Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

Rats received KBr in food for 104 weeks in a testing regime approximating OECD guideline 453.
No detrimental changes were seen in the clinical signs, mortality, food and water consumption, ophthalmoscopic examination, haematology, clinical chemistry, urinalysis or organ weights of the treated animals. There is no evidence for potential carcinogenicity.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1990
Reliability:
2 (reliable with restrictions)
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
GLP compliance:
not specified
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan Inc (Kangawa Japan)
- Age at study initiation: 4 week old
- Weight at study initiation: Not specified
- Fasting period before study: Not specified
- Housing: Housed five to a wire-mesh stainless-steel cage in a barrier-sustained room.
- Diet (e.g. ad libitum): yes
- Water (e.g. ad libitum): yes
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): room temperature: 23-25 °C
- Humidity (%): 45-65%
- Air changes (per hr): 12 air changes/hour
- Photoperiod (hrs dark / hrs light): 12 hours light/dark
The environmental temperature and humidity were within the specified range

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): monthly
- Mixing appropriate amounts with (Type of food): Basal pellet diet (Oriental MF: Oriental Yeast Co, Ldt, Tokypo, Japan)
- Storage temperature of food: 23°C

VEHICLE
- Justification for use and choice of vehicle (if other than water): Not specified
- Concentration in vehicle: 500 ppm for KBr.
- Amount of vehicle (if gavage):
- Lot/batch no. (if required): Not specified
- Purity: Not specified
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Confirmed to be stable.
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
Daily
Post exposure period:
N/A
Remarks:
Doses / Concentrations:
500 ppm
Basis:
nominal in diet
KBr
No. of animals per sex per dose:
60 rats/sex/dose
Control animals:
yes, plain diet
Details on study design:
The rats were randomly allocated to 5 groups: 3 test material groups ( 500, 200, 80) test substance group KBr (500) and basal diet, each consisting of 60 males and 60 females. The randomization was continued until the body-weight ditribution was approximatively the same betweens groups. The KBr groups was fed ad lib the diet containing 500 ppm inorganic bromide prepared with the addition of potassium bromide to the basal diet. The basal diet group was given basal diet alone. Water was given ad lib.
Positive control:
No
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: Once a week for the first 13 week and once every 4 week thereafter.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Once a week for the first 13 week and once every 4 week thereafter. The total bromine intake in rats (mg /kg b.w./day) was calculated from their food consumption and body weights.

FOOD EFFICIENCY:
- Food conversion efficiency was calculated from the ratio of body-weight gain to food consumption.

ORGAN WEIGHTS:
The following organs were weighed and the organ/body weight ratios (relative organ weights) were calculated: brain pituitary, thyroids, with parathyroids, , heart, liver, spleen,kidneys, adrenals, testes and ovaries.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Once a week for the first 13 week and once every 4 week thereafter.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Before the start of the study and at week 104, 10 males and 10 females from the control (basal diet) group and the groups given 500 ppm total bromine were subjected to ophtalmological examination.

HAEMATOLOGY: Yes
- Blood samples were collected using heperinized syringes from the posterior vena cava of ten males and ten females from each group that were killed by exsanguination under ether anaesthesia after 52 week and 104 week.
- Each of the sample was poured into a cup with ethylenediamine tetraacetic acid and haematocrit, haemoglobin concentration, mean corpuscular haemoglobin, mean corpuscular volume, mean corpuscular haemoglobin, concentration and erythrocyte, platelet and leucocyte counts were determined.Differencial leucocyte counts were calculated by multiplying the leucocyte count by the percentage of each leucocyte determined on blood smears stained with May-Grünwald and Giemsa stains.
Plasma from the blood samples was analysed by conventional methods for total protein, albumin, globulin, albumin/globulin ratio, alkaline phosphatase, blood, urea nitrogen, creatinine, glucose, total cholesterol, glutamic-pyruvic transaminase, glutamine-oxoloatic transaminase, 7-glutamyl transpeptidase, total bilirubin, calcium, phosphorus, sodium, potassium and chlorine.


URINALYSIS: Yes
- Urine was collected from 10 males and 10 females in each group at week 52 and 104. Specific gravity was determined using a refractomer on fresh urine obtained by pressing the lumbodorsal portion of the rats. Semi-quantitative observations of pH protein, glucose, ketones, occult blood, urobilinogen and bulirubin were also carried out. Urine 24 hour volume, and sediment were then determined in urine samples that were collected from rats housed in individual urine sampling cages.

