Registration Dossier

Administrative data

Description of key information

ORAL EXPOSURE:
There is no repeated dose toxicity study for cesium sulphate available. Consequently, data from the structural analogous substance cesium chloride were used. Based on the results of a 90-day toxicity study according to OECD guideline 408 the NOAEL for cesium chloride was determined as follows to be 13 mg/kg bw/day for male and female animals
Therefore, the calculated NOAEL for cesium sulphate is 13.93 mg/kg bw/day in male and female animals.
RESPIRATORY EXPOSURE:
According to REACH Regulation (EC) No 1907/2006, Annex IX the test repeated dose toxicity after inhalation does not need to be conducted as repeated dose toxicity studies for oral application are available. In addition, due to the particle size distribution of the substance (d10: 119 µm, d50: 214 µm, d90: 339 µm) no inhalable particles are expected. Inhalation exposure is thus expected to be negligible.
DERMAL EXPOSURE:
According to column 2 of REACH Regulation (EC) No 1907/2006, Annex VIII, IIX, Section 8.6.1, the test repeated dose toxicity after dermal application does not need to be conducted as repeated dose toxicity studies for oral application are available. Moreover, based on its physico-chemical properties and absence of toxicity in acute dermal toxicity studies very limited absorption into the systemic circulation is expected after dermal application. Literature data support this estimation (see IUCLID section 7.1 "Basic toxicokinetics").

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
21 September, 2015 to 15 December, 2016
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
other: RccHan™;WIST
Sex:
male/female
Details on test animals 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
Details on route of administration:
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.
Vehicle:
water
Details on oral exposure:
- Starting with the low concentration (1.3 mg/mL), the formulation was prepared by adding 90% of the final volume of vehicle to the test item. An initial mix, crushing any large particles using a hand spatula, was performed if required and the mixture was transferred to a larger container and mixed using a magnetic stirrer until dissolved. Once the material was fully dissolved the pH was measured. For all preparations, the pH was found to be between 5 and 7 and no adjustment was needed. The solution was transferred to a measuring cylinder and made up to volume before transfer to a suitable container and stirred using a magnetic stirrer. The procedure was repeated for the remaining groups in order of ascending concentration.
- Frequency of preparation: Weekly, and was prepared in advance of the first day of dosing.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- Stability and homogeneity: Before commencement of treatment, the suitability of the proposed mixing procedures was determined and specimen formulations were analyzed to assess the stability of the test item in the liquid matrix.
- Assessment of homogeneity was not relevant as CsCl forms a solution in water.
- Achieved concentration: Samples of each formulation prepared for administration in Weeks 1, 4 and 13 of treatment were analyzed for achieved concentration of the test item.
- Analysis method: ICP-MS
Duration of treatment / exposure:
- Exposure: 90 days
- Recoverty period: 16 weeks
Frequency of treatment:
Daily
Dose / conc.:
0 mg/kg bw/day (actual dose received)
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:
115 males and 54 females
Control animals:
yes, concurrent vehicle
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 oral 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.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Cages were inspected daily for evidence of animal ill-health amongst the occupants. Any deviation from normal was recorded at the time in respect of nature and severity, date and time of onset, duration and progress of the observed condition, as appropriate.
During the acclimatization and recovery periods, observations of the animals and their cages were recorded at least once per day.

- A viability check was performed near the start and end of each working day. Animals were killed for reasons of animal welfare where necessary.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Before treatment commenced and during each week of treatment and recovery, detailed physical examination and arena observations were performed on each animal. On each occasion, the examinations were performed at approximately the same time of day (before dosing), by an observer unaware of the experimental group identities.
After removal from the home cage, animals were assessed for physical condition and behavior during handling and after being placed in a standard arena. Any deviation from normal was recorded with respect to the nature and, where appropriate, degree of severity. Particular attention was paid to possible signs of neurotoxicity, such as convulsions, tremor and abnormalities of gait or behavior.
Findings were either reported as "present" or assigned a severity grade - slight, moderate or
marked.

BODY WEIGHT: Yes
- Time schedule for examinations: The weight of each animal was recorded one week before treatment commenced, on the day that treatment commenced (Week 0), weekly throughout the study and before necropsy.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- The weight of food supplied to each cage, that remaining and an estimate of any spilled was recorded for the week before treatment started and for each week throughout the study.

FOOD EFFICIENCY: No
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Fluid intake was assessed by daily visual observation. Precise measurements were undertaken from Week 10 of treatment.
Water consumption recording: Weekly from Week 10 to the end of the treatment period. During Week 4, 8, 12 and 16 of recovery.
Recorded over a 3-day period on each occasion. In addition, water consumption was recorded for Group 5 males in Recovery Weeks 1, 2, 3 and 5. These measurements were not required by protocol.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Pre-treatement: all animals; Week 12: all animals of Group 1 and 4
Prior to each examination, the pupils of each animal were dilated using tropicamide ophthalmic solution (Mydriacyl). The adnexae, conjunctiva, cornea, sclera, anterior chamber, iris (pupil dilated), lens, vitreous and fundus were examined.

HAEMATOLOGY: Yes
Blood samples were collected after overnight withdrawal of food and prior to dosing (where appropriate) at the following occasions:
- Week 9, prior to premature termination: Group 5
- Week 13: All main study animals (Groups 1 to 4)
- Recovery Week 4: Group 5 Recovery Week 4 animals
- Recovery Week 8: Group 1 and 4 Recovery Week 8 animals
- Recovery Week 12: Group 5 Recovery Week 12 animals
- Recovery Week 12: Group 1 and 4 Recovery Week 12 animals (limited parameter list)
- Recovery Week 16: Group 1 and 4 Recovery Week 16 animals (five animals/group) (limited parameter list)
Blood sampling was performed on the morning after overnight collection of urine with the exception of Group 5 animals terminated early. Animals, were, therefore, deprived of food and water overnight but were allowed access to water for a minimum period of one hour prior to the commencement of blood sampling procedures.
Animals were held under light general anesthesia induced by isoflurane. Blood samples (nominally 0.5 mL) were withdrawn from the sublingual vein, collected into tubes containing EDTA anticoagulant and examined s using a Bayer Advia 120 analyzer.

CLINICAL CHEMISTRY: Yes
Blood samples were collected after overnight withdrawal of food and prior to dosing (where appropriate) at the following occasions:
- Week 9, prior to premature termination: Group 5
- Week 13: All main study animals (Groups 1 to 4)
- Recovery Week 4: Group 5 Recovery Week 4 animals
- Recovery Week 8: Group 1 and 4 Recovery Week 8 animals
- Recovery Week 12: Group 5 Recovery Week 12 animals
- Recovery Week 12: Group 1 and 4 Recovery Week 12 animals (limited parameter list)
- Recovery Week 16: Group 1 and 4 Recovery Week 16 animals (five animals/group) (limited parameter list)
Blood sampling was performed on the morning after overnight collection of urine with the exception of Group 5 animals terminated early. Animals, were, therefore, deprived of food and water overnight but were allowed access to water for a minimum period of one hour prior to the commencement of blood sampling procedures.

URINALYSIS: Yes
Animals were placed in an individual metabolism cage, without water. Urine samples were collected overnight at the following occasions:
- Week 13: All main study animals (Groups 1 to 4)
- Recovery Week 4: Group 5 Recovery Week 4 animals
- Recovery Week 8: Group 1 and 4 Recovery Week 8 animals
- Recovery Week 12: Group 5 Recovery Week 12 animals (See Deviation from Protocol)
- Recovery Week 12: Group 1 and 4 Recovery Week 12 animals (limited parameter list)
- Recovery Week 16: Group 1 and 4 Recovery Week 16 animals (Urine sample frozen (nominally -20°C) pending any future requirement for analysis)


NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Week 12
- Battery of functions tested: sensory activity / grip strength / motor activity

Sensory reactivity and grip strength assessments were performed (before dosing) on all main study animals during Week 12 of treatment. Animals were tested by an observer who was unaware of the treatment group to which each animal belonged. Before the start of observations, cage labels showing the treatment group were replaced by labels stating only the study, animal and cage numbers. Animals were not necessarily all tested on the same day, but the numbers of animals and the times of testing were balanced across the groups on each day of testing.

