Registration Dossier

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2012-06-05 - 2013-02-05
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP and guideline study with structural analogous substance

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2013

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
solid: crystalline
Details on test material:
Please refer to section "Confidential details on test material" below.

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Toxi-Coop Zrt., Cserkesz u. 90., 1103 Budapest, Hungary
- Age at study initiation: young adult males and females, less than 9 weeks old
- Weight at study initiation: m = 163 - 193 g; f = 122 - 150 g
- Fasting period before study: no
- Housing: 2 animals per sex and cage in type II polypropylene/polycarbonate cages.
- Diet: ssniff® SM R/M-Z+H "Autoclavable complete feed for rats and mice – breeding and maintenance" (ssniff Spezialdiäten GmbH, 59494 Soest, Germany), ad libitum.
- Water: tap water from municipal supply, from a 500 mL bottle, ad libitum.
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C
- Humidity: 30 - 70 %
- Air changes: 8 - 12 air exchanges/hour by central air-condition system.
- Photoperiod: 12 hours dark / 12 hours light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The test item was formulated in the vehicle at the appropriate final concentrations. Due to the corrosive properties of the test item, the pH value of the formulations was adjusted to pH 7-9 with HCl prior to gavage administration.

VEHICLE
- Concentration in vehicle: 2.5, 12.5 or 25 mg/mL
- Amount of vehicle: dose volume of 10 mL/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The suitability of the chosen vehicle for the test item at the intended concentrations was analytically verified up front. A sufficient stability (7 days at room temperature) in the chosen vehicle was verified over the range of relevant concentrations at the appropriate frequency of preparation (reported separately).

Five samples (5 mL, each) were taken from different places from each concentration (groups 2, 3 and 4) and from the control substance (group 1) and measured on 2 occasions:
- Date of samplings: June 12, and August 30, 2012
- Date of measurement: June 13, and August 31, 2012.

The samples were stored at room temperature until the analysis.

Measured concentrations varied between 95 and 97 % of the nominal concentrations.
Duration of treatment / exposure:
90 or 91 days
Frequency of treatment:
Once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
25, 125, 250 mg/kg bw/d
Basis:
actual ingested
No. of animals per sex per dose:
- Dose selection rationale: The dose setting based on findings obtained in a previous 28-Day Oral Gavage Toxicity Study with Cesium hydroxide monohydrat 99.95 in the Rat.
Details on study design:
- Dose selection rationale: The dose setting based on findings obtained in a previous 28-Day Oral Gavage Toxicity Study with Cesium hydroxide monohydrat 99.95 in the Rat.
Positive control:
Not required

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were inspected for signs of morbidity and mortality twice daily (at the beginning and end of each day).

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: General clinical observations were made once a day, after treatment at approximately the same time.
Detailed clinical observations were made on all animals outside the home cage in a standard arena once prior to the first exposure and once weekly thereafter. 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 day 0 and then on a weekly basis. Individual body weight changes were calculated. Fasted body weight was measured on the day of necropsy (day 90 or 91).

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

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: During acclimatisation and prior to termination.
- Dose groups that were examined: All dose groups during acclimatisation, the high dose and concurrent control group prior to termination.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: One day after the last treatment.
- Anaesthetic used for blood collection: Yes (isoflurane).
- Animals fasted: Yes
- How many animals: All animals
- 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, differential white blood cell count, reticulocytes, activated partial thromboplastin time, prothrombin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: One day after the last treatment.
- Animals fasted: Yes
- How many animals: All animals
- 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, calcium concentration, sodium concentration, potassium concentration, chloride concentration, albumin concentration, total protein concentration, albumin/globulin ratio
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Gross necropsy was performed on all animals. After examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs was observed, and any abnormality was recorded with details of the location, colour, shape and size.

The following organs/tissues were preserved/processed for histopathological examination:
Adrenals, aorta, bone marrow (femur), brain (cerebrum, cerebellum, pons and medulla oblongata), eyes (lachrymal gland with Harderian glands), female mammary gland, gonads (testes with epididymides, ovaries, uterus with cervix and vagina), gross lesions, heart, kidneys, large intestines (cecum, colon, rectum, including Peyer’s patches), liver, lungs (with main stem bronchi), lymph nodes (submandibular and mesenteric), muscle (quadriceps), esophagus, pancreas, pituitary, prostate, salivary glands (submandibular), sciatic nerve, seminal vesicle with coagulating gland, skin, small intestines (duodenum, ileum, jejunum), spinal cord (at three levels: cervical, mid-thoracic and lumbar), spleen, sternum, stomach, thymus, thyroid + parathyroid, trachea, urinary bladder

HISTOPATHOLOGY: Yes
Full histopathology was performed on the preserved organs or tissues of the animals of the control and high dose groups.
Testes epididymides, prostate and seminal vesicles with coagulating gland were also evaluated histologically in all animals of the low and mid dose groups due to the necropsy and histopathological findings in these organs.

