Sodium bromide

Endpoint summary

Description of key information

Key study: Test method equivalent or similar to OECD Guideline 407. The NOAEL after 4 weeks oral exposure to sodium bromide was determined to be 4800 mg/kg diet (equivalent to 480 mg/kg bw/day for young rats and 240 mg/kg bw/day for older rats).
Key study: Test method equivalent or similar to OECD Guideline 408. The NOAEL after 90 days oral exposure to sodium bromide was determined to be 300 mg/kg diet (equivalent to 30 mg/kg bw/day for young rats and 15 mg/kg bw/day for older rats), on the basis of the effects on the thyroid.
Key study: Test method equivalent or similar to OECD Guideline 408. The NOAEL and the LOAEL for the animals receiving a normal diet was determined to be 1200 ppm (equivalent to 120 mg/kg bw/day for young rats and 60 mg/kg bw/day for older rats) and 4800 ppm (equivalent to 480 mg/kg bw/day for young rats and 240 mg/kg bw/day for older rats), respectively.
Supporting study: Study well documented, meets generally accepted scientific principles, acceptable for assessment. The NOAEL of sodium bromide in dogs was determined to be 100 mg/kg bw/day. 

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:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Test method equivalent or similar to OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents).

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

(The number of animals included in the study is not specified; clinical chemistry and ophtalmoscopic examinations were not performed).

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days.

Frequency of treatment:

Daily.

Remarks:

Doses / Concentrations:
75, 300, 1200, 4800, 19200 mg/kg diet.
Basis:
nominal in diet

No. of animals per sex per dose:

No data.

Positive control:

None

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes.

HAEMATOLOGY: Yes.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (organs examined: musculature, thyroid, prostate and adrenals).
HISTOPATHOLOGY: Yes (organs examined: musculature, thyroid, prostate and adrenals).

Statistics:

No data.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

(in the 19,200 mg/kg diet group)

Mortality:

mortality observed, treatment-related

Description (incidence):

(in the 19,200 mg/kg diet group)

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

(in the 19,200 mg/kg diet group)

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

(in the 19,200 mg/kg diet group)

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

Description (incidence and severity):

(in the 19,200 mg/kg diet group)

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

(in females exposed to ≥1200 mg/kg and in males exposed to ≥4800 mg/kg)

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

(in the highest dosage groups)

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
Depressed grooming and motor incoordination of the hind legs were observed at the highest dose level. These effects may have been due to a disturbance of the central nervous system by bromide.

BODY WEIGHT AND WEIGHT GAIN
A significant growth retardation was observed in both sexes fed 19,200 mg/kg diet.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
The highest dosage group (19,200 mg/kg diet) showed a slight decrease in food conversion.

HAEMATOLOGY
A slight decrease in the concentration of lymphocytes and a doubling in the concentration of neutrophilic granulocytes were found in both sexes of the 19,200 mg/kg diet group. The increase in neutrophilic granulocytes may be regarded as a stress-mediated effect, although it cannot be excluded that the effect was originated from a bacterial infection as a result of the bad physical condition of the animals. The effect on the lymphocytes may be suggestive of a slight suppressive effect on the immune system by bromide.

ORGAN WEIGHTS
The most prominent effects were on the thyroid and the gonads. The relative weight of the thyroid was increased in females from exposed to ≥1200 mg sodium bromide/kg diet and in males at the highest dose level (19,200 mg/kg diet). Males exposed to 4800 and 19200 mg/kg diet showed a decrease in the relative prostate weight.

HISTOPATHOLOGY: NON-NEOPLASTIC
A complex of histopathological changes was observed in the endocrine system. A no-effect level of 300 mg/kg diet was established on the basis of the effects on the thyroid. A remarkable thyroid activation was found for both sexes in the highest dose group. In addition, a decrease in spermatogenesis and a decrease in vacuolization of the zona fasciculata in the adrenals were observed in males. Furthermore, females showed a decrease in the number of corpora lutea.

Dose descriptor:

NOAEL

Effect level:

300 mg/kg diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: (equivalent to 30 mg/kg bw/day for young rats and 15 mg/kg bw/day for older rats). Based on thyroid effects.

Critical effects observed:

not specified

Effect levels:

The effect levels were reported as Concentration of the substance in feed (mg/kg diet). In order to express the dose levels as mg/kg Body Weight Per Day, a conversion factor of 0.1 for young rats and 0.05 for older rats were used (in accordance with the OECD Environment, Health and Safety Publications Series on Testing and Assessment No.51, Paris, 2006).

Conclusions:

The NOAEL after 90 days oral exposure to sodium bromide was determined to be 300 mg/kg diet (equivalent to 30 mg/kg bw/day for young rats and 15 mg/kg bw/day for older rats), on the basis of the effects on the thyroid.

