Caesium fluoride

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

Data on two source substances are available. Data from cesium nitrate are considered to reflect the worst case. The following NOAELs for cesium fluoride are used as key values.

Cesium fluoride NOAEL for general toxicity (male/female): 39 mg/kg bw/day

Cesium fluoride NOAEL for reproductive toxicity (male/female): 39 mg/kg bw/day.

Cesium fluoride NOAEL for F1 offspring (male/female): 39 mg/kg bw/day.

Link to relevant study records

Reference

Reference 1

Endpoint:

two-generation reproductive toxicity

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:

NOAEL

Remarks:

reproduction

Effect level:

105 mg/kg bw/day

Based on:

other: CsF

Sex:

male/female

Basis for effect level:

other: A lack of dose response and the lack of any statistically significant effects in mating indices indicate that prolonged exposure to sodium fluoride in the drinking water did not adversely affect female or male reproduction in the P generation.

Dose descriptor:

NOAEL

Remarks:

reproduction

Effect level:

13.2 mg/kg bw/day

Based on:

other: F-

Sex:

male/female

Basis for effect level:

other: A lack of dose response and the lack of any statistically significant effects in mating indices indicate that prolonged exposure to sodium fluoride in the drinking water did not adversely affect female or male reproduction in the P generation.

Dose descriptor:

NOAEL

Remarks:

reproduction

Effect level:

28.4 mg/kg bw/day

Based on:

other: NaF

Sex:

male/female

Basis for effect level:

other: A lack of dose response and the lack of any statistically significant effects in mating indices indicate that prolonged exposure to sodium fluoride in the drinking water did not adversely affect female or male reproduction in the P generation.

Key result

Critical effects observed:

no

Key result

Dose descriptor:

NOAEL

Remarks:

reproduction

Generation:

F1

Effect level:

105 mg/kg bw/day

Based on:

other: CsF

Sex:

male/female

Basis for effect level:

other: A lack of dose response and the lack of any statistically significant effects in mating indices indicate that prolonged exposure to sodium fluoride in the drinking water did not adversely affect female or male reproduction in the F1 generation.

Dose descriptor:

NOAEL

Remarks:

reproduction

Generation:

F1

Effect level:

13.2 mg/kg bw/day

Based on:

other: F-

Sex:

male/female

Basis for effect level:

other: A lack of dose response and the lack of any statistically significant effects in mating indices indicate that prolonged exposure to sodium fluoride in the drinking water did not adversely affect female or male reproduction in the F1 generation.

Dose descriptor:

NOAEL

Remarks:

Reproduction

Generation:

F1

Effect level:

28.4 mg/kg bw/day

Based on:

other: NaF

Sex:

male/female

Basis for effect level:

other: A lack of dose response and the lack of any statistically significant effects in mating indices indicate that prolonged exposure to sodium fluoride in the drinking water did not adversely affect female or male reproduction in the F1 generation.

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Reference 2

Endpoint:

screening for reproductive / developmental toxicity

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:

NOAEL

Effect level:

39 mg/kg bw/day

Based on:

other: calculated for CsF

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

organ weights and organ / body weight ratios

reproductive function (sperm measures)

reproductive performance

Dose descriptor:

NOAEL

Effect level:

34 mg/kg bw/day

Based on:

other: calculated for Cs

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

organ weights and organ / body weight ratios

reproductive function (sperm measures)

reproductive performance

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

200 mg/kg bw/day (nominal)

System:

male reproductive system

Organ:

testes

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

39 mg/kg bw/day

Based on:

other: calculated for CsF

Sex:

male/female

Basis for effect level:

other: variations in offspring development between postnatal days 0 and 4

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

34.1 mg/kg bw/day

Based on:

other: calculated for Cs

Sex:

male/female

Basis for effect level:

other: variations in offspring development between postnatal days 0 and 4

Key result

Critical effects observed:

no

Reproductive effects observed:

no

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

39 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No data on reproductive toxicity is available for the target substance. Consequently, data from the source substances cesium nitrate and sodium fluoride were used. Due to the lower effect level determined for cesium nitrate, this value is chosen as key value.