ORGAN WEIGHT: Yes
The following organ weights were determined and recorded (wet weight):
Liver, kidneys, testes, epididymides, uterus, thymus, spleen, brain, heart, adrenals, ovaries
Other examinations:
OESTROUS CYCLE
- Time schedule for examinations: During the last two weeks of the treatment period.
- Dose groups that were examined: All dose groups.
- Endpoints: Type of cycle, cycle length, number of cycles during the last two treatment weeks, number of animals with prolonged dioestrus, number of animals with prolonged oestrus

SPERM ANALYSIS
- Time schedule for examinations: At necropsy.
- Dose groups that were examined: Control and high dose group.
- Quantitative examination: Enumeration of the cauda epididymal sperm reserve.
- Qualitative examination: Sperm motility and sperm morphology.
Statistics:
Statistical analysis was done with SPSS PC+ software package for the following data: Body weight, food consumption, hematology and clinical chemistry parameters, 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's Multiple Range test was used to access the significance of intergroup differences. Where significant heterogeneity was found, the normal distribution of data was assessed by means of the Kolmogorov-Smirnov test. In case of not normally distributed data, the non-parametric method of Kruskal-Wallis One-Way analysis of variance was applied. If there was a positive result, the intergroup comparisons were performed using the Mann-Whitney U-test. The rate of mortality, frequency of clinical signs, ophthalmological data, and gross pathologic and histopathologic findings were calculated. Results were evaluated in comparison with values of the control group.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
Daily and weekly clinical observations:
There were no toxic signs related to the test item effect at the daily clinical observations. The behavior and physical condition of animals were considered to be normal at each dose level (250, 125 and 25 mg/kg bw/day) during the treatment period.
Alopecia and/or scab were observed in some male and female animals at 250 mg/kg bw/day (3/10 male and 5/10 female), at 125 mg/kg bw/day (5/10 male and 1/10 female), at 25 mg/kg bw/day (1/10 male and 1/10 female) and in the control group (1/10 male and 1/10 female) with variable frequency and duration. These dermal changes occurred on the neck, back, shoulder or mouth in minimal or slight degree in the most cases. Only one male rat administered with 125 mg/kg bw/day showed scab on the neck in a moderate degree. The fur was transiently sanguineous around the right eye of one male animal (250 mg/kg bw/day) for some days.
Alopecia, scab and sanguineous fur are common clinical signs in this strain of experimental rats of this age and were present in the control and test item treated groups. Therefore these clinical observations had no toxicological meaning in this study.

Mortality:
One female rat administered with 250 mg/kg bw/day died on Day 84. Irritability, piloerection, decreased activity, dyspnea and severe body weight loss were observed before death. Serious involution of thymus and signs of suffocation were detected at the histological examination. Test item related toxic or other degenerative lesions were not found which could explain the progressive weight loss of this animal. The disease of the affected animal could be in connection with a probably individual metabolic disorder occurring sporadically in experimental rats.
One male animal (250 mg/kg bw/day) died after the blood sampling due to over anesthesia. There were no test item related toxic or other lesions in the examined organs of this animal.

