Caesium nitrate

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

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

Adequacy of study:

supporting study

Study period:

2011-05-24 to 2011-06-07

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non GLP 14 day dose range finding study for 28 day repeated dose toxicity study with a structural analogous read-across substance. Please refer to IUCLID section 13 for read-across justification.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2011

Report date:

2011

Materials and methods

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Version / remarks:

adopted 3 October 2008

Deviations:

yes

Remarks:

14-day dose range finder

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Version / remarks:

Regulation (EC) No 440/2008

Deviations:

yes

Remarks:

14 day dose range finder

Test guideline 3

Qualifier:

equivalent or similar to guideline

Guideline:

other: EPA OPPTS 870.3050

Deviations:

yes

Remarks:

14 day dose range finder

GLP compliance:

no

Remarks:

, however the principles of GLP were followed and all data were recorded and retained.

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

cesium hydroxide monohydrate

EC Number:

627-088-9

Cas Number:

35103-79-8

Molecular formula:

CsOH * H2O

IUPAC Name:

cesium hydroxide monohydrate

Test material form:

solid: crystalline

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Toxi-Coop Zrt., Cserkesz u. 90., H-1103 Budapest, Hungary
- Age at study initiation: 6 –8 weeks old
- Weight at study initiation: Male animals: 167 – 181 g; Female animals: 143 – 163 g
- Fasting period before study: no
- Housing: 2 or 3 animals sex/cage in Type III polypropylene/polycarbonate cages.
- Diet: Animals received ssniff® SM R/M-Z+H "Autoclavable complete feed for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest, Germany ad libitum.
- Water: tap water from municipal supply, as for human consumption from a 500 mL bottle ad libitum.
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 30-70
- Air changes (per hr): 8-12 air exchanges/hour by central air-condition system.
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2011-05-24 To: 2011-06-07

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
The test item was formulated in distilled water, in concentrations of 5 mg/mL, 25 mg/mL and 75/50 mg/mL. For the treatment of high dose animals, 75 mg/mL was used from day 0 up to day 6 and 50 mg/mL was used from day 7 onwards. Formulations were prepared beforehand for 3 or 4 days. The pH wat set to pH 7 with HCl.

VEHICLE
- Concentration in vehicle: 5 mg/mL, 25 mg/mL and 75/50 mg/mL
- Amount of vehicle: 10 mL dose preparation/kg bw

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analytical control of dosing solutions (control of concentration) was performed in the Analytical Laboratory of Test Facility once during the study. Samples were taken on study day 7 and measurement was conducted the following day (May 31, and June 01, 2011, respectively). The measured concentrations ranged from 98 % to 100 % of nominal concentrations.
The suitability of the chosen vehicle for the test item was analytically proven. Cesium hydroxide monohydrate was stable at concentrations of 1 and 100 mg/mL in distilled water at room temperature and if refrigerated (5 ± 3 °C) for 7 days.

Duration of treatment / exposure:

14 days

Frequency of treatment:

The test item was administered in a single dose by oral gavage (stomach tube) on a 7 days/week basis every day at similar time (+/- 2 hours). Control animals were treated concurrently with the vehicle only. Animals were not treated on the day of gross pathology. Dosing of both sexes began after 5 days acclimatization and was continued up to and including the day before necropsy.

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 50, 250 and 750/500* mg/L (*Dose reduction from 750 to 500 mg/kg bw/day from day 7 of the study onwards )
Basis:
nominal in water

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The dose setting was based on findings obtained in an acute oral toxicity with cesium hydroxide monohydrate in rats (LD50 = 1026 mg/kg bw in rats with 95% confidence limits of 929-1133 mg/kg bw; Johnson, 1975). The high dose was chosen with the aim of inducing toxic effects but no mortality or severe suffering of animals. The low dose was chosen to induce no toxic effect. The mid dose was interpolated geometrically. 750 mg/kg bw dose of cesium hydroxide monohydrate caused severe toxic signs and death of one male and three female animals on day 6, therefore high dose was reduced to 500 mg/kg bw/day from day 7 onward.