 

Reproductive toxicity screening study (CsNO3)

The purpose of this reproduction/developmental toxicity screening test, conducted according to OECD Guideline 421, was to provide initial information concerning the effect of the test item cesium nitrate on male and female reproductive performance such as gonadal function, mating behavior, conception, pregnancy, parturition as well as on development of the F1 offspring from conception to day 4 post-partum associated with oral administration to rats at repeated doses. Four groups of Hsd.Brl.Han:Wist rats (n=12/sex/group) were administered orally (by gavage) once a day at 0 (vehicle only), 200, 50 and 10 mg CsNO3/kg bw/day at concentrations of 0, 40, 10 and 2 mg/mL corresponding to 5 mL/kg bw dose volume. The dose levels correspond to 136, 34 and 6.8 mg Cs/kg bw/d. The suitability of the chosen vehicle for the test item at the intended concentrations was analytically verified upfront. Cesium nitrate in physiologic saline was stable for 72 hours at room temperature. Concentration of the test item in the dosing formulations varied from 99 % to 100 % of nominal concentrations at both analytical occasions, thereby confirming proper dosing. All animals of the parent (P) generation received test item or vehicle prior to mating (14 days) and throughout mating. Test item or vehicle was administered to male animals post mating (altogether for 56 days) up to the day before the necropsy. To dams, the test item was administered through the gestation period and up postpartal days 3 - 7 (altogether for 40 – 49 days), i.e. up to the day before the necropsy. Observations included mortality, clinical signs, body weight, food consumption, mating, pregnancy and delivery process, as well as development of pups. The dams were allowed to litter, and rear their young up to termination on days 4 postpartum. Pups were weighed and observed for possible abnormalities. Four pups were fixed in isopropanol and stained with Alizarin-Red for skeletal examinations due externally observed abnormalities. All parental animals were subjected to gross pathology one day after the last treatment. Histopathology examination was performed on the testes, epididymides in all male animals (control, low, mid and high dose groups) and on ovaries in female animals of the control and high dose groups.

 

 

Results

 

Mortality

There was no mortality in parental animals at any dose level (200, 50 10, and 0 mg/kg bw/day groups).

 

Clinical observation

Toxic signs related to the test item were not found at general daily and detailed weekly clinical observations. The behavior and physical condition of animals were normal during the entire observation period (pre-mating, mating, post-mating, gestation and lactation periods).

 

Body weight and body weight gain

A test item related depression of the body weight development was detected in male animals at 200 mg/kg bw/day from week 3 up to the end of the study. The body weight development of the parental female animals of 200 mg/kg bw/day was reduced during the last week of the gestation.

 

Food consumption

The daily mean food consumption was reduced in male animals at 200 mg/kg bw/day on week 2 and during the entire post mating period and in female animals of 200 mg/kg bw/day during the lactation period.

 

Reproduction

Variations on the delivery data of dams (higher mean number of post-implantation loss, less total births, less live-borns and viable pups with respect to their controls) were detected at 200 mg/kg bw/day. These findings only slightly differ with respect to the untreated control but a causal link to the treatment with the test item cannot be excluded. There were no differences between the control and test item treated groups (200, 50 and 10 mg/kg bw/day) in the reproductive performance of male and female animals.

 

Necropsy

Specific macroscopic alterations related to the test item were not found in the parental animals during the necropsy.

 

Organ weight

The testes weight (absolute) and epididymides weights (absolute and relative to body and brain weights) were slightly less at 200 mg/kg bw/day with respect to the untreated control. However, the values remained within the ranges of the historical control values.

 

Sperm examinations

Sperm examinations revealed a test item related damage with regards to motility and morphology of sperm cells at 200 mg/kg bw/day.

 

Histopathology

Histopathological examinations did not reveal any toxic or other test item related changes in the testes and epididymides of male animals at 200, 50 or 10 mg/kg bw/day dose level or in ovaries of female animals of 200 mg/kg bw/day group.

 

Offspring

Variations on the offspring development were observed in the slightly higher extra uterine mortality (number and percentage) between postnatal days 0 and 4, and in the less litter weight, litter weight gain and mean pup’s weight and weight gain on postnatal days 0 and 4 in 200 mg/kg bw/day group. These findings only slightly differ with respect to the untreated control but a causal link to the treatment with the test item cannot be excluded. Morphological alterations of the skull were detected in single pups of different litters in the 200 mg/kg bw/day group. As these isolated findings were observed only in individual pups from different litters and were not associated with other morphological alterations, a test item relationship is considered as unlikely. Thus, these scattered occurrences are finally considered as incidental.