BODY WEIGHT AND WEIGHT GAIN
A test item influence on the body weight development was noted for male animals at 250 and 125 mg/kg bw/day. The reduced body weight gain resulted in a less body weight at 250 mg/kg bw/day from Day 21 and at 125 mg/kg bw/day from Day 35 up to the end of the treatment period.
The mean body weight gain was less than in the control group in the male animals at 250 mg/kg bw/day during the entire study with statistical significances on weeks 1, 2, 3, 5, 6, 7, 10, 11, 12 and between Days 0 and 89. Thus, the mean body weight remained below the control value with statistical significances form Day 21 up to and including Day 89. The mean body weight gain was also less in the male animals at 125 mg/kg bw/day with respect to the control in the most cases and with statistical significances on weeks 2 and 5, and the total body weight gain (between Days 0 and 89) remained below the control value, too. The reduced body weight gain in male animals at 125 mg/kg bw/day resulted in a statistically significantly less mean body weight values with respect to controls from Day 35 up to and including Day 89. A slightly higher mean body weight gain was observed in male animals at 25 mg/kg bw/day on weeks 1 and 13, however these slight changes were considered to be without any toxicological relevance.
In the female animals, the body weight was statistically significantly reduced at the high dose level as compared to the control group on Day 84. Sporadic statistical significances were noted for the less mean body weight gain at 250 mg/kg bw/day, on weeks 2 and 9, and between Days 0 and 89, and at 125 mg/kg bw/day on week 2. However these slight changes were not considered toxicologically relevant as these did not induce significant changes in body weight. The mean body weight gain was significantly higher than in the control group at 250 and 25 mg/kg bw/day on week 6 and the total mean body weight gain of female animals administered with 25 mg/kg bw/day also exceeded the control value between Days 0 and 89. These slight changes had no toxicological meaning as these were indicative of biological variations.

FOOD CONSUMPTION
The daily mean food consumption was slightly reduced in male animals at 250 mg/kg bw/day.
The mean daily food intake was slightly less than in the control group in male animals administered with 250 mg/kg bw/day from week 2 during the entire observation period but statistical significances were detected on weeks 3, 5, 6, 10, 11, 12 and 13. Similarly, slight changes were observed at 125 mg/kg bw/day (male), but a significant difference with respect to the control group was only indicated on weeks 5 and 6 therefore were not considered toxicologically relevant.
The mean daily food consumption was unaffected in the female animals. Statistical significance was only noted for the slightly higher value at 25 mg/kg bw/day but the mean daily food consumption of animals at the higher doses were similar to the control value.

OPHTHALMOSCOPIC EXAMINATION
The eyes were without any detected abnormalities in all animals before treatment and in the control and high dose groups at termination of the treatment.

HAEMATOLOGY
Hematological investigations revealed a slightly higher mean white blood cell count (WBC) and mean percentage of reticulocytes (RET) in male and female animals at 250 and 125 mg/kg bw/day.
Small but statistically significant differences were observed in male animals administered with 250 mg/kg bw/day in the higher mean percentage of neutrophil granulocytes (NEU) and less mean percentage of lymphocytes (LYM) with respect to relevant controls. Furthermore, in male animals at 250 mg/kg bw/day, the mean percentage of basophil granulocytes (BASO), the mean corpuscular (erythrocyte) hemoglobin concentration (MCHC) and platelet counts (PLT) were higher than in the control males. A similar change was detected at 25 mg/kg bw/day in the mean corpuscular (erythrocyte) hemoglobin concentration in male animals.
In the female animals, statistical significance was indicated for higher mean percentage of neutrophil granulocytes and for less mean percentage of lymphocytes at 250 and 125 mg/kg bw/day. The mean activated partial thromboplastin time (APTT) was slightly longer in females of the 125 mg/kg bw/day group with respect to the control group.
The statistical significances in NEU, LYM, BASO, MCHC, PLT and APTT indicated only slight differences between the control and test item treated groups, the values were within the historical control ranges and therefore were not considered to be of biological relevance.

CLINICAL CHEMISTRY
The elevated activity of aspartate aminotransferase (AST) referred to a test item related effect in male and female animals at 250 and 125 mg/kg bw/day. Higher concentrations of urea and creatinine (CREA) were indicative of a test item influence on renal function in male animals at 250 and 125 mg/kg bw/day and in female animals at 250 mg/kg bw/day. Changes in enzyme activity and concentrations of creatinine and urea in serum were considered to be signs of adaptation of the organ to the altered demands. Without supporting histopathological changes these effects were judged to be toxicologically not relevant.
A significantly less mean glucose concentration (GLUC) was found at 250 mg/kg bw/day (male and female) and at 125 mg/kg bw/day (male) animals with respect to control probably due to an altered general metabolism in animals of these groups.
The lower potassium levels (K+) at 250 and 125 mg/kg bw/day (male and female) and at 25 mg/kg bw/day (male) were not related to the doses and might be due to the chemically similar structure of cesium and potassium. Potassium wasting without damage in renal tissue might refer to an altered renal function.
Sporadic statistical differences (ALP, Ca2+, Na+, Cl-, ALB, BAC and A/G) were considered to be of little or no biological relevance. Although the mentioned differences between the control and test item treated groups were statistically significant but were small and all values remained within the historical control ranges for these parameters except ALP however a decrease in enzyme activity of ALP has no biological relevance without any degenerative or necrotic changes. Therefore these findings were not considered to be of toxicological relevance.