Executive summary:

A subchronic oral toxicity study was performed with sodium bromide following a method equivalent or similar to OECD Guideline 408. Wistar male and female rats were exposed to the test substance at dietary concentrations of 75, 300, 1200, 4800 and 19,200 mg sodium bromide/kg diet in a 90 -day test. Clinical observations, body weight and food consumption determinations, as well as haematological examinations were performed throughout the test. At the end of the study gross pathology and histopathology examinations were performed in the musculature, the thyroid, the prostate and the adrenal glands. Depressed grooming and motor incoordination of the hind legs were observed only in the highest dose level. These effects may had been due to a disturbance of the central nervous system by bromide levels. A significant growth retardation was also observed in both sexes in the 19,200 mg/kg diet dosage group, along with a slight decrease in food conversion. In the haematologic evaluation performed, a slight decrease in the concentration of lymphocytes and a doubling in the concentration of neutrophilic granulocytes were found in both sexes. The most prominent effects were on the thyroid and the gonads. The relative weight of the thyroid was increased in females exposed to ≥1200 mg sodium bromide/kg diet and in males at the highest dose level (19,200 mg/kg diet). Males exposed to 4800 and 19,200 mg/kg diet showed a decrease in the relative prostate weight. These changes were confirmed by the observation of a complex of histopathological changes in the endocrine system. A remarkable thyroid activation was found for both sexes in the highest dose group. In addition, a decrease in the spermatogenesis and a decrease in the vacuolization of the zona fasciculata in the adrenals were observed in males. Furthermore, females showed a decrease in the number of corpora lutea. The NOAEL after 90 days oral exposure to sodium bromide was determined to be 300 mg/kg diet (equivalent to 30 mg/kg bw/day for young rats and 15 mg/kg bw/day for older rats), on the basis of the effects on the thyroid.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

30 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

There is one 28-day key study and two 90-day key studies performed in rats, with a Kilimish score = 2. Besides, there is a supporting study performed in dogs, with a Klimish score = 3. The overall quality of the database was determined as appropriate for assessment.

Additional information

Key study: Sodium bromide was administered to Wistar rats for 4 weeks at dietary concentrations of 300, 1200, 4800 and 19,200 mg/kg diet. During the course of the study, clinical observations, body weight, food and water consumption determinations, as well as clinical-chemistral determinations were performed. At the end of the study, brain, liver and kidneys were weighed and examined histopathologically. Anomalies were observed only in the highest dose group. The rats of the 19,200 mg/kg group showed signs of motor incoordination of the hind legs and depressed grooming. Organ-weight determinations of brain, liver and kidneys showed a significantly increased relative weight only of the kidneys. In the histopathological examination, no evidence was found of changes attributable to the treatment. No changes in growth and food and water intake were observed. In the clinical chemistry examinations, only the plasma bromide levels were examined. It was found that the plasma concentration of bromide increased steeply during the first week and within 3 weeks reached a plateau level, which was directly proportional to the bromide concentration in the diet. On the basis of these results, the NOAEL after 4 weeks oral exposure of sodium bromide was determined to be 4800 mg/kg diet (equivalent to 480 mg/kg bw/day for young rats and 240 mg/kg bw/day for older rats).

Key study: A subchronic oral toxicity study was performed with sodium bromide following a method equivalent or similar to OECD Guideline 408. Wistar male and female rats were exposed to the test substance at dietary concentrations of 75, 300, 1200, 4800 and 19,200 mg sodium bromide/kg diet in a 90 -day test. Clinical observations, body weight and food consumption determinations, as well as haematological examinations were performed throughout the test. At the end of the study gross pathology and histopathology examinations were performed in the musculature, the thyroid, the prostate and the adrenal glands. Depressed grooming and motor incoordination of the hind legs were observed only in the highest dose level. These effects may had been due to a disturbance of the central nervous system by bromide levels. A significant growth retardation was also observed in both sexes in the 19,200 mg/kg diet dosage group, along with a slight decrease in food conversion. In the haematologic evaluation performed, a slight decrease in the concentration of lymphocytes and a doubling in the concentration of neutrophilic granulocytes were found in both sexes. The most prominent effects were on the thyroid and the gonads. The relative weight of the thyroid was increased in females exposed to ≥1200 mg sodium bromide/kg diet and in males at the highest dose level (19,200 mg/kg diet). Males exposed to 4800 and 19200 mg/kg diet showed a decrease in the relative prostate weight. These changes were confirmed by the observation of a complex of histopathological changes in the endocrine system. A remarkable thyroid activation was found for both sexes in the highest dose group. In addition, a decrease in the spermatogenesis and a decrease in the vacuolization of the zona fasciculata in the adrenals were observed in males. Furthermore, females showed a decrease in the number of corpora lutea. The NOAEL after 90 days oral exposure to sodium bromide was determined to be 300 mg/kg diet (equivalent to 30 mg/kg bw/day for young rats and 15 mg/kg bw/day for older rats), on the basis of the effects on the thyroid.