 

Under the conditions of the present study, cesium nitrate caused reduced body weight, body weight gain, and reduced food consumption (male and female), and changes in delivery data of dams (post-implantation loss, live-borns, viable pups), damage in sperm motility and morphology, slightly reduced weights of testes, epididymides, after oral (by gavage) administration of 200 mg CsNO3/kg bw/day to Hsd.Brl.Han:Wistar rats during the Reproduction/ Developmental Toxicity Screening Test. At 50 and 10 mg CsNO3/kg bw/day, there were no test item related toxic alterations in the parental male or female animals. At 200 mg/kg bw/day, variations in offspring development were detected between postnatal days 0 and 4: higher incidence of clinical signs, higher extra uterine mortality, depressed body weight development (for litter and pup’s weights). These findings only slightly differed from the untreated controls but a causal link to the treatment with the test item could not be excluded. Also morphological alterations of the skull in individual pups of different litters were observed. These scattered occurrences, only observed in individual pups from different litters, are considered as incidental.

Based on these observations the No Observed Adverse Effect Levels (NOAEL) were determined as follows:

 

NOAEL for general toxicity (male/female): 50 mg/kg bw/day

NOAEL for reproductive toxicity (male/female): 50 mg/kg bw/day

NOAEL for F1 Offspring (male/female): 50 mg/kg bw/day

 

Conclusively, the calculated NOAEL for cesium and cesium fluoride were determined as follows:

 

NOAEL for general toxicity (male/female): 34.1 mg Cs/kg bw/day (39 mg CsF/kg bw/day)

NOAEL for reproductive toxicity (male/female): 34.1 mg Cs/kg bw/day (39 mg CsF/kg bw/day)

NOAEL for F1 offspring (male/female): 34.1 mg Cs/kg bw/day (39 mg CsF/kg bw/day)

 

 

Two-generation study with NaF

In a two generation reproduction study, sodium fluoride was administered to Sprague-Dawley rats in drinking water at concentrations of 0, 25, 100, 175 or 250 ppm (equivalent to mg/L) (Collins et al., 2001). The concentrations are equivalent to 0, 1.3, 5.1, 6.4 and 12.8 mg F/kg bw/d. The selection of the concentrations tested was based on former carcinogenicity and developmental toxicity studies. Male and female rats of the P and F1 generations (P: 48 rats; F1: 36 rats) were treated daily for 10 weeks before mating. The following examinations were made for the parental animals: clinical signs and mortality, body weight, food consumption, test substance intake, reproductive performance, organ weights and gross pathology that included examination of the teeth (stained or molted teeth or whitening of the teeth). Offspring examinations included viability (survival indices), clinical signs, body weight, organ weight and histopathology. The results showed that sodium fluoride in drinking water administered to rats at levels up to 250 ppm (equivalent to 250 mg/L and 28 mg NaF/kg bw/d) had no adverse effects on reproduction throughout two generations. No cumulative toxic effects were observed in the different generations. For reproduction in rats the observed NOEC for the P generation and F1 generation was 250 ppm. The lack of dose response and the lack of any statistically significant effects indicate that prolonged exposure to NaF in drinking water did not adversely affect reproduction in either the P or F1 generation.

Based on these observations the No Observed Adverse Effect Levels (NOAEL) were determined as follows:

 

NOAEL for general toxicity (male/female): 28 mg/kg bw/day

NOAEL for reproductive toxicity (male/female): 28 mg/kg bw/day

NOAEL for F1 Offspring (male/female): 28 mg/kg bw/day

 

Conclusively, the calculated NOAEL for fluoride and cesium fluoride were determined as follows:

NOAEL for general toxicity (male/female): 13.2 mg F/kg bw/day (105.3 mg CsF/kg bw/day)

NOAEL for reproductive toxicity (male/female): 13.2 mg F/kg bw/day (105.3 mg CsF/kg bw/day)

NOAEL for F1 offspring (male/female): 13.2 mg F/kg bw/day 12.8 mg F/kg bw/day (105.3 mg CsF/kg bw/day)

 

Conclusion

Taken together, the value derived from CsNO3 study, i. e. 39 mg CsF/kg bw/d is chosen as key value for reproduction toxicity as it reflects the worst case for this endpoint.

Effects on developmental toxicity

Description of key information

Data on two source substances are available. Data from cesium hydroxide monohydrate are considered to reflect the worst case for developmental toxicity. The following NOAELs for cesium fluoride are used as key values.