Positive control:

none

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Detailed clinical observations were made on all animals once a day, after treatment at approximately the same time. Observations were performed on the skin, fur, eyes and mucous membranes, autonomic activity (lachrymation, piloerection, pupil size, respiratory pattern, occurrence of secretions and excretions), circulatory and central nervous system, somatomotor activity and behavior pattern, changes in gait, posture and response to handling. Special attention was directed towards the observation of tremors, convulsions, salivation, diarrhea, lethargy, sleep and coma.

BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed with an accuracy of 1 g on days 0, 7 and 13. Individual body weight changes were calculated between days 0-7, 7-13 and 0-13, latter for the total body weight gain. Fasted body weight was measured on day of necropsy (day 14).

FOOD CONSUMPTION:
The food consumption was determined with an accuracy of 1 g on days 7 and 13 by reweighing the non-consumed diet.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: before sacrifice
- Anaesthetic used for blood collection: Yes (Isofluran)
- Animals fasted: Yes
- How many animals: all
- Parameters checked:
White Blood Cell (leukocyte) count, Red Blood Cell (erythrocyte) count, Hemoglobin concentration, Hematocrit (relative volume of erythrocytes), Mean Corpuscular (erythrocyte) Volume, Mean Corpuscular (erythrocyte) Hemoglobin, Mean Corpuscular (erythrocyte) Hemoglobin Concentration, Platelet (thrombocyte) count, Reticulocytes, Differential white blood cell count, Activated partial Thromboplastin Time, Prothrombin Time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: before sacrifice
- Animals fasted: Yes
- How many animals: all
- Parameters checked:
Alanine Aminotransferase activity, Aspartate Aminotransferase activity, Gamma Glutamyltransferase activity, Alkaline Phosphatase activity, Total Bilirubin concentration, Creatinine concentration, Urea concentration, Glucose concentration, Cholesterol concentration, Bile acids, Inorganic phosphate concentration, Calcium concentration, Sodium concentration, Potassium concentration, Chloride concentration, Total Protein concentration, Albumin concentration, Albumin/globulin ratio

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
Gross necropsy was performed on each animal. Dead animals were subjected to gross pathology immediately after the death. Surviving animals were euthanized by exsanguination after verification of narcosis by Isoflurane CP® one day after the last treatment. After examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs were observed, and any abnormality was recorded with details of the location, color, shape and size. The following organs/tissues were preserved in 4 % buffered formaldehyde solution except testes and epididymides, which were fixed in modified Davidson solution.
adrenals
aorta
bone marrow (femur)
brain (representative regions: cerebrum, cerebellum and pons and medulla oblongata)
eyes (lachrymal gland with Harderian glands)
female mammary gland
gonads (testes with epididymides, ovaries, uterus with vagina)
gross lesions
heart
kidneys
large intestines (coecum, colon, rectum, including Peyer’s patches),
liver
lungs (with main stem bronchi; inflation with fixative and then immersion;)
lymph nodes (submandibular and mesenteric)
muscle (quadriceps)
esophagus
pancreas
pituitary
prostate
salivary glands (submandibular)
sciatic nerve
seminal vesicle with coagulating gland
skin
small intestines (representative regions: duodenum, ileum, jejunum)
spinal cord (at three levels: cervical, mid-thoracic and lumbar)
spleen
sternum
stomach
thymus
thyroid + parathyroid
trachea
urinary bladder

HISTOPATHOLOGY: No

ORGAN WEIGHT: YES
The following organ weights were determined and recorded:
With precision of 0.01g: liver, kidneys, testes, epididymides, uterus, thymus, spleen, brain and heart, prostate and seminal vesicles with coagulating glands
With precision of 0.001g: adrenals, ovaries

Other examinations:

none

Statistics:

Statistical analysis was done with SPSS PC+ software package for the following data:
- body weight
- food consumption
- hematology
- clinical chemistry
- organ weight data
The heterogeneity of variance between groups was checked by Bartlett’s homogeneity of variance test. Where no significant heterogeneity was detected a one-way analysis of variance (ANOVA) was carried out. If the obtained result was significant Duncan Multiple Range test was used to access the significance of inter-group differences.
Where significant heterogeneity was found, we examined the normal distribution of data by Kolmogorov-Smirnov test. In case of not normal distribution, we applied the non-parametric method of Kruskal-Wallis One-Way analysis of variance. If there was a positive result, the inter-group comparisons were performed using Mann-Whitney U-test.
The frequency of clinical symptoms and pathologic findings were calculated.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
Mortality:
750 mg/kg bw/day dose of cesium hydroxide monohydrate caused death of one male (1/5) and three female (3/5) animals on day 6. Before death, decreased activity (1/5 male and 3/5 female), prone position (1/5 female), hunched back (2/5 female), dyspnoea (1/5 male and 3/5 female), piloerection (1/5 male and 3/5 female), incoordination (1/5 male and 3/5 female), convulsions (1/5 male and 2/5 female), tremor (1/5 female), irritability (2/5 female), diarrhea (1/5 male) and sanguineous hair around the mouth and forelimbs (1/5 male) were observed.
There was no mortality in the control, 50 or 250 mg/kg bw/day groups during the course of 14-day observation period.

Clinical signs:
750 mg/kg bw/day
Irritability was noted for two female animals (2/5) on day 6. There were no other clinical signs in the surviving animals either at 750 or 500 mg/kg bw/day during the observation period.
50 and 250 mg/kg bw/day
No clinical signs were found in either group except one male rat (1/5) at 50 mg/kg bw/day, on which slight eye inflammation was observed from day 2 up to termination of the treatment.
In summary, 750 mg/kg bw/day dose of cesium hydroxide monohydrate was lethal for some animals (1/5 male and 3/5 female) after 7 days administration. Clinical signs related to the test item were detected only on day of death. Irritability and inflammation of eyes were considered to be individual signs, these occur also in untreated experimental rats.

BODY WEIGHT AND WEIGHT GAIN
750/500 mg/kg bw/day
The mean body weight was less than in the control group (male and female animals) on days 7 and 13 due to the significantly reduced body weight gain during week 1. This resulted in a significantly less total body weight gain (determined between days 0 and 13).
250 mg/kg bw/day group
The mean body weight was similar to the control value both in male and female animals during the entire observation period, although the body weight gain remained below that of the control on week 1. The summarized body weight gain was slightly less than the control value.
50 mg/kg bw/day
There were no differences in the mean body weight between the control and test item treated group (male and female).
The mean body weight gain of male animals was slightly less than the control value resulting in a slightly less total body weight gain. No changes were observed in female animals.
In summary, a dose related test item influence on the body weight development was found at 750, 250 and 50 mg/kg bw/day for male and at 750 and 250 mg/kg bw/day for female animals during the first week (between day 0 and 7) of treatment. The slightly lower body weight gain did not resulted in body weight changes at 250 and 50 mg/kg bw/day. The less mean terminal body weight (measured on day 13) in male and female animals dosed with 750/500 mg/kg bw/day and the less total body weight gain at 750/500, 250 and 50 mg/kg bw/day in male animals and at 750/500 and 250 mg/kg bw/day in female animals, were a consequence of the reduced body weight gain during the first week as there were no differences in the body weight gain during the second week (between days 7 and 13) comparing to the control group.

FOOD CONSUMPTION
750/500 mg/kg bw/day group
The mean daily food consumption was reduced in comparison with the control value during the study (without statistical significance in male animals on week 2).
50 and 250 mg/kg bw/day
The mean daily food intake was similar to that of control group both in the male and female animals.
In summary, a test item influence on the food consumption was observed at 750/500 mg/kg bw/day (male and female) during the first and second weeks of treatment period in accordance with the body weight values.