During Week 12 of treatment (before dosing), the motor activity of each main study animal was measured using a Rodent Activity Monitoring System (Version 2.0.5), with hardware supplied by Pearson Technical Services and software developed and maintained by Envigo. Animals were tested individually in clear polycarbonate cages and motor activity was measured by counting infra-red beam breaks over ten 6-minute intervals (one hour total). Ten beams were set at two height levels (five low and five high) to detect cage floor and rearing activity respectively. Animals were not necessarily all tested on the same day, but the numbers of animals and the times of testing were balanced across the groups on each day of testing.

IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
All main study and recovery animals were subject to a detailed necropsy. After a review of the history of each animal, a full macroscopic examination of the tissues was performed. All external features and orifices were examined visually. Any abnormality in the appearance or size of any organ and tissue (external and cut surface) was recorded and the required tissue samples preserved in appropriate fixative. The retained tissues were checked before disposal of the carcass.

Schedule Main study animals of Groups 1 to 4 were killed following 13 weeks of treatment. Group 5 animals were killed prematurely in Week 9 for animal welfare reasons; females on
Day 59 and males on Day 63. Group 1 and 4 animals assigned to the recovery phase were
killed and after 8, 12 or 16 weeks of recovery, which followed 13 weeks of treatment. Group 5 animals were killed following 59 days of treatment and either 4 or 12 weeks of recovery. The necropsy and CASA investigations for Group 5 animals after 12 weeks of recovery were conducted on the same day as for Groups 1 and 4 after 8 weeks of recovery.

ORGAN WEIGHTS: Yes
For bilateral organs, left and right organs were weighed together, unless specified above.
Requisite organs were weighed for main study and recovery animals killed at scheduled
intervals.

HISTOPATHOLOGY: Yes
Full List: All animals killed or dying prematurely. Main study animals of Group 5 killed after 8 weeks of treatment. Main study animals of Groups 1 and 4 killed after 13 weeks of treatment.
Male reproductive tissues (testes, seminal vesicles and epididymis), kidneys and macroscopic abnormalities only: All main study animals of Groups 2 and 3 killed after 13 weeks of treatment. All recovery phase animals, i.e. all Group 5 animals killed after 4 or 12 weeks of recovery and all Group 1 and 4 animals killed after 8, 12 or 16 weeks of recovery.
Tissues which were considered to exhibit a reaction to treatment in Group 4: adrenals, heart, salivary gland (submandibular and sublingual), stomach, spleen. Mammary tissue (males only): All main study animals of Groups 2 and 3 killed after 13 weeks of treatment. Recovery phase animals of Groups 1 and 4 killed after 8 weeks of recovery
Other examinations:
SPERM ANALYSIS

Immediately after scheduled sacrifice (main study and recovery) of each male, including Group 5 males at planned early termination, the left vas deferens, epididymis and testis were removed and the epididymis and testis were weighed.

The following tests were performed:
- Sperm motility - all groups. A sample of sperm was expressed from the vas deferens into prewarmed (approximately 37C) medium M199, which contained 0.5% w/v bovine serum albumin (BSA Fraction V). A sample for assessment was taken into a 100 µm depth cannula by capillary action and, where possible, at least 200 sperm per animal analysed using the Hamilton Thorne IVOS Computer Assisted Sperm Analyser (CASA).
- Sperm morphology – all groups. A 200 µL aliquot of the sperm/medium mixture was diluted with 800 µL of 10% neutral buffered formalin. After staining with nigrosine and eosin an air-dried smear was prepared. Slides were examined by light microscopy for the assessment of sperm morphology. At least 200 sperm were assessed for each male, where possible.
- Sperm count - all groups. The left cauda epididymis of each male was weighed and then the tunica was removed. The portion obtained was weighed then homogenised for at least thirty seconds in 10 mL of a mixture of 0.9% saline and 0.01% merthiolate (SM). An aliquot of this mixture was added to a pre-prepared IDENT stain tube before being assessed for sperm count using CASA.
- Homogenisation-resistant spermatid count – all groups. After removal of the tunica, the left testis of each male was homogenised for at least thirty seconds in 25 mL of SM. An aliquot of this mixture was added to a pre-prepared IDENT stain tube before being assessed for homogenisation-resistant spermatid count using CASA.
Statistics:
The study report contains serial observations pertaining to all weeks of study completed, together with signs data collected during the necropsy period. In the case of clinical signs, body weight and food consumption data, only information from the final week of the acclimatization period are presented.
Summary statistics (e.g. means and standard deviations) presented in this report were calculated from computer-stored individual raw data (except differential white blood cells and cited parameters in urinalysis). Group mean values and standard deviations were frequently calculated using a greater number of decimal places than presented in the appendices. It was, therefore, not always possible to derive exact group values from the data presented in the appendices.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Treatment was generally well tolerated up to Week 9, though animals from all treated groups, but particularly those receiving 127 or 253 mg/kg/day, became irritable and vocal from Week 7 when handled for dosing.

In Week 9 of treatment, animals receiving 253 mg/kg/day showed deterioration in condition. Convulsions were observed for two females and one male resulting in these animals dying or being killed for welfare reasons. Other animals receiving this dose level showed signs included hunched posture, partially closed eyelids, piloerection, tremors, dull eyes, rapid or irregular breathing, red staining on the nose and under- or over-activity. As this dose level was not tolerated, treatment was stopped in Week 9 (Day 58 for females and Day 59 for males).

From approximately Week 7, a higher incidence dorsal hair loss and of encrustations or skin abrasions, particularly on the lower jaw, head and paws were observed for animals receiving 127 or 253 mg/kg/day. Red or brown staining around the nose (chromodacryorrhea) was also observed for a few animals receiving 127 or 253 mg/kg/day from Week 7 reflecting the poorer health status of these animals.

A slightly high incidence of chin rubbing was observed immediately after dosing in Weeks 7 and 8, predominantly for animals receiving 253 mg/kg/day, but also for occasional animals of other treated groups. This sign is not uncommon in studies where the test material is administered by oral gavage and, as such, is considered of no toxicological importance. During the recovery period, the condition of the animals generally improved, though the deterioration of two males that previously received 253 mg/kg/day, three days following cessation of treatment (No. 108) and during Week 7 of recovery (No. 105) was attributed to previous treatment.
Mortality:
mortality observed, treatment-related
Description (incidence):
One male and three females receiving 253 mg/kg/day died or were killed during the treatment period and a further two males that received this dose level died or were killed during the
recovery period. These deaths were attributed to treatment or previous treatment with CsCl.

Female, No. 147 (253 mg/kg/day) was found dead at the 1-2 hour post-dose observation on Day 49, Week 7 of treatment. There was no signs seen ante-mortem. Macropathology findings at necropsy included blood in the thoracic cavity and pale frothy fluid in the trachea. At microscopic examination, treatment-related findings were seen in the adrenals, salivary glands, skin, skeletal muscle around the bone of the sternum, ovaries and uterus. Atrophy/mucification was also seen in the vagina.

Female No. 145 (253 mg/kg/day) had a convulsion prior to dosing on Day 58, Week 9 of treatment and died immediately after. The animal showed bodyweight loss during the week prior to death and was recorded as having thin build. Necropsy examination revealed dark areas on the stomach, the caecum was devoid of contents, the thymus was small and there were scabs on the forelimbs. Treatment-related microscopic findings were seen in the adrenals, salivary glands, skeletal muscle around the bone of the sternum, ovaries and uterus, skin and extremities. Atrophy/mucification was also seen in the vagina.

Female No. 141 (253 mg/kg/day) had a convulsion lasting approximately 2 minutes during the afternoon of Day 58 (Week 9). Following the convulsion the animal showed tremors, welfare reasons. The animal showed bodyweight loss during Weeks 7 and 8. Necropsy examination revealed abnormally coloured (bright red) blood, pale areas on the heart and kidneys, all lobes of the lungs were red, the spleen was an abnormal colour (brown), small thymus and scabs on the fore and hind-limbs. Treatment-related microscopic findings were seen in the adrenals, heart, salivary glands, stomach, ovaries, uterus and extremities.