Cesium fluoride NOAEL for maternal toxicity (male/female): 9 mg/kg bw/day

Cesium fluoride NOAEL for developmental toxicity (male/female): 136 mg/kg bw/day.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

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

Species:

rat

Dose descriptor:

NOAEL

Effect level:

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

Based on:

other: F-

Basis for effect level:

other: maternal toxicity

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

other: CsF

Basis for effect level:

other: maternal toxicity

Key result

Abnormalities:

no effects observed

Dose descriptor:

NOAEL

Effect level:

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

Based on:

other: F-

Sex:

male/female

Basis for effect level:

other: developmental toxicity

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

other: CsF

Sex:

male/female

Basis for effect level:

other: developmental toxicity

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Reference 2

Endpoint:

developmental toxicity

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

Species:

rat

Key result

Dose descriptor:

NOAEL

Effect level:

9 mg/kg bw/day

Based on:

other: calculated for CsF

Basis for effect level:

body weight and weight gain

food consumption and compound intake

Dose descriptor:

NOAEL

Effect level:

7.9 mg/kg bw/day

Based on:

other: calculated for Cs

Basis for effect level:

body weight and weight gain

food consumption and compound intake

Key result

Abnormalities:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

136 mg/kg bw/day (nominal)

Based on:

other: calculated for CsF

Sex:

male/female

Basis for effect level:

other: no effects observed

Dose descriptor:

NOAEL

Effect level:

119 mg/kg bw/day (nominal)

Based on:

other: calculated for caesium

Sex:

male/female

Basis for effect level:

other: no effects observed

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

136 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP and guideline study

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No data on developmental toxicity is available for the target substance. Consequently, data from the source substances cesium hydroxide monohydrate and sodium fluoride were used.

 

OECD 414, CsOH:
Groups of 27 sperm-positive female Hsd. Brl. Han: Wistar rats were treated with the test item by oral administration daily at three dose levels of 10, 40 and 150 mg/kg bw/day from day 5 up to and including day 19 post coitum (according to OECD 414, EU Method B.31 and EPA OPPTS 870.3700). The dose levels had been selected based on a dose range finding study in pregnant rats of the same strain at dose levels of 10, 30, 100 and 350 mg/kg bw/day with excessive toxicity at the highest dose level. The dose levels correspond to 7.9, 32 and 119 mg Cs/kg bw/d. A control group of 25 sperm positive females was included and the animals were given the vehicle distilled water. The treatment volume was 10 mL/kg bw. During the study, mortality was checked for and clinical observations were performed. Body weight and food consumption of the dams were also recorded. The day when sperm was detected in the vaginal smear was regarded as day 0 of gestation. A Caesarean section and gross pathology were performed on gestational day 20. The number of implantations, early and late resorptions, live and dead fetuses in each uterine horn and the number of corpora lutea were recorded. Each fetus was weighed and examined for sex and gross external abnormalities. The placentas were weighed and examined externally. About half of each litter was preserved for visceral examination and the other half of the litters were preserved for skeletal evaluation. At visceral examination the bodies were micro dissected by means of a dissecting microscope. The heads were examined by Wilson's free-hand razor blade method. After cartilage-bone staining the skeletons were examined by means of a dissecting microscope. All abnormalities found during the fetal examinations were recorded. In total, there were 18, 20, 22 and 23 evaluated litters in the control, 10, 40 and 150 mg/kg bw/day groups, respectively.

 

Results:

 

Mortality

None of the pregnant females died in the course of the study before scheduled necropsy.

 

Clinical observations

There were no clinical signs or treatment related necropsy findings recorded for the dams.

 

Food consumption

A statistically significant reduction in the food consumption was observed in the mid and high dose group (40 and 150 mg/kg bw/day) from gestational day 14 up to necropsy if compared to the control. This reduction in the food consumption was observed in association with a statistically significantly lower body weight gain in the high dose group noted during the last three days of the study and during the whole in-life phase.

 

Body weight

Corrected body weight gain in the mid and high dose groups was also statistically significantly reduced. These findings were attributed to an effect of the test item. The slightly reduced food consumption of the dams which was statistically significant in the mid dose group (40 mg/kg bw/day) between days 11 to 14 (without a dose response) and the slightly lower food consumption of the dams in the low dose group (10 mg/kg bw/day) associated with no changes in the body weight parameters and were considered to be incidental. There were no significant differences in the body weight and body weight gain of the dams in the low and mid dose groups (10 and 40 mg/kg bw/day).