NEUROBEHAVIOUR
Functional observation battery:
Functional observation battery did not demonstrate any treatment-related difference with respect to the controls in the behavior or in reactions to different type of stimuli at the end of the treatment period (Day 88; male and female, 250, 125 and 25 mg/kg bw/day).
Variations in startle reflex (1/10 male at 125 mg/kg bw/day and 1/10 male at 25 mg/kg bw/day) and positional struggle (1/9 female at 250 mg/kg bw/day) were within the normal biological variation with respect to behavior, reactions to different type of stimuli or manipulations.

ORGAN WEIGHTS
Test item related changes were detected in weights of testes and epididymides (absolute and relative to body and brain weights) at 250 mg/kg bw/day, in testes weight related to the body weight, and in epididymides weights (absolute and relative to body and brain weights) at 125 mg/kg bw/day. The mean absolute thymus weights (male and female) and thymus weight relative to brain weight (male) were less than in the control group in animals administered with 250 mg/kg bw/day. Related histopathological findings (damaged spermatogenesis in most of the animals and serious involution of thymus in some male and female animals) were also observed at 250 mg/kg bw/day.
Slight, but statistically significant differences were detected in the kidneys weights (absolute and relative to body and brain weights) of male and female animals at 250 mg/kg bw/day with respect to the controls. Similar findings were also noted for kidneys weights (absolute and relative to body and brain weights) of the male and female animals at 125 mg/kg bw/day and for kidney weight relative to brain weight in female animals only at 25 mg/kg bw/day. However kidney weight values remained within the historical control ranges and there were no related histopathological lesions in the kidneys, therefore these changes were considered to be signs of adaptation of the organ to the altered demands.
The significantly less liver weights (absolute and relative to brain weight) reflected a test item influence in male animals administered with 250 or 125 mg/kg bw/day probably in accordance with the body weight alterations. The changes in liver weight were with small degree, were not dose dependent and hepatocellular damage were not detected at the histopathological examination therefore liver weight changes were not considered to be toxicologically relevant.
The mean brain (250 mg/kg bw/day male and female, 125 mg/kg bw/day male) and heart weights (250 mg/kg bw/day female, 125 mg/kg bw/day male), each relative to body weight, were slightly higher and the absolute heart and spleen weights (250 mg/kg bw/day male) were less with respect to the appropriate control value. These slight, but statistically significant differences between the control and test item treated groups in the weights of the brain, heart and spleen were probably due to the body weight changes in these groups, therefore these were judged to be toxicologically irrelevant.

GROSS PATHOLOGY
Necropsy observation revealed smaller than normal testes and epididymides which were induced by the treatment with test item at 250 mg/kg bw/day (9/10 male animals).
There were no test item related macroscopic changes in the dead female animal (250 mg/kg bw/day). Necropsy findings of dead animal (undernourishment, uneven fur, red colored lungs with white spots, dark, smaller than normal thymus, empty gastrointestinal tract, dark mucous membrane in the stomach) referred to an individual disease, which was also supported by the results of histopathological examination.
Erythematous mucous membrane of stomach was only noted for one male animal (1/10) at 250 mg/kg bw/day, which however might be indicative a possible local effect of the test item.
Pyelectasia was detected in one side kidney in one female animal of the high dose (250 mg/kg bw/day) group. This renal finding was considered to be an individual alteration as there were no pathological changes at histological examination and it occurs also in not treated experimental rats.
Dermal alterations (alopecia and/or scabs) were observed in some animals at 250 mg/kg bw/day (1/10 male and 2/10 female) and at 125 mg/kg bw/day (2/10 male).
These dermal changes are common in this strain of experimental rats, were not related to doses and therefore were not considered to have toxicological relevance.
Slight or moderate hydrometra occurred in the mid (125 mg/kg bw/day, 1/10) and low (25 mg/kg bw/day, 3/10) dose groups. Hydrometra related to the female sexual cycle is a frequent observation in experimental rats.
All these findings (pyelectasia, dermal changes and hydrometra) were considered to be without any toxicological relevance in this study.