Male No. 27 (253 mg/kg/day) had a convulsion lasting approximately 40 seconds prior to dosing on Day 60. Following the convulsion the animal showed tremors, rapid breathing, piloerection and salivation and was killed for welfare reasons. Necropsy examination revealed pale areas on the adrenals and kidneys, swollen epididymides and the stomach showed darkened areas and thickened glandular mucosa. Treatment-related microscopic findings were seen in the adrenals, heart, kidneys, salivary glands, skeletal muscle around the bone of the femur, mammary glands, spleen, stomach, epididymides and testes.

Male No. 108 (253 mg/kg/day) was found dead three days following cessation of treatment (Day 63). There were no signs observed ante-mortem. Necropsy examination revealed pale areas on the heart and kidneys, dark areas on the pituitary and stomach, swollen epididymides, distended urinary bladder and scabs on the forelimbs, jaw and tail. Treatment-related microscopic findings were seen in the adrenals, heart, salivary glands, epididymides, testes, skin and extremities.

Male No. 105 (253 mg/kg/day) was killed for welfare reasons during Week 7 of the recovery phase. Clinical signs included a hunched posture, irregular breathing, pallor and piloerection. Necropsy examination revealed abnormal (dark) contents in the cecum and jejunum, small epididymides and small and soft testes. At microscopic examination, treatment-related findings were seen in the salivary glands, adrenals, heart, kidneys, epididymides, testes, skin and extremities.

In addition, one male (No. 62) receiving the intermediate dose of 127 mg/kg/day was killed due to poor condition in Week 13 of treatment. The factor contributory to the death of this animal at microscopic examination was considered to be gastrointestinal tract lesions. Clinical signs comprised decreased activity, irregular breathing, thin build, hair loss, yellow and loose feces, partially closed eyelids with dull and dark eyes, abnormal (swaying) gait and hunched posture. Necropsy examination revealed a perforated and thickened jejunum with multiple firm dark masses, multiple firm pale masses and pale areas on the liver, pale areas on the kidneys, dark mesentery, peritoneum and mesenteric lymph nodes, pale payer’s patches, dark areas, thickened non-glandular mucosa and a depression on the glandular mucosa of the stomach, small and dark thymus, scabs on the lower jaw and hair loss. The animal had lost 37g in bodyweight in the week prior to dispatch. Treatment-related microscopic findings were seen in the adrenals, kidneys, heart, salivary glands, epididymides, testes and skin. Microscopic changes were also seen in the gastrointestinal tract, liver and some other tissues. The factor contributory to death was considered to be the gastrointestinal tract lesions. The degenerative and inflammatory responses seen were considered unrelated to treatment as they were only seen in this one animal.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight gain (Week 0-8) for animals receiving 253 mg/kg/day was statistically significantly lower than that of the controls (0.75X and 0.67X control for males and females, respectively). From Week 7, the effect on body weight became more pronounced, with females showing body weight losses and body weight gain of males falling to approximately half that of the controls.

Overall body weight gain (Weeks 0-13) for males receiving 127 mg/kg/day was also statistically significantly lower than that of the controls (0.89X control). Body weight gain for animals receiving 13 and 38 mg/kg/day and females receiving 127 mg/kg/day were unaffected by treatment.

Weight gain during the recovery period was markedly higher than controls for males which previously received 127 or 253 mg/kg/day, with the greatest gains occurring during the first 8 weeks following cessation of treatment (1.4X and 1.8X control for Weeks R0-R8 at 127 and 253 mg/kg/day, respectively). Absolute body weights for males receiving 127 mg/kg/day were also similar to those of the controls by Week 8 of recovery, indicating full recovery from the previous effect of treatment. Absolute body weight at the end of the 12-week recovery period for males previously receiving 253 mg/kg/day was still lower than controls (0.85X control value for Week R12) indicating partial recovery.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption (Weeks 1-8) for animals receiving 253 mg/kg/day was low when compared with that of the controls (0.89X and 0.90X control for males and females,
respectively).

Food consumption for males receiving 127 mg/kg/day was slightly low from Week 6 when compared to the controls resulting in a slightly low overall value, (0.95X control).

Food consumption for animals receiving 13 or 38 mg/kg/day and females receiving 127 mg/kg/day was not clearly affected by treatment.

During the recovery phase, food consumption for males previously receiving 127 or 253 mg/kg/day was similar to or slightly higher than that of the controls (1.1X and 1.4X controls for Weeks R1-R12, respectively), indicating recovery from the previous effect of treatment.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Visual observation of water consumption indicated a potential effect of treatment. Quantitative measurements were, therefore, undertaken from week 10 of treatment. Water consumption for males and females receiving 38 or 127 mg/kg/day and females receiving 13 mg/kg/day was high during Weeks 10 to 13, when compared with that of the controls. There was no clear dose-relationship, particularly in females where the highest consumption was observed in the low dose group. Males receiving 13 mg/kg/day were unaffected by treatment.

During the recovery period (up to Week 16 of recovery), water consumption for males previously treated with 127 mg/kg/day remained slightly higher than that of the Controls. After Week 4 of recovery, however, the amount of water consumed was lower than that measured during the treatment period, indicating at least partial recovery. Water consumption during the recovery phase for males which previously received 253 mg/kg/day was high at the start of the recovery period, reduced as the recovery period progressed, indicating recovery from the previous effects of treatment.
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
The hematological investigation during Week 9 of treatment for males and females receiving 253 mg/kg/day, prior to early termination, revealed, when compared with the control values for samples obtained in Week 13, low haematocrit, hemoglobin concentration and erythrocyte count, associated with increased reticulocyte counts, in both sexes. There was also an increase of the red cell distribution width and a reduction in mean cell haemoglobin concentration in both sexes and high mean cell volume in males.

Total leucocyte counts were also high in Week 9 for males and females receiving 253 mg/kg/day. These were predominantly a consequence of increased neutrophil counts which were high in both sexes, though lymphocyte, eosinophil and monocyte counts were also high for females receiving this dose level.

The mean activated partial thromboplastin times were reduced, when compared with the controls, for males and females receiving 253 mg/kg/day. The hematological investigation during Week 13 of treatment for males and females receiving 127 mg/kg/day showed similar effects to those seen in the higher dose group after 9 weeks of treatment. Haematocrit, hemoglobin concentration and erythrocyte counts were low in both sexes, associated with increased reticulocyte counts. There was also an increase in red cell distribution width in both sexes and low mean cell hemoglobin and mean cell hemoglobin concentration in females. In addition, hemoglobin concentration for females receiving 38 mg/kg/day was slightly low when compared with the controls, attaining statistical significance.

Total leucocyte counts were increased in Week 13 for animals receiving 127 mg/kg/day, associated with increased neutrophil, lymphocyte, eosinophil and monocyte counts in both sexes. Prothrombin times were considered to be slightly increased in Week 13 of treatment, when compared with the controls, for animals receiving 127 mg/kg/day. Although the group mean prothrombin time for males receiving this dose was similar to that of the controls, the group mean control value was higher than expected due to a very high value for one animal (1M 43, 52.6 sec). When this anomalous value was excluded, the group mean was 22.8 sec for the controls compared with a group mean value of 26.0 sec for males receiving 253 mg/kg/day.

The mean activated partial thromboplastin times were reduced, when compared with the controls, for males receiving 38 or 127 mg/kg/day.

All other differences from controls observed during the treatment period were minor, lacked dose relationship or were confined to one sex and were therefore attributed to normal biological variation.

During Week 4 of recovery for males which previously received 253 mg/kg/day, effects on red blood cell parameters comprising low haematocrit, hemoglobin concentration and erythrocyte count, associated with increased reticulocyte counts, and increased red cell distribution width and mean cell volume in males were still apparent. White blood cell counts were also slightly high compared with the controls. The magnitude of effect for all parameters was less than that at Week 9 of treatment, indicating partial recovery from previous treatment.

During Week 8 of recovery for males which previously received 127 mg/kg/day, haematocrit and red blood cell counts were still slightly low and mean cell hemoglobin, mean cell hemoglobin concentration and mean cell volume slightly high, when compared with controls. White blood cell counts (including neutrophil, lymphocyte, eosinophil, basophil and monocyte counts) were still statistically significantly higher than controls. Prothrombin time was still increased compared to controls. The magnitude of effect was reduced compared with Week 13 of treatment, indicating partial recovery from previous treatment.