 

Developmental/teratogenic toxicity

There was no effect related to the administration of the test item in the preimplantation loss, intrauterine mortality of the conceptuses, the number of implantations, viable fetuses and their sex distribution. The mean fetal weight, placental and relative placental weight were similar across the control and test item treated groups. The distribution of external, visceral and skeletal variations was homogenous among the experimental groups. There were no malformations found during external and visceral evaluation of the fetuses and there were no significant differences in the skeletal malformations if compared to the control.

 

In conclusion, oral treatment of pregnant rats from gestation days 5 to 19 (i.e. the day before Caesarean section) with cesium hydroxide monohydrate did not cause death, clinical signs or macroscopical alterations at necropsy at the dose levels of 10, 40 and 150 mg/kg bw/day. The test item did not reveal any adverse effect on the pregnancy of the dams, the preimplantation loss, the intrauterine mortality of the conceptuses, the number of viable fetuses and their sex distribution. The development of fetuses evaluated at external, visceral and skeletal examination and determined by the fetal body weight was undisturbed, the test item caused no fetal malformations at the dose levels of 10, 40 and 150 mg/kg bw/day.

The reduced food consumption from day 14 onwards and the lower corrected body weight gain of the dams at the dose levels of 40 and 150 mg/kg bw/day as well as the reduced body weight gain in the last three days of the in-life phase of the dams in the 150 mg/kg bw/day dose group were attributed to the treatment with the test item.

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

 

NOAEL maternal toxicity: 10 mg/kg bw/day

NOAEL developmental toxicity: 150 mg/kg bw/day

 

Conclusively, the calculated NOAEL for cesium fluoride were determined as follows:

Cesium fluoride NOAEL for maternal toxicity: 9 mg/kg bw/day

Cesium fluoride NOAEL for developmental toxicity: 136 mg/kg bw/day.

 

Heindel et al. 1996, NaF
In a developmental toxicity study in accordance with EPA guideline OPPTS 870.3700, sodium fluoride was administered to 26 female Sprague-Dawley rats/dose in water at dose levels of 0, 50, 150 or 300 ppm (corresponding to 0, 7.5, 22.5, 45 mg/kg bw/d) from days 6 to 15 of gestation. The dose level corresponds to 0, 3.5, 10.4, 20.9 mg F/kg bw/d.

No treatment-related clinical signs were observed in confirmed-pregnant animals during or after administration of sodium fluoride. Effects were only observed in the highest tested dose. Maternal body weight gain during the first 2 days of exposure (GD 6 to 8) was significantly reduced relative to controls. Maternal water consumption was significantly decreased throughout GD 6 to 15. Maternal food consumption was also decreased from GD 8 to 10, but did not differ from controls for any other period of measurement. Maternal liver and kidney weights on GD 20 were not different from control. Examination of uteri demonstrated that 100% (26/26), 96% (25/26), 89% (23/26), and 96% (25/26) of the mated animals in the control through high-dose groups were pregnant.

No embryotoxic or teratogenic effects related to exposure to sodium fluoride in drinking water was observed at any dose level.

 

Based on these observations the No Observed Adverse Effect Level (NOAEL) for sodium fluoride was determined as follows:

NOAEL maternal toxicity: 22.5 mg/kg bw/day

NOAEL developmental toxicity: 45 mg/kg bw/day

 

Conclusively, the calculated NOAEL for cesium fluoride were determined as follows:

NOAEL for maternal toxicity: 10.4 mg F/kg bw/day (83 mg CsF/kg bw/day)

NOAEL for developmental toxicity: 20.9 mg F/kg bw/day (167 mg CsF/kg bw/day)

 

Based on re-calculated values, data obtained with CsOH are considered to reflect the worst case and thus values of this study are applied as key values for further risk assessment.

Justification for classification or non-classification

Based on the result of the subchronic repeated dose oral toxicity study (see IUCLID section 7.5.1) cesium hydroxide monohydrate and thus, also cesium fluoride cause interference with the male reproductive system (testis, epididymis, spermatogenesis) and are classified as Repr. 2 (H361f) according to Regulation (EC) No 1272/2008.