HISTOPATHOLOGY: NON-NEOPLASTIC
In the dead female animal (250 mg/kg bw/day) serious involution of thymus and signs of suffocation were detected at the histological examination. Toxic or other degenerative organic lesions, which could explain the progressive weight loss, were not found. The disease of this animal could be in connection with a probably individual metabolic disorder occurring sporadically in experimental rats.
In the male animal (250 mg/kg bw/day), found dead after the blood sampling due to over anesthesia, slight involution of thymus and signs of damaged spermatogenesis (decreased intensity of spermatogenesis, lack of mature spermatozoa in the seminiferous tubuli of testes and in the ductuli of epididymides, decreased number of spermatids in a proportion of seminiferous tubuli and giant-cells in the tubuli of the testes) were detected at the histological examination.
Histological examination revealed in the testes of animals treated with 250 mg/kg bw/day of the test item decreased intensity of spermatogenesis (9/10), and lack of mature spermatozoa in the seminiferous tubuli of testes (9/10) and in the ductuli of epididymides (9/10). In a proportion of seminiferous tubuli of affected animals decreased number of spermatids (9/10) was observed too, however the Sertoli-cells and spermatogonia were intact, suggesting a reversible phenomenon. Some giant-cells also were detected in the tubuli of these testes (10/10).
These findings were not observed in the testes and epididymides of animals belonging to the 125 and 25 mg/kg bw/day dose groups and in the control group (10/10, 10/10 and 10/10, respectively).
The interstitial cells in the testes and the histological picture of pituitary, seminal vesicles and prostate was normal in all treated and control animals.
The degree of involution seemed to be accelerated in some male and female animals belonging to the 250 mg/kg bw/day dose group compared with the animals of the control group. Involution of thymus was observed in minimal (3/10), mild (3/10) or moderate (1/10) degree in male animals at 250 mg/kg bw/day and in minimal degree in the control males (3/10). In females, thymus involution was detected in minimal (2/10), moderate (1/10) or severe (1/10) degree at 250 mg/kg bw/day and in minimal (3/10) or mild (1/10) degree in the control females. The differences in the degree of thymus involution in this age is a physiological phenomenon, however taking into account the significant differences with respect to controls, a test item influence cannot be excluded.
A focal pulmonary alveolar emphysema (in minimal or mild degree) occurred sporadically in animals at 250 mg/kg bw/day (1/10 male and 1/10 female) and in the control group (3/10 male and 1/10 female) and was considered to be the consequence of hypoxia, dyspnea and circulatory disturbance developed during exsanguination.
The hyperplasia of bronchus associated lymphoid tissue (BALT) in some 250 mg/kg bw/day treated animals (2/10 male and 2/10 female) and in the control group (2/10 male and 2/10 female) was a physiological phenomenon.
The subacute lymphocytic pyelitis in some female animals (3/10, at 250 mg/kg bw/day) could be in connection with a local infection.
The dilatation of the uterine horns in one female animal (1/10 at 250 mg/kg bw/day) is a slight neuro-hormonal phenomenon in connection with the sexual function – estrus phase – of the inner genital organs.

SPERM EXAMINATIONS
Sperm examinations revealed a test item related damage of sperm cells at 250 and 125 mg/kg bw/day.
Some separated head and fragments of sperm tail, i.e. lack of intact sperm cells was detected in ductus deferens sperm samples in all animals (10/10) administered with 250 mg/kg bw/day. The percent of motile sperm cells and sperms with normal morphology (head and tail connected) was significantly less in all animals (10/10) at 125 mg/kg bw/day with respect to the control animals.
Determination of the total sperm cell count in animals administered with 250 mg/kg bw/day was not feasible in the absolute lack of sperm cells. There was no significant difference in the total sperm cell count between the control and test item treated groups (125 and 25 mg/kg bw/day)

EXAMINATION OF ESTROUS CYCLE
A test item influence on the estrous cycle cannot be verified and cannot be excluded with the results of this study. There were no differences in the number of animals with an irregular estrous cycle in the low dose group as compared to the control group.
There were no animals with regular estrous cycle in group of 250 mg/kg bw/day. 9/9 female rat showed irregular estrous cycle i.e. were in prolonged diestrus during the last two week of the study (pseudo-pregnancy). Similar observations were made in 7/10 females at 125 mg/kg bw/day, in 6/10 females at 25 mg/kg bw/day and in 5/10 control animals. It should be underlined however that the number of control animals with irregular cycle (5/10) was also high in this study, as compared to the historical control data (5/96).