During Week 12 of recovery, there was almost complete recovery for males which previously received 127 mg/kg/day. There was still a statistically significant reduction in red blood cell count, and prothrombin time was still slightly increased for previously treated males compared to controls. All other parameters had recovered.

There were no changes in Week 12 of recovery for males which previously received 253 mg/kg/day that were attributed to previous treatment. During Week 16 of recovery, prothrombin time for males which previously received 127 mg/kg/day was still marginally higher than that of the controls, attaining statistical significance. This minor difference was considered not of toxicological importance. Red blood cell count for the previously treated males was similar to controls.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
The biochemical examination during Week 9 of treatment for males and females receiving 253 mg/kg/day, prior to early termination, revealed, when compared with the control values for samples obtained in Week 13, an increase in aspartate amino-transferase and creatinine kinase activities for both sexes. Plasma urea was markedly increased in both sexes; glucose concentration was low in males only. Cholesterol concentration was reduced in both sexes and triglyceride concentration was increased for females only. Potassium was markedly reduced in both sexes. Phospholipids were reduced and chloride slightly reduced in both sexes. Magnesium was reduced in males only and bicarbonate in females only.

Total protein concentrations were markedly reduced in both sexes at 253 mg/kg/day; attributed to reductions of both the albumin and globulin fractions. There were also reductions in albumin-globulin ratio that was due to a proportionately greater reduction of albumin levels.

The biochemical examination of the blood plasma in Week 13 revealed, when compared with controls, an increase in aspartate amino-transferase and creatinine kinase activities for both sexes receiving 127 mg/kg/day.

There was a decrease of alanine amino-transferase activity for males receiving 127 mg/kg/day, though this is not considered of toxicological significance.

Plasma urea concentration was markedly higher than controls in Week 13 for animals receiving 127 mg/kg/day (1.64X and 1.29X control for males and females, respectively) and slightly high for males receiving 38 mg/kg/day (1.15X control). Creatinine concentrations were statistically significantly higher than those of the controls in Week 13 for males and females receiving 127 mg/kg/day (1.36X and 1.28X control, respectively).

Lactate was statistically significantly increased in males receiving 127 mg/kg/day; females were not clearly affected. Bicarbonate was slightly decreased in animals receiving 127 mg/kg/day, but only attaining statistical significance in the females.

Plasma cholesterol and phospholipid concentrations were low for males and females receiving 127 mg/kg/day and males receiving 38 mg/kg/day. There effect on cholesterol did not show a dose-relationship in males.

Potassium concentrations were low to very low, with a clear dose-relationship, for both sexes receiving 38 or 127 mg/kg/day. Magnesium concentrations were low for both sexes receiving 127 mg/kg/day and males receiving 38 mg/kg/day with a clear dose-effect relationship. Chloride concentration was marginally low for both sexes receiving 127 mg/kg/day and males receiving 38 mg/kg/day without clear dose-relationship.

Total protein concentrations were statistically significantly lower than controls in Week 13 at all doses in males. This was attributed to small reductions of both the albumin and globulin fractions. Conversely, in females receiving 127 mg/kg/day there was a slight increase in globulin levels resulting in a decrease in albumin-globulin ratio.

All other differences from controls observed during the treatment period were minor, lacked dose relationship or were confined to one sex and were therefore attributed to normal biological variation.
The biochemical examination during Week 4 of recovery for males which previously received 253 mg/kg/day indicated partial recovery. Many of the changes seen in Week 9 of treatment were still apparent, but to a lesser degree. These comprised increased aspartate amino-transferase activity and urea concentration and decreased cholesterol, phospholipid, potassium, chloride, magnesium and total protein concentrations, associated with reduced albumin and globulin fractions.

At the biochemical examination during Week 8 of recovery for males which previously received 127 mg/kg/day, many of the findings present at the end of treatment had recovered. Changes still evident comprised reduced potassium, and slightly reduced chloride and magnesium concentrations and whilst total protein for previously treated males was similar to controls, albumin concentration was still slightly reduced and globulin fractions were slightly high resulting in a statistically significant decrease in albumin-globulin ratio. In addition, glucose concentration was slightly but statistically significantly lower than controls, though this was not apparent at the end of the treatment period for animals of this dose group (but apparent at 253 mg/kg/day in Week 9).

For males which previously received 253 mg/kg/day, the biochemical investigations in Week 12 of recovery revealed, when compared to control animals sampled in Recovery Week 8, low triglyceride, phospholipid and potassium concentrations. Marginally low albumin and marginally high globulin fractions resulted in a low albumin-globulin ration.

Aspartate amino-transferase activity was still marginally higher than that of the controls, and lactate concentration was also high, though this had been similar to controls at the Recovery Week 4 investigations.

All blood chemistry parameters for males which previously received 127 mg/kg/day were considered to have recovered by Week 12 of recovery. A slightly low albumin value attained statistical significance, but this slight difference from controls was considered not to be of biological significance. Re-evaluation of this parameter in Week 16 of recovery confirmed that this change had completely resolved.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Urinalysis investigations were not performed prior to early termination in Week 9 of animals receiving 253 mg/kg/day for welfare reasons.

The urinalysis investigation in Week 13 of treatment revealed, when compared with the controls, high urinary volume by males and females receiving 127 mg/kg/day and this associated with low specific gravity. Urinary sodium, potassium and chloride outputs were high for both sexes at 127 mg/kg/day. Magnesium, calcium and creatinine levels were also high in males, though the difference magnesium and creatinine did not attain statistical significance. Glucose output was low in both sexes at 127 mg/kg/day and total protein was low in males at 127 mg/kg/day. The pH of the urine was low for females receiving 127 mg/kg/day. In addition, blood in the urine (small to large amount) was recorded for 1/10 males and 2/10 females receiving 127 mg/kg/day, compared with none in the controls.

There were no other changes in the appearance and/or composition of the urine that were attributable to treatment. Low calcium output for females which received 127 or 253 mg/kg/day showed no dose-relationship and was in the opposite direction to the effect seen in males and, therefore was attributed to normal biological variation.

During Week 4 of recovery urinalysis investigations for males which previously received 253 mg/kg/day revealed (when compared with controls sampled in Week 13 of treatment which were performed on the same day) high urinary volume with associated low specific gravity, high urinary creatinine, magnesium, sodium, potassium and chloride outputs and low total protein output. The pH of the urine was also low. In addition, blood in the urine (moderate to large amount) was recorded for 2/10 males.

During Week 8 of recovery for males which previously received 127 mg/kg/day, urine volume was still higher than that of the controls and associated with low specific gravity. Blood in the urine was apparent (large amount) for 1/9 males and creatinine, magnesium and potassium outputs were also still slightly high compared with controls, though partial recovery was evident.
In Week 12 of recovery, blood was present in the urine (large amount) for one animal (No. 106) that previously received 253 mg/kg/day. There were no other changes in the urine that were attributed to previous treatment, demonstrating full recovery had occurred for the remainder of the animals.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
SENSORY REACTIONS

Sensory reactivity responses and grip strength were considered to be unaffected by treatment. Excessive vocalisation during the testing procedures was recorded for a small number of
females of all treated groups assessed (13, 38 or 127 mg/kg/day), reflecting the clinical observations during the study.

Group mean forelimb and hindlimb grip strength values for all treated male groups were high compared with Controls, with statistical significances attained in all treated groups for forelimb grip strength and at 127 mg/kg/day for hindlimb grip strength. All forelimb grip strength values, including those of the controls, were however, below the historical control data range (0.89 to 1.07 kg), except for males at 127 mg/kg/day, which was within the historical control range. Mean forelimb grip strength for females receiving 127 mg/kg/day was also slightly high compared with Controls and also above the historical control data range (0.73 to 0.94 kg for forelimbs and 0.33 to 0.46 kg for hindlimbs), but without statistical significance. One male and two females in the control group were reluctant to grip the forelimb bar and values for these animals were lower. The differences were, therefore, attributed to atypically low scores for the controls.

