydroxide monohydrate, cesium chloride and sodium fluoride were used in a weight of evidence approach. Both cesium salts were applied to male and female Wistar rats for 90 days. Sodium fluoride was applied for 2 years to male and female Fischer 344 rats. The key results of all studies are summarised below.

 

Sub-chronic oral toxicity with CsCl (according to OECD 408)

A study was conducted to assess the systemic toxicity of cesium (Cs⁺) in a 13-week oral gavage study in Han Wistar rats followed by a recovery period of up to 16 weeks (Webley, 2016). This study was designed to investigate in more detail the relationship between the toxicity produced by Cs⁺ (e.g. uremia, hypokalemia, alkalosis) and male reproductive effects (e.g. decrease in sperm motility, decrease in spermatogenesis and histopathological changes in the testes.

Four groups received the vehicle or cesium chloride (CsCl) at doses of 13, 38 and 127 mg/kg bw/day (equivalent to 10, 30 and 100 mg Cs/kg bw/day) for 13 weeks, followed by an 8, 12- or 16-week recovery period. A fifth treated group received cesium chloride (CsCl) at 253 mg/kg bw/day (equivalent to 200 mg Cs/kg/day) for a reduced treatment period of 59 days because of excessive toxicity, followed by an approximate 4- or 12-week recovery period.

 

Oral administration of cesium chloride (CsCl) to Han Wistar rats at doses of 13, 38, 127 or 253 mg/kg bw/day (equivalent to 10, 30, 100 or 200 mg Cs/kg bodyweight/day) resulted in pathological changes in the mandibular and sublingual salivary glands, heart, stomach, spleen, adrenals, mammary glands, skin and subcutis, epididymides and testes of animals treated at 253 mg/kg bw/day for 59 days or 127 mg/kg bw/day for 13 weeks. Additional changes were seen in the kidneys, skeletal muscles, extremities, ovaries and uterus of animals treated at 253 mg/kg bw/day. At 38 mg/kg bw/day, treatment-related changes were seen in the adrenals and testes. In addition, changes in the blood and urine indicative of an effect on kidney function were apparent at doses of 38 mg/kg bw/day and above; in particular, there was a clear increase in plasma urea and decrease in plasma potassium which was dose-related and marked at the 127 and 253 mg/kg bw/day dose levels. There was a dose-dependent detrimental effect on maturation of the sperm with most sperm breaking down within the epididymis. Treatment at 127 or 253 mg/kg bw/day resulted in most males showing no motile or normal sperm and significant reductions in sperm numbers. There was also a significant reduction in total sperm number in the cauda epididymis at 38 mg/kg bw/day and a slight effect on sperm morphology.

 

The dose of 253 mg/kg bw/day clearly exceeded the maximum tolerated dose and treatment at this dose level was stopped in Week 9. Recovery from all treatment-related changes was demonstrated, though one male receiving 127 mg/kg bw/day, still showed changes in the testes with associated low sperm numbers, all of which were immotile and abnormal after 16 weeks of recovery. No change on sperm numbers, morphology or motility or any pathological changes were seen at 13 mg/kg /day, nor were there any indications of an effect on the kidney. Consequently, based on these findings, the NOAEL was 13 mg CsCl/kg bw/day (equivalent to 10 mg Cs/kg bw/day and 11.8 mg CsF/kg bw/d).

 

Sub-chronic oral toxicity with CsOH (according to OECD 408)

The aim of this 90-Day toxicity study was to obtain first information on the toxic potential of cesium hydroxide monohydrate in rats at three dose levels following 90-day oral administration. The study was performed in compliance with the OECD guideline No. 408, EU method B.26 and EPA guideline OPPTS 870.3100. The test item was administered orally (by gavage) to Hsd.Brl.Han: Wistar rats (n=10 animals/sex/group) once a day at 0 (vehicle control), 250, 125 and 25 mg/kg bw/day doses corresponding to concentrations of 0, 25, 12.5 and 2.5 mg/mL, applied in a dose volume of 10 mL/kg bw for 90 days. The dose levels correspond to 199, 99 and 19.8 mg Cs/kg bw/d.

Under the conditions of the present study, the 250 mg/kg bw/day dose of cesium hydroxide monohydrate caused reduced body weight, body weight gain, and reduced food consumption (male), and changes in haematology parameters (white blood cell count and percentage of reticulocyte – male and female).Clinical chemistry showed in an elevated activity of Aspartate Amino transferase in males and females of the 250 bw dose group as well as higher concentrations of urea and creatinine and lower mean glucose concentration in males and females. The latter findings are indicative of an impaired kidney function. Damage in spermatogenesis (smaller than normal testes, reduced weights of testes and epididymides, decreased intensity of spermatogenesis, accompanied with lack of mature spermatozoa in the seminiferous tubuli in the testes and in the ductuli of epididymides, and decreased number of spermatids in a proportion of seminiferous tubuli) after the 90-day oral (gavage) administration in Hsd.Brl.Han: Wistar rats was observed. These test item-related changes were toxicologically relevant.

 

A test item influence on the oestrous cycle could not be excluded as none of the female animals in the dose group of 250 mg/kg bw/day had a regular oestrous cycle. However, the concurrent control group showed significantly less animals with irregular oestrous cycle then the historical controls. At this dose level, slight changes in thymus weights were noted in male and female animals, which were associated with an accelerated involution process as compared with the controls. The toxicological significance of this finding was equivocal.