HAEMATOLOGY
750/500 mg/kg bw/day
In the male animals, statistical significances were noted for the slightly higher mean values of white blood cell count (WBC), percent of neutrophil granulocytes (NE), and mean corpuscular hemoglobin concentration (MCHC), and for the lower means of percent of lymphocytes (LY) and activated partial thromboplastin time (APTT).
In the female animals, mean values of white blood cell count, percent of neutrophil granulocytes, mean corpuscular hemoglobin concentration and platelet count (PLT) were above the control value with statistical significance. The percent of lymphocytes, hematocrit (HCT) and mean corpuscular volume (MCV) were slightly below the appropriate control value.
250 mg/kg bw/day
In the male animals, statistical significance was found at the higher percent of neutrophil granulocytes along with a lower percent of lymphocytes. The white blood cell count slightly exceeded the control value without statistical significance.
In the female animals, the white blood cell count was higher than in the control group. Percent of neutrophil granulocytes were slightly higher than in the control group without statistical significance.
50 mg/kg bw/day
There were no statistically significant differences in the examined hematological parameters between the control and test item treated groups (male and female animals).
In summary, changes in the white blood cell parameters (WBC, NE) were considered to be a test item related effect in male and female animals dosed with 750/500 and 250 mg/kg bw/day. Although values were within the historical control range at 250 mg/kg bw/day in male and female animals and at 750/500 mg /kg bw/day in male animals, in surviving female animals (n=2), these parameters exceeded significantly the control (and historical control) values. It should be mentioned however, the mean values of control group were below the historical control means especially for percent of neutrophil granulocytes (the latter was due to the very low values of 3/5 male and 1/5 female control animals).
The statistically significant differences in some other hematology parameters (MCHC, APTT, PLT, HCT and MCV) were with low degree and were within of historical control data so these were judged to be without toxicological significance.

CLINICAL CHEMISTRY
750/500 mg /kg bw/day
Statistical significant differences were noted for male animals in activity of aspartate aminotransfrease (AST), on concentrations of creatinine (CREA), bile acids (BAC), calcium (Ca2+), potassium (K+), albumin (ALB) and total protein (TPROT).
In the female animals, statistical significances were found in activity of aspartate aminotransfrease and alkaline phosphatase (ALP), in concentration of creatinin, urea, phosphorous (Pi), sodium (Na+) and chloride (Cl-).
250 mg/kg bw/day
In the male animals, the mean concentration of phosphorous, potassium and chloride were slightly less than the appropriate control value.
In female animals, the mean creatinin, urea and phosphorous concentrations were slightly higher while chloride concentration was less than mean values of control group.
50 mg/kg bw/day
The only statistical significance was noted for male animals in concentration of phosphorous. All other examined parameters were similar to the control value (male and female).
In summary, the higher urea and creatinine levels suggest an effect on the renal function in female animals treated with 750/500 mg/kg bw/day and 250 mg /kg bw/day. In male animals at 750/500 mg/kg bw/day, similar finding was found in creatinine level in a smaller degree.
Slightly higher enzyme activity of AST at 750/500 mg /kg bw/day (male and female) remained within the historic control range and in the lack of histopathological examination their biological significance is equivocal. Additionally some statistically significant differences in alkaline phosphatase activity, in levels of bile acid, phosphorous, calcium, sodium, potassium, total protein and albumen were judged to be of little or no biological significance as the mean values were within range of historical controls or these were without dose-response relationship. Phosphorous concentration in female animals suggested a treatment-related pattern of changes, but the mean values remained within the normal historic range in all groups and statistical significance was probably due to the relative low control value.