Mean hindlimb grip strength values for males receiving 38 or 127 mg/kg/day were slightly above the historical control data range (0.41 to 0.49 kg), attaining statistical significance at 127 mg/kg/day. Mean hindlimb grip strength values for treated females were similar to those of the controls, with mean values for both control and females receiving 127 mg/kg/day being marginally above the historical control data range (0.33 to 0.46 kg). These minor differences were considered not of toxicological significance.

MOTOR ACTIVITY

Motor activity in Week 12 was considered to be unaffected by treatment.

Group mean motor activity scores were similar to Controls at all doses in males. The majority of the low beam 6-minute interval scores and the total low beam scores (a measure of cage floor activity) for all treated females were slightly high compared with Controls, but attained statistical significance on just two occasions (12-minute interval for females receiving 38 or 127 mg/kg/day and at the 24-minute interval for low beams for females receiving 127 mg/kg/day). The high beam 6-minute interval and total high beam scores (a measure of rearing activity) were similar to those of the controls, the only statistical difference (36-minute interval for females receiving 127 mg/kg/day) being in the opposite direction to the low beam score. Considering that the differences from controls seen for the low beam scores were minimal, with no similar effect in high beam scores which are usually more sensitive to effects, and in one sex only, the differences were attributed to natural variation.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Analysis of organ weights for animals receiving 253 mg/kg/day was made difficult because of the bodyweight effect and lack of concurrent control animals. When compared with background data and control animals killed four weeks later, there were indications of low liver and thymus weights in both sexes and low epididymides and testes weights in males.

Analysis of organ weights for animals killed after 13 weeks of treatment revealed, when compared with the controls, low absolute and bodyweight-adjusted epididymides weights and low absolute testes weights for males at 127 mg/kg/day, increased bodyweight-adjusted kidney weights in both sexes at 127 mg/kg/day (attaining statistical significance in females only) and increased absolute kidney weights for females at 127 mg/kg/day, decreased absolute and bodyweight-adjusted liver weights for males at 13, 38 or 127 mg/kg/day; increased absolute and bodyweight-adjusted spleen weights for females at 127 mg/kg/day; decreased absolute and bodyweight-adjusted thymus weights in both sexes at 127 mg/kg/day.

In addition, the absolute and bodyweight-adjusted weights uterus and cervix weights were decreased in females at 127 mg/kg/day; though the differences did not attain statistical significance. Bodyweight-adjusted adrenal weights for males at 127 mg/kg/day were slightly high compared to controls, but did not attain statistical significance.

Analysis of organ weights following a 4-week recovery period for males given 253 mg/kg/day revealed (when compared with controls killed after 13 weeks of treatment which were performed on the same day) reduced absolute epididymides, liver, testes and thymus weights and increased kidney weights.

Following 8 weeks of recovery, absolute epididymides weights were still statistically significantly lower than those of the controls and absolute and bodyweight-adjusted kidney weights were still statistically significantly higher than those of the controls for males previously treated at 127 mg/kg/day. Absolute and bodyweight-adjusted liver and thymus weights and absolute testes weights were slightly lower than those of the controls, but the differences were minimal and did not attain statistical significance indicating partial recovery.

There were no statistically significant differences in organ weights between controls and males previously treated at 127 mg/kg/day following 12 weeks of recovery. For animals that previously received 253 mg/kg/day, absolute epididymides, liver, testes and thymus weights remained low following 12 weeks of recovery, at least in part due to the low bodyweights still evident in these animals.

There were no differences after 16 weeks of recovery that were attributed to previous treatment. A slight difference in kidney weights attained statistical significance after 16 weeks of recovery, but the difference was minimal and considering the lack of any difference after 12 weeks of recovery, this was considered due to normal biological variation.

A difference in brain weight for previously attained statistical significance but since no similar change was observed on completion of treatment or on any of the previous recovery occasions, this was considered a consequence of normal variation.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
The macroscopic examination performed after 9 or 13 weeks of treatment revealed: pale adrenals at 127 or 253 mg/kg/day; pale areas in the kidney at 253 mg/kg/day and males at 127 mg/kg/day; scabs and depressions on the skin and subcutis at 127 or 253 mg/kg/day; scabs on the forepaws at 253 mg/kg/day; darkening of the salivary glands in both sexes at 127 mg/kg/day and at 38 and 13 mg/kg/day in males; soft testes at 127 mg/kg/day and small testes and epididymides at 253 mg/kg/day; dark areas; depressions and thickening in the stomach at 253 mg/kg/day. Following 12 weeks of recovery, the changes in the mandibular salivary gland, epididymides and testes were still evident in a small number of animals that previously received 253 mg/kg/day, whilst all changes at 127 mg/kg/day had recovered. Following 16 weeks of recovery, treatment-related changes in the salivary gland and testes were evident for 1/5 males previously receiving 127 mg/kg/day.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathological changes related to treatment were seen in the mandibular and sublingual salivary glands (degranulation and atrophy), heart (myocardial degeneration/inflammation), stomach (foveolar/mucosal hyperplasia), spleen (males only - increased extramedullary haemopoiesis), adrenals (diffuse hypertrophy of the zonal glomerulosa), mammary glands (males only – atrophy), skin and subcutis (epidermal scabs/ulceration and hyperplasia, and dermal/ subcutaneous inflammation), epididymides (reduced sperm content and cell debris at 127 and 253 mg/kg/day and ductal atrophy and sperm granuloma at 127 mg/kg/day) and testes (tubular degeneration/atrophy) of animals treated at 253 mg/kg/day for 59 days or 127 mg/kg/day for 13 weeks. Additional changes were seen in the kidneys (males only, tubular basophilia), skeletal muscles (myofibre degeneration), extremities (epidermal scabs/ulceration and hyperplasia, and dermal/ subcutaneous inflammation), ovaries (decreased corpora lutea) and uterus (atrophy) of animals treated at 253 mg/kg/day. At 38 mg/kg/day, treatment-related changes were seen in the adrenals (diffuse hypertrophy of the zonal glomerulosa) and testes (minimal tubular degeneration/atrophy). No treatment-related change was seen at 13 mg/kg/day. Full recovery was demonstrated in the kidneys, stomach, spleen, epididymides and mammary glands. Partial recovery was demonstrated in the salivary glands, heart, adrenals after 8 weeks of recovery and in the testes after 16 weeks of recovery.
Histopathological findings: neoplastic:
not examined
Other effects:
effects observed, treatment-related
Description (incidence and severity):
SPERM ANALYSIS

Treatment with cesium chloride at 13 mg/kg/day for 90 days produced no adverse effects on sperm motility, concentration or morphology.

Following 13 weeks of treatment with cesium chloride at 38 mg/kg/day, slight but statistically significant changes in sperm morphology, motility (increase of beat cross frequency only), and a reduction in sperm number in the cauda epididymis were seen.

Treatment at 127 mg/kg/day resulted in most males showing no motile or normal sperm and significant reductions in cauda epididymal sperm numbers compared to Control animals. Additionally, testicular sperm numbers were lower than Controls; this change was not statistically significant. Similar results were seen for sperm motility, morphology and cauda epididymal sperm following only 59 days treatment at 253 mg/kg/day, however effects on testicular sperm numbers were not apparent. Abnormalities seen at the two highest dose levels were mostly decapitate sperm with irregular and/or frayed midpiece and/or tails. A high incidence of flattened head was also apparent. Results suggest an effect on maturation of the sperm with most sperm breaking down within the epididymis.

Following a 4 week recovery period for animals which received 253 mg/kg/day, a progression of effects was apparent; all sperm were immotile and abnormal. Sperm numbers in both the cauda epididymis and testis were markedly lower than seen at the end of treatment with cesium chloride at 253 mg/kg/day.

Following an 8 week recovery period those males previously treated at 127 mg/kg/day showed some evidence of recovery, however values for motility, counts and morphology were still significantly lower than those of the Control males.

Following a 12 week recovery period males previously treated with cesium chloride at 127 mg/kg/day showed values for motility and morphology approaching Control levels. Epididymal sperm numbers were lower than Controls but this difference was not statistically significant. Additionally in males previously treated at 253 mg/kg/day, sperm motility and normal morphology values were low; this was reflected in the motion parameters, however some evidence of recovery was apparent.

