Registration Dossier

Diss Factsheets

Administrative data

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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report date:
2016

Materials and methods

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)

Test material

Constituent 1
Chemical structure
Reference substance name:
Caesium chloride
EC Number:
231-600-2
EC Name:
Caesium chloride
Cas Number:
7647-17-8
Molecular formula:
ClCs
IUPAC Name:
cesium;chloride
Test material form:
solid: particulate/powder
Details on test material:
- Batch number: 179-22C
- Expiry date: July 2016
- Purity: 99.9% w/w
Radiolabelling:
no

Test animals

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

Administration / exposure

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
- Recovery period: 16 weeks
Doses / concentrationsopen allclose all
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.

Results and discussion

Metabolite characterisation studies

Metabolites identified:
no

Any other information on results incl. tables

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

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 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.

Applicant's summary and conclusion

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. 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. 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 (Webley, 2016).