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

A thorough necropsy was performed on the 10 male and 10 demale rats per group that were killed at week 52 and on all surviving rats that were killed at week 104. The following organs were weighed and the organ/body weight ratios (relative organ weights) were calculated: brain pituitary, thyroids, with parathyroids, , heart, liver, spleen,kidneys, adrenals, testes and ovaries. Samples of these organs and of the spinal cord, sicatic nerve, thymus, bone with marrow, cervical and mesenteric lymph nodes, aorta, salivary gland, oesophagus, forestomach, glandular stomach, small and large intestine, trachea lung, urinary bladder, epididymides, prostate, seminal vesicles, uterus, eyes, Harderian glands, skeletal muscle, skin, mammary glands (female) and all gross lesions are fixed in 10% neutral buffered formalin, embedded in parrafin wax, sectioned at 5 µm and stained with haemotoxylin and eosin. Detailed microscopic examinations were carried out on all of the organs mentioned above from all rats from each group.
A thorough necropsy was also performed on rats that were found dead or were killed in extremis during the study. As far as possible, the organs and tissues in this rats were preserved and examined.
Other examinations:
No
Statistics:
The multiple comparison test (Dunnett’s or Scheffé’s method) was used to analyse data on body weight, food consumption, water consumption, urinalysis (specific gravity and urine volume), haematology, blood biochemistry and organ weights in order to determine the significance of the results. Mortality was evaluated by life-table analysis. The Mann-Whitney U test was applied to the urinalysis data except for those on specific gravity and urine volume. Fisher’s exact probability test was used for the analysis of data on ophthalmology and gross histopathology. The significance of the differences between the basal diet and treated groups was estimated at 5 and 1% levels of probability
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No effects were observed on the behaviour of the rats treated with KBr.
Mortality:
mortality observed, treatment-related
Description (incidence):
No effects were observed on the behaviour of the rats treated with KBr.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Higher body weights than those in the basal diet group were noted in the KBr group at weeks 1-6 (males) and at weeks 1, 10, 16, 24-36 and 44 (females).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Higher food consumption was seen at weeks 3 and 4 (males) and at weeks 1-4 (females) of the KBr treated group. The compound intake was equivalent to 16.5 mg/kg bw/day (males) and 20.0 mg/kg bw/day (females).
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Water consumption was statistically significantly higher in the treated group than in the control group at weeks 1-2, 7-8, 10, 13 and 24 in females).
Ophthalmological findings:
effects observed, treatment-related
Description (incidence and severity):
Several of the lesions observed in the treated and control groups were considered to be spontaneous. There was no lesion that showed a statistically significantly increased incidence.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
There were no significant differences between groups in haematological indices.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Treated males showed a slightly increased concentration in calcium at week 52. However, this result was within the normal range seen in historical data, and there were no statistically significantly different differences between the treated and control gr
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Urinalysis revealed statistically significant increases in mean values of specific gravity and in the number of rats showing a moderate degree of urobilinogen in males of the treated group at week 52 in comparison with the control. However, these changes
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Liver, kidneys, adrenals, testes, ovaries, spleen, brain, heart, pituitary, thyroids with parathyroids - There were no significant changes in the absolute weights of any organ in any of the treated groups in comparison with the control group.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
No abnormal observations (not including tumour formation) were noted by the author.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
The overall incidence of prostatitis (20/60) was significantly increased in comparison with the control group (10/60). This lesion is described by the author as a focal inflammatory lesion characterised by neutrophilic infiltration into the glandular spac
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY:
- No effects were observed on the behaviour of the rats in group fed Kbr containing diets. The number of rats that survived to 104 week in the basal diet and KBr 500 ppm groups were respectively, 42 and 43 (males) and 39 and 40 (females). Therefore, there was no statiscally significant difference in mortality between the group fed the basal diet and those fed KBr-supplement diets.

BODY WEIGHT AND WEIGHT GAIN:
- Higher body weights than those in the basal diet were noted in KBr (500) group at week 1-6 in males and at week 1, 10, 16, 24-36 and 44 in females.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
- Higher food consumption was seen at week 3 and 4 in males at week 1-4 in females. Throughout the study, the overall mean intake of totale bromine in he KBr (500) was 16.5 mg/kg bw/day in males and 20 mg/kg bw/day in females.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
- Water consumption in the KBr group is significantly higher than that in the basal diet group at week 1-2, 7-8, 10, 13 and 24 in females.

OPHTHALMOSCOPIC EXAMINATION
- Ophtalmological examination revealed several lesions that were considered to be spontaneous in the KBr (500) and basal diet group at week 104. But there was no lesion that showed a significantly increased incidence in comparison with the basal diet group.