Group mean results suggest that recovery was incomplete for males previously treated at 127 mg/kg/day following a 16 week off dose period, though all sperm parameters when compared with controls, with the exception of total sperm in the cauda epididymis, did not attain statistical significance. Examination of individual data, however, showed 4/5 males to exhibit values similar to Controls. Only one male in this group showed low sperm numbers, all of which were immotile and abnormal.
Dose descriptor:
NOAEL
Effect level:
13 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks:
CsCl
Sex:
male/female
Basis for effect level:
other: No change on sperm numbers, morphology or motility or any pathological changes. No indications of an effect on the kidney.
Remarks on result:
other: equivalent to 10 mg Cs/kg bw/day)
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 13.93 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks:
Cs2SO4 (MM: 149.9128)
Sex:
male/female
Basis for effect level:
other: No change on sperm numbers, morphology or motility or any pathological changes. No indications of an effect on the kidney.
Remarks on result:
other: equivalent to 10 mg Cs/kg bw/day
Critical effects observed:
yes
Lowest effective dose / conc.:
38 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
Conclusions:
Under the study conditions, the NOAEL for cesium chloride in rats was considered to be 13 mg/kg bw/day (equivalent to 10 mg Cs/kg bw/day).
Based on this results the calculated NO(A)EL for cesium sulfate is 13.93 mg/kg bw/day (calculated from CsCl to Cs to CsSO4 (MM: 361.87)).
Executive summary:

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. This study was designed to investigate 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).

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. During the study, clinical condition, body weight, food consumption, water consumption, ophthalmoscopy, hematology (peripheral blood), blood chemistry, urinalysis, sperm analysis, organ weight, macropathology and histopathology investigations were undertaken.

Three males and three females which received 253 mg/kg bw/day died or were killed prematurely due to poor condition during treatment or the subsequent recovery period. The histopathological examination did not identify any factors contributory to death, but the clinical deterioration of the animals was attributed to treatment with CsCl. In addition, one male receiving the intermediate dose of 127 mg/kg bw/day was killed due to poor condition in Week 13 of treatment. The factor contributory to the death of this animal at microscopic examination was considered to be gastrointestinal tract lesions and was not attributed to treatment due to the isolated incidence.

Treatment was generally well tolerated up to Week 9, though treated animals, particularly at 127 or 253 mg/kg bw/day were generally more irritable and vocal from Week 7. In Week 9 of treatment, animals receiving 253 mg/kg bw/day showed deterioration in condition. Convulsions were observed for two females and one male resulting in these animals dying or being killed for welfare reasons. Other animals receiving this dose level showed signs included hunched posture, partially closed eyelids, piloerection, tremors, dull eyes, rapid or irregular breathing, red staining on the nose and under- or over-activity. 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.

Dorsal hair loss, red or brown staining around the nose (chromodacryorrhea) and encrustations or skin abrasions, particularly on the lower jaw, head and paws were observed for animals receiving 127 or 253 mg/kg bw/day. During the recovery period, the condition of the animals generally improved, though the deterioration of two males, necessitating premature sacrifice during the recovery period were attributed to previous treatment.

Sensory reactivity responses, grip strength and motor activity were considered to be unaffected by treatment.

Body weight gain and food consumption were low for males and females receiving 253 mg/kg bw/day. Bodyweight gain was also low for males receiving 127 mg/kg bw/day, whilst food consumption was only slightly lower than that of the controls. Recovery was demonstrated after cessation of treatment.

Water consumption was increased for males receiving 38 mg/kg bw/day or above and at all doses in females, without dose-relationship. Recovery was demonstrated after cessation of treatment, but intake remained slightly high in the off-dose period for males which had previously received 253 mg/kg bw/day.

There were no treatment-related ophthalmic findings.

Disturbances in red blood cell indices for animals receiving 127 or 253 mg/kg bw/day (Week 13 and 9 of treatment, respectively) included: low haematocrit, hemoglobin concentration and erythrocyte counts, associated with increased reticulocyte counts; increased red cell distribution width; low mean cell hemoglobin and mean cell hemoglobin concentration. A high mean cell volume was also apparent in males at 253 mg/kg bw/day. The only change at 38 mg/kg bw/day was slightly low hemoglobin concentration in females only. Recovery was demonstrated for all parameters by Week 16 of recovery.

Treatment-related findings in white blood cell parameters for animals receiving 127 or 253 mg/kg bw/day (Week 13 and 9 of treatment, respectively) included: increased total leucocyte counts, associated with increased neutrophil, lymphocyte, eosinophil and monocyte counts. All of these findings showed complete recovery by Week 12 of recovery.

Activated partial thromboplastin times were reduced for both sexes receiving 253 mg/kg bw/day and for males receiving 38 or 127 mg/kg bw/day. Recovery was demonstrated. Prothrombin times were slightly increased in Week 13 of treatment for animals receiving 127 mg/kg bw/day. Prothrombin time was still slightly lower than that of the controls at the end of the recovery period, but the increase was very mild and not of toxicological significance.

Treatment-related biochemical changes in blood plasma included: increased aspartate amino-transferase and creatinine kinase activities for both sexes at 127 or 253 mg/kg bw/day; decreased alanine amino-transferase activity for males receiving 127 mg/kg bw/day; increased urea in both sexes at 127 or 253 mg/kg bw/day and males at 38 mg/kg bw/day; increased creatinine concentrations in both sexes at 127 mg/kg bw/day; low glucose concentration in males at 253 mg/kg bw/day; reduced cholesterol concentration in both sexes at 127 or 253 mg/kg bw/day and males at 38 mg/kg bw/day, without dose-relationship; increased triglyceride concentration for females at 253 mg/kg bw/day; low phospholipid concentrations for animals of both sexes at 127 or 253 mg/kg bw/day and males at 38 mg/kg bw/day; potassium concentrations were low to very low for both sexes receiving 38, 127 or 253 mg/kg bw/day with a clear dose-relationship; marginally reduced chloride in both sexes at 127 or 253 mg/kg bw/day and males at 38 mg/kg bw/day without clear dose-relationship; low magnesium for both sexes at 127 mg/kg bw/day and males receiving 253 or 38 mg/kg bw/day; increased lactate in males at 127 mg/kg bw/day; slightly low bicarbonate in females at 253 mg/kg bw/day and both sexes at 127 mg/kg bw/day. Total protein concentrations were markedly reduced in both sexes at 253 mg/kg bw/day and slightly reduced in males at all other doses; attributed to reductions of both the albumin and globulin fractions. A reduction in albumin-globulin ratio indicated that there was a proportionately greater reduction of albumin levels. In females at 127 mg/kg bw/day there was a slight increase in globulin levels resulting in a decrease in albumin-globulin ratio.

All of these findings showed complete recovery by Week 12 of recovery. Treatment-related changes in urinary parameters in Week 13 of treatment for animals receiving 127 mg/kg bw/day included: high urinary volume, associated with low specific gravity; high urinary sodium, potassium and chloride outputs in both sexes and high magnesium, calcium and creatinine levels in males (the difference in magnesium and creatinine did not attain statistical significance); low glucose output in both sexes and low total protein in males; low urine pH for female; blood in the urine was recorded for 2/10 males and 2/10 females at 127 mg/kg bw/day. Recovery was demonstrated.

Sperm analysis indicated a dose-dependent detrimental effect, predominantly on the epididymis with marked effects observed at the 127 and 253 mg/kg bw/day doses. Treatment for 13 weeks at 127 mg/kg bw/day resulted in most males showing no motile or normal sperm and significant reductions in cauda epididymal sperm numbers compared to Control animals. Additionally, testicular sperm numbers were lower than Controls; this change was not statistically significant. Similar results were seen for sperm motility, morphology and cauda epididymal sperm following 59 days treatment at 253 mg/kg bw/day, however effects on testicular sperm numbers were not apparent. Abnormalities seen at 127 and 253 mg/kg bw/day were mostly decapitate sperm with irregular and/or frayed midpiece and/or tails. A high incidence of flattened head was also apparent. Results suggest an effect on maturation of the sperm with most sperm breaking down within the epididymis. At 38 mg/kg bw/day, slight but statistically significant changes in sperm morphology, motility (increase of beat cross frequency only), and a reduction in sperm number in the cauda epididymis were seen. There were no adverse effects on sperm motility, concentration or morphology effects at 13 mg/kg bw/day. Partial recovery was evident following 12-weeks off dose for animals previously treated at 253 mg/kg bw/day. Following a 16 week off dose period for animals which received 127 mg/kg bw/day, 4/5 males showed complete recovery, whilst one male in this group still showed low sperm numbers, all of which were immotile and abnormal.

