Sodium bromide

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2004

Materials and methods

Principles of method if other than guideline:

Female Wistar rats were mated and dosed with a high and a low dose of sodium bromide in their drinking water from 2nd to the 28th day postpartum.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Sodium bromide

EC Number:

231-599-9

EC Name:

Sodium bromide

Cas Number:

7647-15-6

Molecular formula:

BrNa

IUPAC Name:

Active bromine generated from sodium bromide and sodium hypochlorite

Details on test material:

- Name of test material (as cited in study report): sodium bromide

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 8-10 weeks.
- Diet (e.g. ad libitum): standard pelleted diet, ad libitum.
- Water (e.g. ad libitum): tap water, ad libitum.

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

VEHICLE
- Concentration in vehicle: 1 or 5 g Br-/l.

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

30 female rats were mated with 30 males of proven fertility.

Duration of treatment / exposure:

Days 2 to 28 postpartum.

Frequency of treatment:

Daily.

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 1 and 5 g Br-/l.
Basis:
nominal in water
(A dose of 5 g Br-/l water equals to a mean daily dose of bromide of about 220 mg).

No. of animals per sex per dose:

5 dams/group.
8 pups/dam.

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: the bromide levels tested were chosen in compliance with the literature data, with the aim of ensuring that the mean intake of bromide in the animals would be effective and at the same time nonlethal.

Examinations

Maternal examinations:

DETAILED CLINICAL OBSERVATIONS: Yes.

BODY WEIGHT: Yes
- Time schedule for examinations: at regular intervals.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes.
- Time schedule for examinations: at regular intervals.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes.
- Time schedule for examinations: at regular intervals.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: No.

Fetal examinations:

- External examinations: Yes: size and weight were examined for each pup.

Statistics:

All statistical evaluation of the data was performed by nonparametric Kruskal-Wallis analysis of variance followed by the Mann-Whitney test for pairwise post hoc comparison. The difference is considered significant when p < 0.05.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Food and water consumption: There was a gradual increase in the consumption of food in the course of lactation in both the control dams and the rats of the low-Br group, and there were no significant differences between these two groups with regard to the amount of food consumed. In the case of animals of the high-Br group, there were no changes in the food consumption during the whole lactation period. Starting from the second week of the nursing period, the amount of food consumed by these rats was markedly lower than that consumed by the control rats and the rat of the low-Br group. The same was true for the consumption of drinking water.
Body weight: the enhanced intake of bromide in the course of the lactation period did not influence significantly the body weight of the lactating rats of the low-Br group. In contrast, in the rats of the high-Br group, it caused a mild but gradual decrease of the average body weight.

Effect levels (maternal animals)

Dose descriptor:

LOAEL

Effect level:

847.13 mg/kg bw/day (nominal)

Based on:

other: bromide ions.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Mortality: all of the pups in the control group survived, whereas in the low-Br and in the high-Br experimental groups, 94.8% and 56.3% of the young survived, respectively.
Body weight: there was a very marked effect of excess bromide on the body weight of the young whose mothers drank water with the addition of 5 g bromide per liter. The body weight in these suckling were progressively lower in comparison with the control young and the young of the low-Br group.

Effect levels (fetuses)

Dose descriptor:

LOAEL

Effect level:

847.13 mg/kg bw/day (nominal)

Based on:

other: bromide ions.

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Table 1. Body Weight of the Dams on the 2nd, 15th, and 28th Postpartum Days, and the Difference Between the Values of the Body Weights at the End (28th day) and in the Beginning (2nd day) of the Nursing Period (Body Weight Gain).

Group	Body weight (g) on post-partum day*
	2	15	28	Difference (28-2)
Control	278.0 ± 16.9	302.8 ± 19.1	279.8 ± 20.5	1.8 ± 7.9
Low-Br	248.0 ± 11.1	278.6 ± 8.0	262.6 ± 7.9	14.6 ± 11.2
High-Br	286.2 ± 17.9	264.0 ± 40.2	229.0 ± 74.9	-57.2 ± 67.7^a,b

* Values are means ± SD, n = 5

^a,bSignificantly diferent from the control group (^ap = 0.008) and from the low-Br group (^bp = 0.008).

Effect level: 5 g Bromide ions per liter was the lowest dose that produced adverse effects to the rats in the experiment. According to the author, this dose equals to a daily dose of bromide of about 220 mg per rat). Assuming a median weight of 259.7 g of the animals in the high bromide dose group, the lowest observed adverse effect level was established to be 847.13 mg Br-/kg bw/day, which equals to 1086.88 mg NaBr/kg bw/day.

Applicant's summary and conclusion

Conclusions:

The LOAEL for maternal toxicity and teratogenicity was established to be 847.13 mg Br-/kg bw/day (equivalent to 1086.88 mg NaBr/kg bw/day).

Executive summary:

In the present study Female Wistar rats were mated and dosed with a high and a low dose of sodium bromide (5 and 1 g Br-/l, respectively) in their drinking water from 2nd to 28th day postpartum. Maternal examinations included clinical and body weight observations, as well as food and water consumption determinations. External examinations were performed for each pup. From the present study it can be concluded that excessive bromide intake in lactating rat dams affects both their own organisms and the organisms of their suckling young. However, marked effects were found only in dams that drank water with the addition of 5 bromide per liter (equivalent to a daily dose of bromide of about 220 mg per rat). In these dams a stagnation in the extent of the consumption of diet and water in the course of the nursing period were observed. Besides, as a consequence of an excessive intake of bromide in the course of the lactation period in the dams of the high-Br group, a gradual decrease in their average body weight was observed. Very pronounced effects of high bromide levels in the organism of the mothers were also observed in the young of the high-Br group. In this group, only 56% of the young survived. Their mean body weight on day 27 of life was less than 40% of the body weight of the control young and the general condition was very poor. Thus, the LOAEC for maternal toxicity and teratogenicity was established to be 220 mg bromide/day/rat (equivalent to 847.13 mg Br-/kg bw/day and 1086.88 mg NaBr/kg bw/day).