Sodium bromide

Toxicity to reproduction

Administrative data

Endpoint:

three-generation reproductive toxicity

Remarks:

based on test type (migrated information)

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:

1983

Materials and methods

Principles of method if other than guideline:

Male and female Wistar rats received 0, 75, 300, 1200, 4800 and 19200 mg NaBr in the diet during three successive generations. The study was designated to evaluate the reproductive and developmental effects of sodium bromide in multiple generations as well as the effect on the thyroid function in the parental animals.

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

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 4 months.

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on mating procedure:

Male rats of proven fertility were mated with females.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Three generations.

Frequency of treatment:

Daily.

Details on study schedule:

In three successive generations, at least two litters per female rat were raised. In the first generation a third litter was raised for the investigation of the transplacental transport of bromide. Furthermore, an additional litter was bred with parent animals of the highest dose group which were changed to the control diet in order to investigate the reversibility of the observed effects.

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 75, 300, 1200, 4800 and 19200 mg NaBr/kg diet.
Basis:
nominal in diet

No. of animals per sex per dose:

Males: 9-10 animals/dose group.
Females: 7-11 animals/dose group (F0); 14-19 animals/dose group (F1); 10 animals/dose group (F2).

Control animals:

yes, plain diet

Details on study design:

Because of the diminished fertility in the two highest dose groups, second and third generations were bred only from the groups dosed with sodium bromide up to 1200 mg/kg diet.

Positive control:

None.

Examinations

Parental animals: Observations and examinations:

CLINICAL OBSERVATIONS: Yes.

BODY WEIGHT: Yes.

OTHER:
HAEMATOLOGY: haematological examinations were carried out 3 weeks before each mating and directly after the weaning of the last litter.
THYROID FUNCTION: the thyroid hormone (T4) concentration in serum was determined in parent animals of the F0 generation.

Oestrous cyclicity (parental animals):

No data.

Sperm parameters (parental animals):

No data.

Litter observations:

PARAMETERS EXAMINED
The following parameters were examined: number and sex of pups, viability, presence of gross anomalies, body weight and bromide ion levels in foetal kidneys.

Postmortem examinations (parental animals):

ORGAN WEIGHTS
The tissues indicated in Table 2 were weighed: adrenals, thyroid, pituitary, ovaries, uterus, testes, prostate.

Postmortem examinations (offspring):

ORGAN WEIGHTS
The tissues indicated in Table 2 were weighed: adrenals, thyroid, pituitary, ovaries, uterus, testes, prostate.

Statistics:

No data.

Reproductive indices:

Fertility index (no. of pregnancies x 100/no. of matings).

Offspring viability indices:

Viability index (no. of pups alive at day 5 x 100/no. of pups born alive); Lactation index (no. of pups alive at day 21 x 100/no. of pups alive at day 5).

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

not examined

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

(≥ 4,800 mg/kg)

Details on results (P0)

BODY WEIGHT
Body weight determinations did not reveal a clear pattern of dose-related effects.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
The fertility was nil in the 19,200-mg group and was markedly reduced in the 4,800-mg group. The reversibility of the effects on reproduction was studied in parent animals fed a diet containing 19,200 mg NaBr/kg for 7 months followed by a control diet for 3 months before mating. The results were as follows: fertility index, 62%; viability index, 61%; lactation index, 90%. Although the viability was lower than in the control and lower dose groups, the fertility index and lactation index were similar.

ORGAN WEIGHTS (PARENTAL ANIMALS)
Organ-weight determinations did not reveal a clear pattern of dose-related effects in the successive generations. Only the adrenals of the females of the F0-generation showed a dose-dependent decrease in relative weight.

OTHER FINDINGS (PARENTAL ANIMALS)
HAEMATOLOGY: it was found a dose-related increase of the bromide levels in plasma, placenta and kidneys.
THYROID FUNCTION: a decrease in thyroid hormone (T4) concentration was found in the serum of the parent animals of the P-generation. The no-effect level for thyroid function was fixed at 300 mg/kg. This finding is indicative of an inhibitory action of bromide on the synthesis of thyroid hormones.

Effect levels (P0)

1

Dose descriptor:

NOAEL

Remarks:

(reproductive)

Effect level:

1 200 mg/kg diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on fertility index (equivalent to 120 and 60 mg/kg b.w./day for young and older rats, respectively).