Analysis of organ weights for animals killed after 9 or 13 weeks of treatment revealed low epididymides and absolute testes weights at 127 or 253 mg/kg bw/day; increased kidney weights at 127 mg/kg bw/day; decreased liver weights for males at 13, 38 or 127 mg/kg bw/day and both sexes at 253 mg/kg bw/day; increased spleen weights for females at 127 mg/kg bw/day; decreased thymus weights at 127 or 253 mg/kg bw/day; slightly low uterus and cervix weights in females at 127 mg/kg bw/day (without statistical significance) and slightly high adrenal weights for males at 127 mg/kg bw/day (without statistical significance). Recovery was demonstrated.

The macroscopic examination performed after 9 or 13 weeks of treatment revealed: pale adrenals at 127 or 253 mg/kg bw/day; pale areas in the kidney at 253 mg/kg bw/day and males at 127 mg/kg bw/day; scabs and depressions on the skin and subcutis at 127 or 253 mg/kg bw/day; scabs on the forepaws at 253 mg/kg bw/day; darkening of the salivary glands in both sexes at 127 mg/kg bw/day and at 38 and 13 mg/kg bw/day in males; soft testes at 127 mg/kg bw/day and small testes and epididymides at 253 mg/kg bw/day; dark areas; depressions and thickening in the stomach at 253 mg/kg bw/day. Following 12 weeks of recovery, the changes in the mandibular salivary gland, epididymides and testes were still evident in a small number of animals that previously received 253 mg/kg bw/day, whilst all changes at 127 mg/kg bw/day had recovered.

Following 16 weeks of recovery, treatment-related changes in the salivary gland and testes were evident for 1/5 males previously receiving 127 mg/kg bw/day. Histopathological changes related to treatment were seen in the mandibular and sublingual salivary glands (degranulation and atrophy), heart (myocardial degeneration/inflammation), stomach (foveolar/mucosal hyperplasia), spleen (males only - increased extramedullary haemopoiesis), adrenals (diffuse hypertrophy of the zonal glomerulosa), mammary glands (males onlyatrophy), skin and subcutis (epidermal scabs/ulceration and hyperplasia, and dermal/ subcutaneous inflammation), epididymides (reduced sperm content and cell debris at 127 and 253 mg/kg bw/day and ductal atrophy and sperm granuloma at 127 mg/kg bw/day) and testes (tubular degeneration/atrophy) 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 (males only, tubular basophilia), skeletal muscles (myofibre degeneration), extremities (epidermal scabs/ulceration and hyperplasia, and dermal/ subcutaneous inflammation), ovaries (decreased corpora lutea) and uterus (atrophy) of animals treated at 253 mg/kg bw/day.

At 38 mg/kg bw/day, treatment-related changes were seen in the adrenals (diffuse hypertrophy of the zonal glomerulosa) and testes (minimal tubular degeneration/atrophy). No treatment-related change was seen at 13 mg/kg bw/day. Full recovery was demonstrated in the kidneys, stomach, spleen, epididymides and mammary glands. Partial recovery was demonstrated in the salivary glands, heart, adrenals after 8 weeks of recovery and in the testes after 16 weeks of recovery.

In conclusion,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 considered to be 13 mg/kg bw/day (equivalent to 10 mg Cs/kg bw/day) (Webley, 2016).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
13.93 mg/kg bw/day
Study duration:
subchronic
Species:
rat

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

Key study summary with cesium chloride (Read-across for Cesium sulfate)

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. This study was designed to investigate 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).

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. During the study, clinical condition, body weight, food consumption, water consumption, ophthalmoscopy, hematology (peripheral blood), blood chemistry, urinalysis, sperm analysis, organ weight, macropathology and histopathology investigations were undertaken.

Three males and three females which received 253 mg/kg bw/day died or were killed prematurely due to poor condition during treatment or the subsequent recovery period. The histopathological examination did not identify any factors contributory to death, but the clinical deterioration of the animals was attributed to treatment with CsCl. In addition, one male receiving the intermediate dose of 127 mg/kg bw/day was killed due to poor condition in Week 13 of treatment. The factor contributory to the death of this animal at microscopic examination was considered to be gastrointestinal tract lesions and was not attributed to treatment due to the isolated incidence.

Treatment was generally well tolerated up to Week 9, though treated animals, particularly at 127 or 253 mg/kg bw/day were generally more irritable and vocal from Week 7. In Week 9 of treatment, animals receiving 253 mg/kg bw/day showed deterioration in condition. Convulsions were observed for two females and one male resulting in these animals dying or being killed for welfare reasons. Other animals receiving this dose level showed signs included hunched posture, partially closed eyelids, piloerection, tremors, dull eyes, rapid or irregular breathing, red staining on the nose and under- or over-activity. 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.

Dorsal hair loss, red or brown staining around the nose (chromodacryorrhea) and encrustations or skin abrasions, particularly on the lower jaw, head and paws were observed for animals receiving 127 or 253 mg/kg bw/day. During the recovery period, the condition of the animals generally improved, though the deterioration of two males, necessitating premature sacrifice during the recovery period were attributed to previous treatment.

Sensory reactivity responses, grip strength and motor activity were considered to be unaffected by treatment.

Body weight gain and food consumption were low for males and females receiving 253 mg/kg bw/day. Bodyweight gain was also low for males receiving 127 mg/kg bw/day, whilst food consumption was only slightly lower than that of the controls. Recovery was demonstrated after cessation of treatment.

Water consumption was increased for males receiving 38 mg/kg bw/day or above and at all doses in females, without dose-relationship. Recovery was demonstrated after cessation of treatment, but intake remained slightly high in the off-dose period for males which had previously received 253 mg/kg bw/day.

There were no treatment-related ophthalmic findings.

Disturbances in red blood cell indices for animals receiving 127 or 253 mg/kg bw/day (Week 13 and 9 of treatment, respectively) included: low haematocrit, hemoglobin concentration and erythrocyte counts, associated with increased reticulocyte counts; increased red cell distribution width; low mean cell hemoglobin and mean cell hemoglobin concentration. A high mean cell volume was also apparent in males at 253 mg/kg bw/day. The only change at 38 mg/kg bw/day was slightly low hemoglobin concentration in females only. Recovery was demonstrated for all parameters by Week 16 of recovery.

Treatment-related findings in white blood cell parameters for animals receiving 127 or 253 mg/kg bw/day (Week 13 and 9 of treatment, respectively) included: increased total leucocyte counts, associated with increased neutrophil, lymphocyte, eosinophil and monocyte counts. All of these findings showed complete recovery by Week 12 of recovery.

Activated partial thromboplastin times were reduced for both sexes receiving 253 mg/kg bw/day and for males receiving 38 or 127 mg/kg bw/day. Recovery was demonstrated. Prothrombin times were slightly increased in Week 13 of treatment for animals receiving 127 mg/kg bw/day. Prothrombin time was still slightly lower than that of the controls at the end of the recovery period, but the increase was very mild and not of toxicological significance.