 

At 125 mg/kg bw/day, depression of the body weight development (male), altered hematology parameters (slightly higher mean white blood cell count and higher mean percentage of reticulocytes (male and female)). Clinical chemistry showed in an elevated activity of Aspartate Amino transferase in males and females of the 125 mg/kg bw dose group as well as higher concentrations of urea and creatinine and lower mean glucose in males of this dose group, reduced weight of epididymides, impaired sperm motility and changes in sperm morphology were indicative of adverse test item related effects.

 

At 25 mg/kg bw/day, there were no test item related adverse effects.

 

Based on these observations the No Observed (Adverse) Effect Level (NO(A)EL) for cesium hydroxide monohydrate was determined as follows:

 

NOAEL: 25 mg/kg bw/day for male and female animals (equivalent to 19.8 mg Cs/kg bw/day and 22.6 mg CsF/kg bw/d).

 

chronic oral toxicity with NaF (similar to OECD 453)

The repeated dose toxicity of sodium fluoride was assessed in a two year study equivalent or similar two OECD guideline 453. Sodium fluoride was administered to Fischer rats in water at dose levels of 0, 25, 100, 175 ppm (equivalent to 0, 3.75, 15, and 26.3 mg/kg bw/d assuming 150 mL water/kg bw/d). This corresponds to 0, 1.7, 7, 12.2 mg F/kg bw/d. 100 animals/sex received 0 and 175 ppm and 70 animals/sex received 25 and 100 ppm. Interim sacrifices of ten animals per sex per group occurred at 27 weeks and 66 weeks. The other animals were treated for up to 104 weeks.

There were no compound related effects in mortality, clinical signs, organs weights, body weight, bodyweight gain, feed consumption, water consumption and hematology.

Abnormalities were observed in the teeth of rats dosed with 100 and 175 ppm sodium fluoride. There was a dose-related increase in tooth mottling and whitish discoloration typical of dental fluorosis (these alterations to the incisors were more frequent in males than females). For all treatment groups, dose-related fluoride concentrations in bone were significantly increased over control values for all evaluation periods. Fluoride content of bone also increased as a function of age.

Dose related increases in serum and urine fluoride concentration was observed in male and female animals of the two highest doses.

Non-neoplastic lesions of bone occurred in control and exposed male and/or female rats and included fibrous osteodystrophy and osteosclerosis. Fibrous osteodystrophy was always associated with advanced nephropathy, principally in male rats, and was considered to be due to renal secondary hyperparathyroidism. Osteosclerosis is a sponstaneous bone disease of unknown cause that occurs in aging F344/N rats, primarily females. In the teeth of male and female rats treated with 100 or 175 ppm sodium fluoride there was evidence of dentine dysplasia and ameloblast degeneration.

For all treatment groups, dose-related fluoride concentrations in bone were significantly increased over control values for all evaluation periods. Fluoride content of bone also increased as a function of age.

There was equivocal evidence of carcinogenic activity of sodium fluoride in this 2-year drinking water study based on the occurrence of a small number of osteosarcomas in male rats dosed at concentrations of 100 and 175 ppm. The findings are weakly supportive of an association between sodium fluoride administration in drinking water, but are considered inconclusive. No evidence of carcinogenic activity was found in male rats receiving 25 ppm sodium fluoride in drinking water or in female rats receiving up to 175 ppm sodium fluoride in drinking water. It should be noted that a concurrent 2-year toxicology and carcinogenicity study of sodium fluoride in drinking water using male and female B6C3F1 mice did not find evidence of carcinogenic activity at concentrations up to 175 ppm.

A LOAEL was set to 25 ppm and corresponds to 3.75 mg NaF/kg bw/d (dental fluorosis and osterosclerosis) based on a daily water consumption of 150 mL/kg bw/d (Heindel et al. 1995) (equivalent to 1.7 mg F/kg bw/day and 13.9 mg CsF/kg bw/d). This being in line with a LOAEL reported in the disseminated REACH Dossier of NaF (ECHA, 2021), where a LOAEL of 4 mg/kg bw/d day is used as key value for risk assessment.

 

Conclusion

The above data demonstrates that cesium cation and fluoride anion affect different targets in the organisms. Cesium competes with potassium for transport through potassium channels and can also substitute for potassium in activation of the sodium pump and subsequent transport into the cell leading to uremia, hypokalemia and alkalosis and thus to kidney function impairment. Fluoride interferes with hydroxyl ions in bone apatite and can also be incorporated into growing apatite crystals. It further can bind to enamel matrix proteins (Eanes and Reddi, 1979; Bawden et al, 1987) leading to dental fluorosis and osterosclerosis. Hence an over-proportionate toxicity due to synergistic effects can be excluded and the approach of taking into account the worst case ion for (no) effect level derivation is appropriate. 

Based on the two 90 d studies with the structural analogues cesium hydroxide hydrate and cesium chloride as well as a 2 year study with sodium fluoride the following effects levels were determined:

NOAEL (CsOH): 25 mg/kg bw/day for male and female animals (equivalent to 19.8 mg Cs/kg bw/day)

NOAEL (CsCl): 13 mg CsCl/kg bw/day (equivalent to 10 mg Cs/kg bw/day)

LOAEL (NaF): 3.75 mg/kg bw/d (equivalent to 1.7 mg F/kg bw/d)

No effects were observed up to 19.8 mg Cs⁺/kg bw/d. The lowest observed adverse effect level is 1.7 mg F/kg bw/d. Re-calculation results in a NOAEL of 22.6 mg/kg bw/d and a LOAEL of 13.9 mg/kg bw/d for cesium fluoride. The LOAEL value is chosen as key value for risk assessment as it reflects worst case.

Justification for classification or non-classification

Based on the effects seen on adrenals and kidneys with the read across substances and in accordance with Regulation (EC) No 1272/2008, cesium fluoride is classified for STOT RE Cat. 2 (H373).