2

Dose descriptor:

NOAEL

Remarks:

(developmental)

Effect level:

1 200 mg/kg diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on viability index (equivalent to 120 and 60 mg/kg b.w./day for young and older rats, respectively).

Remarks on result:

other: Generation: F1, F2 (migrated information)

3

Dose descriptor:

NOAEL

Remarks:

(systemic)

Effect level:

300 mg/kg diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on thyroid function (equivalent to 30 and 15 mg/kg b.w./day for young and older rats, respectively).

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

(≥ 4,800 mg/kg)

Body weight and weight changes:

no effects observed

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Details on results (F1)

VIABILITY (OFFSPRING)
In the 4,800-mg group the viability of the offspring was lower than in the other groups. In this group, the viability of the young was greater in the second litter than in the first. Furthermore, during lactation of the first litter all of the young alive at day 5 died before day 21. In the second litter of this group, however, all animals alive at day 5 were still alive at day 21.

BODY WEIGHT (OFFSPRING)
Body weight determinations did not reveal a clear pattern of dose-related effects.

ORGAN WEIGHTS (OFFSPRING)
Organ-weight determinations given in Table 2 did not reveal a clear pattern of dose-related effects.

BROMIDE CONCENTRATIONS
The bromide levels in foetal kidneys demonstrate that foetuses in utero were exposed to bromide, since the concentration of bromide in the kidneys corresponding dams and foetuses is almost equal.

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Table 1. Breeding results in reproduction study on sodium bromide fed to rats at dietary levels up to 19200 mg/kg. 

	Values for groups fed NaBr at dietary levels (mg/kg) of:
Generation	0	75	300	1200	4800	19200
	Fertility index*
F0	70	70	72	65	25	0
F1	62	54	44	53	-	-
F2	52	67	80	45	-	-
	Viability index*
F0	90	98	96	92	32, 61+	-
F1	92	88	80	97	-	-
F2	96	98	93	98	-	-
	Lactation index*
F0	95	96	95	94	0, 100+	-
F1	93	85	72	80	-	-
F2	99	99	99	99	-	-
	Mean body weight at day 21
F0	40	45	43	43	-, 38+	-
F1	41	43	40	38	-	-
F2	36	38	38	36	-	-

*Fertility index = no. of pregnancies x 100/no. of matings; viability index = no. of pups alive at day 5 × 100/no. of pups born alive; lactation index = no. of pups alive at day 21 × 100/no. of pups alive at day 5.

+ Data are given separately for first and second litter.

Table 2. Reproduction study in rats fed sodium bromide at dietary levels up to 4800 mg/kg: mean body weights and relative organ weights determined at the end of each generation.

Generation	Parameter^+		Values for groups fed NaBr at dietary levels (mg/kg) of:
			0	75	300	1200	4800
Males
F0		No./group…	9	9	9	10	10
	Body weight (g)		422	398	383	391	362
	Adrenals		0.011	0.011	0.011	0.011	0.012
	Thyroid		0.0060	0.0057	0.0056	0.0060	0.0060
	Pituitary		0.0029	0.0029	0.0029	0.0030	0.0033
	Testes		0.680	0.745	0.776**	0.744	0.712
	Prostate		0.119	0.130	0.121	0.135	0.134
F1		No./group…	10	10	10	10	-
	Body weight (g)		409	391	388	395	-
	Adrenals		0.010	0.010	0.011	0.012	-
	Thyroid		0.0063	0.0064	0.0060	0.0067	-
	Pituitary		0.0026	0.0026	0.0027	0.0028	-
	Testes		0.771	0.759	0.769	0.763	-
	Prostate		0.077	0.093	0.093	0.102*	-
F2		No./group…	10	10	10	10	-
	Body weight (g)		438	373**	397**	378**	-
	Adrenals		0.010	0.010	0.009	0.010	-
	Thyroid		0.0076	0.0074	0.0079	0.0081	-
	Pituitary		0.0032	0.0031	0.0027**	0.0029	-
	Testes		0.787	0.821	0.679	0.793	-
	Prostate		0.103	0.102	0.109	0.104	-
Females
F0		No./group…	7	11	9	12	11
	Body weight (g)		254	256	249	243	249
	Adrenals		0.020	0.019	0.019	0.017*	0.017**
	Thyroid		0.0062	0.0066	0.0066	0.0073	0.0073
	Pituitary		0.0056	0.0055	0.0052	0.0052	0.0046
	Ovaries		0.022	0.021	0.022	0.025	0.024
	Uterus		0.171	0.166	0.180	0.150	0.143
F1		No./group…	19	15	14	16	-
	Body weight (g)		244	254	252	241	-
	Adrenals		0.018	0.018	0.017	0.017	-
	Thyroid		0.0073	0.0070	0.0074	0.0083	-
	Pituitary		0.0047	0.0052	0.0049	0.0053*	-
	Ovaries		0.026	0.029	0.027	0.027	-
	Uterus		0.167	0.159	0.150	0.140*	-
F2		No./group…	10	10	10	10	-
	Body weight (g)		267	244	259	241**	-
	Adrenals		0.019	0.018	0.017	0.018	-
	Thyroid		0.0096	0.0083	0.0094	0.0103	-
	Pituitary		0.0053	0.0048	0.0050	0.0056	-
	Ovaries		0.027	0.024	0.027	0.027	-
	Uterus		0.188	0.160	0.179	0.164	-