Treatment-related biochemical changes in blood plasma included: increased aspartate amino-transferase and creatinine kinase activities for both sexes at 127 or 253 mg/kg bw/day; decreased alanine amino-transferase activity for males receiving 127 mg/kg bw/day; increased urea in both sexes at 127 or 253 mg/kg bw/day and males at 38 mg/kg bw/day; increased creatinine concentrations in both sexes at 127 mg/kg bw/day; low glucose concentration in males at 253 mg/kg bw/day; reduced cholesterol concentration in both sexes at 127 or 253 mg/kg bw/day and males at 38 mg/kg bw/day, without dose-relationship; increased triglyceride concentration for females at 253 mg/kg bw/day; low phospholipid concentrations for animals of both sexes at 127 or 253 mg/kg bw/day and males at 38 mg/kg bw/day; potassium concentrations were low to very low for both sexes receiving 38, 127 or 253 mg/kg bw/day with a clear dose-relationship; marginally reduced chloride in both sexes at 127 or 253 mg/kg bw/day and males at 38 mg/kg bw/day without clear dose-relationship; low magnesium for both sexes at 127 mg/kg bw/day and males receiving 253 or 38 mg/kg bw/day; increased lactate in males at 127 mg/kg bw/day; slightly low bicarbonate in females at 253 mg/kg bw/day and both sexes at 127 mg/kg bw/day. Total protein concentrations were markedly reduced in both sexes at 253 mg/kg bw/day and slightly reduced in males at all other doses; attributed to reductions of both the albumin and globulin fractions. A reduction in albumin-globulin ratio indicated that there was a proportionately greater reduction of albumin levels. In females at 127 mg/kg bw/day there was a slight increase in globulin levels resulting in a decrease in albumin-globulin ratio.

All of these findings showed complete recovery by Week 12 of recovery. Treatment-related changes in urinary parameters in Week 13 of treatment for animals receiving 127 mg/kg bw/day included: high urinary volume, associated with low specific gravity; high urinary sodium, potassium and chloride outputs in both sexes and high magnesium, calcium and creatinine levels in males (the difference in magnesium and creatinine did not attain statistical significance); low glucose output in both sexes and low total protein in males; low urine pH for female; blood in the urine was recorded for 2/10 males and 2/10 females at 127 mg/kg bw/day. Recovery was demonstrated.

Sperm analysis indicated a dose-dependent detrimental effect, predominantly on the epididymis with marked effects observed at the 127 and 253 mg/kg bw/day doses. Treatment for 13 weeks at 127 mg/kg bw/day resulted in most males showing no motile or normal sperm and significant reductions in cauda epididymal sperm numbers compared to Control animals. Additionally, testicular sperm numbers were lower than Controls; this change was not statistically significant. Similar results were seen for sperm motility, morphology and cauda epididymal sperm following 59 days treatment at 253 mg/kg bw/day, however effects on testicular sperm numbers were not apparent. Abnormalities seen at 127 and 253 mg/kg bw/day were mostly decapitate sperm with irregular and/or frayed midpiece and/or tails. A high incidence of flattened head was also apparent. Results suggest an effect on maturation of the sperm with most sperm breaking down within the epididymis. At 38 mg/kg bw/day, slight but statistically significant changes in sperm morphology, motility (increase of beat cross frequency only), and a reduction in sperm number in the cauda epididymis were seen. There were no adverse effects on sperm motility, concentration or morphology effects at 13 mg/kg bw/day. Partial recovery was evident following 12-weeks off dose for animals previously treated at 253 mg/kg bw/day. Following a 16 week off dose period for animals which received 127 mg/kg bw/day, 4/5 males showed complete recovery, whilst one male in this group still showed low sperm numbers, all of which were immotile and abnormal.

Analysis of organ weights for animals killed after 9 or 13 weeks of treatment revealed low epididymides and absolute testes weights at 127 or 253 mg/kg bw/day; increased kidney weights at 127 mg/kg bw/day; decreased liver weights for males at 13, 38 or 127 mg/kg bw/day and both sexes at 253 mg/kg bw/day; increased spleen weights for females at 127 mg/kg bw/day; decreased thymus weights at 127 or 253 mg/kg bw/day; slightly low uterus and cervix weights in females at 127 mg/kg bw/day (without statistical significance) and slightly high adrenal weights for males at 127 mg/kg bw/day (without statistical significance). Recovery was demonstrated.

The macroscopic examination performed after 9 or 13 weeks of treatment revealed: pale adrenals at 127 or 253 mg/kg bw/day; pale areas in the kidney at 253 mg/kg bw/day and males at 127 mg/kg bw/day; scabs and depressions on the skin and subcutis at 127 or 253 mg/kg bw/day; scabs on the forepaws at 253 mg/kg bw/day; darkening of the salivary glands in both sexes at 127 mg/kg bw/day and at 38 and 13 mg/kg bw/day in males; soft testes at 127 mg/kg bw/day and small testes and epididymides at 253 mg/kg bw/day; dark areas; depressions and thickening in the stomach at 253 mg/kg bw/day. Following 12 weeks of recovery, the changes in the mandibular salivary gland, epididymides and testes were still evident in a small number of animals that previously received 253 mg/kg bw/day, whilst all changes at 127 mg/kg bw/day had recovered.

Following 16 weeks of recovery, treatment-related changes in the salivary gland and testes were evident for 1/5 males previously receiving 127 mg/kg bw/day. Histopathological changes related to treatment were seen in the mandibular and sublingual salivary glands (degranulation and atrophy), heart (myocardial degeneration/inflammation), stomach (foveolar/mucosal hyperplasia), spleen (males only - increased extramedullary haemopoiesis), adrenals (diffuse hypertrophy of the zonal glomerulosa), mammary glands (males onlyatrophy), skin and subcutis (epidermal scabs/ulceration and hyperplasia, and dermal/ subcutaneous inflammation), epididymides (reduced sperm content and cell debris at 127 and 253 mg/kg bw/day and ductal atrophy and sperm granuloma at 127 mg/kg bw/day) and testes (tubular degeneration/atrophy) 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 (males only, tubular basophilia), skeletal muscles (myofibre degeneration), extremities (epidermal scabs/ulceration and hyperplasia, and dermal/ subcutaneous inflammation), ovaries (decreased corpora lutea) and uterus (atrophy) of animals treated at 253 mg/kg bw/day.

At 38 mg/kg bw/day, treatment-related changes were seen in the adrenals (diffuse hypertrophy of the zonal glomerulosa) and testes (minimal tubular degeneration/atrophy). No treatment-related change was seen at 13 mg/kg bw/day. Full recovery was demonstrated in the kidneys, stomach, spleen, epididymides and mammary glands. Partial recovery was demonstrated in the salivary glands, heart, adrenals after 8 weeks of recovery and in the testes after 16 weeks of recovery.

In conclusion,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 considered to be 13 mg/kg bw/day (equivalent to 10 mg Cs/kg bw/day) (Webley, 2016).


Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
According to REACH Regulation (EC) No 1907/2006, Annex IX the test repeated dose toxicity after inhalation does not need to be conducted as repeated dose toxicity studies for oral application are available. In addition, due to the particle size distribution of the substance (d10: 119 µm, d50: 214 µm, d90: 339 µm) no inhalable particles are expected. Inhalation exposure is thus expected to be negligible.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
According to REACH Regulation (EC) No 1907/2006, Annex IX the test repeated dose toxicity after inhalation does not need to be conducted as repeated dose toxicity studies for oral application are available. In addition, due to the particle size distribution of the substance (d10: 119 µm, d50: 214 µm, d90: 339 µm) no inhalable particles are expected. Inhalation exposure is thus expected to be negligible.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
According to column 2 of REACH Regulation (EC) No 1907/2006, Annex VIII, IIX, Section 8.6.1, the test repeated dose toxicity after dermal application does not need to be conducted as repeated dose toxicity studies for oral application are available. Moreover, based on its physico-chemical properties and absence of toxicity in acute dermal toxicity studies very limited absorption into the systemic circulation is expected after dermal application. Literature data support this estimation (see IUCLID section 7.1 "Basic toxicokinetics").

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
According to column 2 of REACH Regulation (EC) No 1907/2006, Annex VIII, IIX, Section 8.6.1, the test repeated dose toxicity after dermal application does not need to be conducted as repeated dose toxicity studies for oral application are available. Moreover, based on its physico-chemical properties and absence of toxicity in acute dermal toxicity studies very limited absorption into the systemic circulation is expected after dermal application. Literature data support this estimation (see IUCLID section 7.1 "Basic toxicokinetics").

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: epididymides; urogenital: testes

Justification for classification or non-classification

Cesium sulphate is not classified concerning STOT because the effects are already covered by the classification Repr. 2 (H361f) according to Regulation (EC) No 1272/2008.