ORGAN WEIGHTS
750/500 mg/kg bw/day
In the male animals, significantly lower weights were noted for heart and seminal vesicles (absolute, both), for spleen and prostate (absolute and relative to the brain weight) and for liver and thymus weights (absolute and relative to the body and brain weights) when compared to the control. The organ weights relative to the body weight were higher than the control value in case of brain, kidneys and testes.
In the female animals, heart weight (absolute) and thymus weight (absolute and relative to the body and brain weights) were less than those in the control group.
250 mg/kg bw/day
In the male animals, liver weights (absolute and relative to body weight) and spleen weights (absolute and relative to brain weight) were less while kidneys weight relative to body and brain weight was higher than in the control group.
In the female animals, the only statistical significance was indicated in kidney weight relative to the body weight.
50 mg/kg bw/day
In the male animals, statistical significance was noted for lower liver weights (absolute and relative to body weight) and spleen weights (absolute and relative to brain weight) and for prostate weight (absolute).
In female animals, no differences were found in the examined organ weights with respect to controls.
In summary, the absolute organ weights and organ weights relative to the body weight were not considered to be relevant for evaluation because of the degree of body weight changes at 750/500 mg/kg bw/day. Statistically significant changes in the kidneys weight relative to the brain weight at 250 mg/kg bw/day (male animals) were not considered to be toxicologically significant because of the low degree and in the absence of similar changes at the higher dose (750/500 mg/kg bw/day).
The significantly less organ weights relative to brain weight (liver, thymus, spleen and prostate in male animals and thymus in female animals) reflected a test item influence at 750/500 mg/kg bw/day probably in accordance with the body weight alteration and histopathological examinations are necessary to reveal the nature of changes in these organs.
Statistically significant differences in liver weights (absolute and relative to body weight) and spleen weight (absolute and relative to the brain weight) in male animals treated with 50 and 250 mg/kg bw/day were small and were probably a consequence of lower values in the control group as these occurred in a similar degree in both doses.

GROSS PATHOLOGY
In dead male animal (1/5, 750 mg/kg bw/day), dark brown liver, in the stomach dark brown, reddish liquid content and reddish mucous membrane, in the small intestines dark brown content and on the skullcap hemorrhage were observed at the macroscopic observation of organs.
In dead female animals (3/5, 750 mg/kg bw/day), dark brown spots on the lungs, dark brown liver (3/3), empty stomach with reddish mucous membrane (2/3), foamy content in the stomach (1/3) and hemorrhage on the skullcap (2/3) were found.
750/500 mg/kg bw/day
Smaller than normal testis (1/4, male) and pale kidneys (2/4 male) and in the thymus (1/2 female) hemorrhage were observed in surviving animals.
250 mg/kg bw/day
Pale kidneys were noted for one male animal (1/5) and slight emphysema in the lungs for two females (2/5).
50 mg/kg bw/day
There were no macroscopic findings in male animals (5/5). In female animals, slight or moderate hydrometra (2/5), hemorrhage in the thymus (1/5) and pale kidneys (1/5) occurred.
Control group
Pale kidneys (2/5 male) slight hydrometra (2/5), slight pulmonary emphysema (1/5 male and 1/5 female) and a compact formation on the accessory lobe of the liver (1/5 male) were observed.
In summary, in dead animals necropsy finding referred to the local effect of test item in the stomach and intestines (dark brown, reddish content and reddish mucous membrane, foamy content) and to a circulatory disturbance (dark brown spots on the lungs, dark brown liver) causing death of animals. Hemorrhage on the skullcap was probably originated from a mechanical injury.
In surviving animals, gross necropsy did not reveal clear evidence of test item related macroscopic changes. Pale kidneys were present in the control and test item treated groups with similar incidence and paleness of kidneys occurs commonly in untreated animals. Histopathological examinations could reveal the feature of these findings.
Smaller than normal testis and liver lobe alteration were considered to be individual lesions. These are common findings also in untreated rats and they occurred in single animals in this study. Pulmonary emphysema (as pale raised areas in the lungs), hemorrhage in the thymus due to the euthanasia procedure and hydrometra indicative of sexual cycle of females are frequent observations in experimental rats, which has no toxicological meaning.

Effect levels

Dose descriptor:

NOAEL

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

A read-across was applied using study results from a 14 -day toxicity study with cesium hydroxide monohydrate.
Based on these observations the doses for a 28-day oral toxicity study (main study) with cesium hydroxide monohydrate were determined as follows:
Group 1 Vehicle control
Group 2 25 mg/kg bw/day
Group 3 50 mg/kg bw/day

Executive summary:

A read-across was applied using study results from a 14 -day toxicity study with cesium hydroxide monohydrate.