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
25 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on depression of body weight development and food consumption, hematology parameters (weight blood cell count and percentage of reticulocytes) and damage in spermatogenesis.
Dose descriptor:
NOAEL
Effect level:
38.7 mg/kg bw/day (nominal)
Based on:
other: calculated for cesium iodide
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
There is no repeated dose toxicity study for cesium iodide available. Consequently, data from the structural analogous substance cesium hydroxide monohydrate were used.
Under the conditions of the present study, the 250 mg/kg bw/day dose of cesium hydroxide monohydrate caused reduced body weight, body weight gain, and reduced food consumption (male), and changes in hematology parameters (white blood cell count and percentage of reticulocyte – male and female). Damage in spermatogenesis and decreased number of spermatids in a proportion of seminiferous tubuli after the 90-day oral (gavage) administration in Hsd.Brl.Han: Wistar rats was observed.

At 125 mg/kg bw/day, depression of the body weight development (male), altered clinical pathology parameters (slightly higher mean white blood cell count and higher mean percentage of reticulocytes (male and female), reduced weight of epididymides and damage of sperm motility and morphology) were indicative of adverse test item related effects.

At 25 mg/kg bw/day, there were no test item related toxic alterations.

Based on these observations the No Observed Adverse Effect Level (NOAEL) for cesium hydroxide monohydrate was determined as follows:
NOAEL: 25 mg/kg bw/day for male and female animals

The calculated NOAEL for cesium iodide is 38.7 mg/kg bw/day in male and female animals.
Executive summary:

There is no repeated dose toxicity study for cesium iodide available. Consequently, data from the structural analogous substance cesium hydroxide monohydrate were used.

The aim of this 90-Day toxicity study was to obtain first information on the toxic potential of cesium hydroxide monohydrate in rats at three dose levels following 90 -Day oral administration. The study was performed in compliance with the OECD guideline No. 408, EU method B.26 and EPA guideline OPPTS 870.3100. The test item was administered orally (by gavage) to Hsd.Brl.Han: Wistar rats (n=10 animals/sex/group) once a day at 0 (vehicle control), 250, 125 and 25 mg/kg bw/day doses corresponding to concentrations of 0, 25, 12.5 and 2.5 mg/mL, applied in a dose volume of 10 mL/kg bw for 90 days. A sufficient stability of cesium hydroxide monohydrate in the chosen vehicle was analytically verified up front. cesium hydroxide monohydrate was stable for 7 days at room temperature and in a refrigerator. Concentrations of the test item in the dosing formulations varied from 95 % to 97 % of nominal concentrations at all analytical occasions, thereby confirming proper dosing. Animals were observed for mortality twice a day in the course of the study. Daily general clinical observations and weekly detailed clinical observations were performed. A functional observation battery was conducted in the last week of treatment. The body weight and food consumption were measured and evaluated weekly. Clinical pathology examinations including hematology and clinical chemistry were conducted one day after the last treatment. Gross pathology was performed on animals on the day following the last treatment. The absolute and relative weights of selected organs were measured. Full histopathology was performed on the preserved organs or tissues of the animals of the control and high dose groups. Testes epididymides, prostate and seminal vesicles with coagulating gland were also evaluated histologically in all animals of the low and mid dose groups due to the necropsy and histopathological findings in these organs. The results of study were interpreted comparing test item treated groups with respect to controls, which were administered concurrently with vehicle (distilled water) only.

 

Conclusion

Under the conditions of the present study, the 250 mg/kg bw/day dose of cesium hydroxide monohydrate caused reduced body weight, body weight gain, and reduced food consumption (male), and changes in hematology parameters (white blood cell count and percentage of reticulocyte – male and female). Damage in spermatogenesis (smaller than normal testes, reduced weights of testes and epididymides, decreased intensity of spermatogenesis, accompanied with lack of mature spermatozoa in the seminiferous tubuli in the testes and in the ductuli of epididymides, and decreased number of spermatids in a proportion of seminiferous tubuli) after the 90-day oral (gavage) administration in Hsd.Brl.Han: Wistar rats was observed. These test item-related changes were considered to be toxicologically relevant.

 

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

 

At 125 mg/kg bw/day, depression of the body weight development (male), altered clinical pathology parameters (slightly higher mean white blood cell count and higher mean percentage of reticulocytes (male and female), reduced weight of epididymides and damage of sperm motility and morphology) were indicative of adverse test item related effects.

 

At 25 mg/kg bw/day, there were no test item related toxic alterations.

 

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

NOAEL: 25 mg/kg bw/day for male and female animals.

Therefore, the calculated NOAEL for cesium iodide is 38.7 mg/kg bw/day in male and female animals.