Key study: A ninety day feeding study with Wistar rats on a normal chloride and a low chloride diet was performed with sodium bromide. In the study with a normal chloride diet 10 rats/sex/dose were exposed to 0, 75, 300, 1200, 4800 and 19200 ppm sodium bromide, whereas in the low chloride experiment 10 rats/sex/dose received 0, 8, 31, 125, 500 and 2000 ppm of the test substance. During the studies the weight gain, the food intake, the bromide and total halogenide concentrations in plasma were determined regularly. At the end of the experiments clinical-chemical determinations were carried out in blood, urine and liver. Bromide and total halogenide were determined in plasma and several organs. The organs were weighed and examined histopathologically. Grooming was depressed in the animals of the highest dosage groups in both experiments and they also showed motor incoordination of their hind legs. No mortality was observed in the animals on a normal chloride diet, whereas in the study with a low chloride diet, 3 males and 3 females of the highest dosage group died. In the animals with a low chloride intake, the growth of the 2000 ppm group was strongly retarded. The growth of the highest dosage group of the animals with a normal chloride intake was only somewhat retarded. The hematological investigations revealed a striking increase in the percentage and the total number of neutrophil granulocytes in the highest dosage groups of both experiments. Moreover, in the animals on a low chloride diet, the total leucocyte count was increased in the 2000 ppm group. As an overall tendency it can be seen that in both experiments the relative weights of the adrenals and thyroid were increased in the highest sodium bromide groups, whereas the weights of the pituitary, ovaries and testes were decreased. Histopathological changes were seen in the animals of the 4800 and the 19200 ppm group with a normal chloride diet. In the animals on a low chloride diet, hystopathological changes were found at 500 and 2000 ppm dosage levels. From the results of the present experiment it can be concluded that the low level of chlorine in diet enhances the toxicity of sodium bromide, while the target organs are still the same. The NOAEL and the LOAEL for the animals receiving a normal diet was determined to be 1200 ppm (equivalent to 120 mg/kg bw/day for young rats and 60 mg/kg bw/day for older rats) and 4800 ppm (equivalent to 480 mg/kg bw/day for young rats and 240 mg/kg bw/day for older rats), respectively. For the animals on a low chloride diet, the NOAEL was stated to be 125 ppm (equivalent to 12.5 mg/kg bw/day for young rats and 6.25 mg/kg bw/day for older rats) and the LOAEL was 500 ppm (equivalent to 50 mg/kg bw/day for young rats and 25 mg/kg bw/day for older rats).

Supporting study: experimental bromide intoxication was produced in dogs through the administration of sodium bromide doses from 100 until 400 mg/kg in diet, in 4 different dosage schedules: the first dosage group was administered a dose of 100 mg/kg; groups 2 and 3 were given an initial dose of 100 and 200 mg/kg, respectively, and thereafter these doses were increased 100 or 200 mg/kg at intervals of 6 weeks, achieving doses up to 400 and 600 mg/kg, respectively; in order to create intoxication rapidly, the fourth group was dosed with the test substance at 400 and 500 mg/kg. Animals were dosed daily until death occurred (between day 44 and day 185 of the experiment).On the basis of the study results, it was concluded that the rapid elevation of the blood bromide level increases the lethality of sodium bromide: at the same dose of sodium bromide, the dogs of the groups 2 and 3 survived for longer than those of the group 4, which were administrated an initial dose one or two times higher. Gastrointestinal and central nervous system signs were seen in exposed animals, as well as skin lesions. Central nervous system sings were seen in animals exposed to 200 mg/kg and included slight ataxia, stupor, severe ataxia and coma. Gastrointestinal signs appeared almost as frequently as did those of neurotoxicity and included diarrhoea, bloody stool and vomiting. Skin lesions, which were observed in animals exposed to ≥ 200 mg/kg and consisted in non suppurative white macules, were found to be not related to blood bromide levels. Emaciation and weight loss occurred in most dogs even at doses which caused no other signs of toxicity. This finding occurred on undiminished ingestion of food, suggesting that bromide may interfere with absorption of nutrients from the gastrointestinal tract. On the basis of these results, the NOAEL of sodium bromide in dogs was determined to be 100 mg/kg bw/day.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study with the longest duration (90-days) and lowest effect level was chosen.

Justification for classification or non-classification

Based on the available data, sodium bromide is not classified for specific target organ toxicity by repeated exposure (STOT-RE) according to CLP Regulation (EC) no 1272/2008.