The aim of this 14-Day toxicity study was to obtain first information on the toxic potential of cesium hydroxide monohydrate in rats at three dose levels to allow a dose-setting for a 28-day oral toxicity study.

The test item was administered orally (by gavage) to Hsd.Brl.Han: Wistar rats (n=5 animals/sex/dose) once a day at 0 (vehicle control), 50, 250 and 750/500 mg/kg/day doses applied in concentrations of 25, 125 and 375/250 mg/mL, a corresponding to dose volume of 2 mL/kg bw for 14 days. Stability and concentration of test item in distilled water were confirmed analytically. Cesium hydroxide monohydrate proved to be stable at room temperature for 7 days (recovery was 101 % of starting concentrations at 1 mg/mL and 102 % at 100 mg/mL). Content of formulations administered to animals ranged from 99.1 % to 100.2 % of nominal concentrations in distilled water. Detailed clinical observations were made on all animals once a day, after treatment at approximately the same time. Body weight and food consumption were measured weekly. Clinical pathology and gross pathology examinations were conducted at the end of the treatment period. Selected organs were weighed. The results were interpreted comparing treatment groups with respect to controls, which were treated concurrently with vehicle (distilled water) only.

Results:

Mortality

One male and three female animals were found dead after the treatment with 750 mg/kg bw/day dose of cesium hydroxide monohydrate on day 6.

Clinical observations

Test item related clinical signs were observed only in dead animals at 750 mg/kg bw/day before the death. Decreased activity, prone position, hunched back, dyspnoea, piloerection, incoordination, convulsions, tremor, irritability, diarrhea and sanguineous hair around the mouth and forelimbs occurred. For surviving animals individual clinical signs (inflammation of eye, irritability) were noted which are common in untreated experimental rats.

Body weight and body weight gain

The body weight development was reduced at 750, 250 mg/kg bw/day (male and female) and 50 mg/kg bw/day (male) on week 1 resulting in lower total body weight gain at the end of study. The body weight was significantly less that in the control group at 750/500 mg/kg bw/day at the termination of the treatment.

Food consumption

A test item influence on the mean daily food consumption was observed at 750/500 mg/kg bw/day during the entire study.

Clinical pathology

Clinical pathology examinations revealed a higher white blood cell count along with higher percent of neutrophil granulocytes in male and female animals at 750/500 and 250 mg/kg bw/day. Changes in urea and creatinine concentrations in female animals at 750/500 and 250 mg/kg bw/day, and in creatinine concentrations in male animals at 750/500 mg/kg bw/day reflected an influence on metabolic activity of kidneys.

Organ pathology

Gross pathology revealed test item related local changes in the stomach and small intestines in dead animals. Specific macroscopic alterations related to treatment with the test item were not found in surviving animals at the terminal necropsy. No test item related organ weight changes were found after the 14-day treatment period.

Conclusion

Under the condition of the present study, cesium hydroxide monohydrate caused clinical signs and death in male (1/5) and female (3/5) animals, reduction in body weight development and food consumption after 7 days oral administration at 750 mg/kg bw/day to Hsd.Brl.Han: Wistar rats.

At 750/500 mg/kg bw/day, a test item influence was observed in white blood cell parameters (WBC, NE; male and female), in concentrations of creatinine (male and female) and urea (female). At 250 mg/kg bw/day, lesser but significant changes in some of these parameters (body weight, hematology and clinical chemistry parameters) occurred in male and female animals. At 50 mg/kg bw/day, the body weight gain of male animals was slightly depressed.

Based on these observations the doses for a 28-day oral toxicity study (main study) with cesium hydroxide monohydrate were determined as follows:

Group 1 Vehicle control

Group 2 25 mg/kg bw/day

Group 3 50 mg/kg bw/day

Group 4 250 mg/kg bw/day