HAEMATOLOGY:
- There was no relevant difference between groups in haemotological indices. Males of the KBr (500) showed a slightly increased concentration n calcium at week 52 but the value was within the normal ranges of the historical data and there was no stastically difference between treated and control groups at week 104. Therefore, no toxicological significance is attached to this slight change seen at week 52. In addtion, a slight, but significant, decrease in blood urea nitrogen was seen in males of the KBr (500) group at week 52. Though such decrease is of no toxicological significance.

URINALYSIS:
- Urinalysis revealed significant increases in mean values of specific gravity and in the number of rats showing a moderate degree of urobilinogen at week 52 in comparison with basal diet group. However, these changes probably represent incidental findings with no toxicological significance, since the values of these parameters were within the normal range of the historical data. Moreover, this change are not found at week 104.

ORGAN WEIGHTS:
- No significance difference in the absolute weights of any organ in any treated groups in comparison with the basal diet group.

HISTOPATHOLOGY: NON-NEOPLASTIC:
- In the treated KBr group, the overall incidence of prostatitis (20/60) is significantly increased in comparison with the basal diet group (10/60). This lesion is described by the author as a focal inflammatory lesion characterised by neutrophilic infiltration into the glandular spaces, and had a morphological resemblance to the prostatic inflammation that occurs spontaneously in male F344 rats. There is no aggravation in the severity of prostatitis in the KBr (500) groups: the severity of the prostatitis in this group was very similar to that in the basl diet group. Therefore, the increased incidence of prostatitis is of no toxicological significance and is incidental.

HISTOPATHOLOGY: NEOPLASTIC:
- The incidence of mononuclear cell leukaemia in females of the KBr (500) group (11/60) was significantly higher than that in the basal diet group (4/60). Histopatologically, all tumours observed in this study were similar to those that are known to occur spontaneously in this strain of rats. Therefore it is concluded that the increase incidence of mononuclear cell leukaemia is not attributable to the treatment with KBr, but is fortuitus.

GROSS PATHOLOGY:
- No significance difference between treated and control groups
Dose descriptor:
NOAEL
Basis for effect level:
other: see 'Remark'
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Conclusions:
Rats received KBr in food for 104 weeks in a testing regime approximating OECD guideline 453. Animals were assessed regularly for signs of toxicity, and standard biochemical and urinalysis changes. Tissues were examined for tumour formation at interim, terminal sacrifice and when any other unplanned deaths occurred.
No detrimental changes were seen in the clinical signs, mortality, food and water consumption, ophthalmoscopic examination, haematology, clinical chemistry, urinalysis or organ weights of the treated animals.
Histologically, all tumours observed in this study were similar to those that are known to occur spontaneously in this strain of rats. Although the incidences of prostatitis (20/60) in males, and mononuclear cell leukaemia in treated females (11/60) were significantly increased, historical control data indicate that these increases were within the ranges of incidence previously observed for control animals at the testing laboratory and so neither increased incidence was considered to be treatment related.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Justification for classification or non-classification

Based on the conclusions from outlined above from subchronic toxicity studies and human dietary experience, it is considered unnecessary to conduct carcinogenicity studies or additional repeat dose toxicity studies.

Additional information

Rats received KBr in food for 104 weeks in a testing regime approximating OECD guideline 453.

No detrimental changes were seen in the clinical signs, mortality, food and water consumption, ophthalmoscopic examination, haematology, clinical chemistry, urinalysis or organ weights of the treated animals.

Histologically, all tumours observed in this study were similar to those that are known to occur spontaneously in this strain of rats. Although the incidences of prostatitis (20/60) in males, and mononuclear cell leukaemia in treated females (11/60) were significantly increased, historical control data indicate that these increases were within the ranges of incidence previously observed for control animals at the testing laboratory and so neither increased incidence was considered to be treatment related.

Sodium bromide is an inorganic salt that dissociates to its composite ions in aqueous solutions at environmental pH and temperature. Comparison of the available data on the various bromide salts have shown that the bromide ion is the relevant ion for determination of the toxicological profile with simple cations such as potassium, sodium or ammonium, that are ubiquitous in nature, having little or no influence on the bromide ion properties. It is therefore justified to read-across data from other inorganic bromide salts to sodium bromide.

The results from in vitro genotoxicity studies showed that sodium bromide was not genotoxic under the test conditions. Furthermore, the repeated dose studies did not show any evidence of cellular change, even in potential target tissues such as the endocrine (thyroid) or neural systems, that could be considered preneoplastic change (e.g. hyperplasia or metaplasia). No reports were found to indicate potential neoplastic change as a consequence of normal human exposure to bromide in the diet. Therapeutic exposure has not been associated with neoplastic change.