⁺All organ weights are expressed in g/100 g body weight.

Asterisks indicate means differing significantly from that of the corresponding control group: *-0.01 ≤ p < 0.05; **-0.001 ≤ p < 0.01.

Table 3. Bromide concentration (corrected for control values) in plasma, tissues and 20 -day foetuses of female rats fed sodium bromide at 75 -4800 mg/kg diet for 7 months.

Dietary concentration of NaBr (mg/kg)	Maternal levels of Br-			Br- in foetal kidneys (mmol/kg)
	Plasma (mmol/litre)	Placenta (mmol/kg)	Kidneys (mmol/kg)
75	0.5 ± 0.1	0.4 ± 0.1	0.3 ± 0.1	0.3 ± 0.1
300	2.2 ± 0.1	1.4 ± 0.1	1.4 ± 0.3	0.9 ± 0.1
1200	7.8 ± 0.9	6.3 ± 1.5	4.4 ± 1.1	3.2 ± 0.8
4800	27.6 ± 2.8	16.7 ± 1.5	15.3 ± 1.4	11.0 ± 0.6

Values are means ±SD for groups of seven animals.

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).

Applicant's summary and conclusion

Conclusions:

The NOAEL for reproductive and developmental toxicity was determined to be 1200 mg/kg diet (equivalent to 120 and 60 mg/kg bw/d for young and older rats, respectively).

Executive summary:

A three-generation reproduction study was performed with the test substance sodium bromide on Wistar rats at dietary concentrations of 0, 75, 300, 1200, 4800 and 19,200 mg NaBr/kg diet. For the performance of the experiment, male rats of proven fertility were mated with females for the first time at the age of 4 months. In three successive generations, at least two litters per female rat were raised. Besides, in the first generation a third litter was raised for the investigation of the transplacental transport of bromide and an additional litter was bred with parent animals of the highest dose group which were changed to the control diet in order to investigate the reversibility of the observed effects. Fertility index, viability and lactation indices were evaluated for each generation. Haematological examinations were made and the thyroid function was evaluated. Body- and organ-weights were also determined. The bromide concentration determination in foetal kidneys of the third litter of the first generation showed that foetuses in utero were indeed exposed to bromide. Body- and organ-weight determinations did not reveal a clear pattern of dose-related effects in the successive generations. The fertility was found to be nil in the 19,200 -mg group and was markedly reduced in the 4800 -mg group. Nevertheless, the decrease in fertility appeared to be reversible upon bromide withdrawal. In the 4800 -mg group also the viability of the offspring was lower than in the other groups. Macroscopic examination of all pups provided no evidence of anomalies. Besides the effects on fertility and viability, the most prominent effect observed in the present study was a decrease in thyroid hormone (T4) concentration in the serum of the parent animals of the P -generation. This finding is indicative of an inhibitory action of bromide on the synthesis of thyroid hormones. On the basis of the effect of sodium bromide on the thyroid function, a no-effect level of 300 mg/kg diet was determined (equivalent to 30 and 15 mg/kg bw/d for young and older rats, respectively). On the basis on the fertility and viability indices, the NOAEL for reproductive and developmental toxicity was determined to be 1200 mg/kg diet (equivalent to 120 and 60 mg/kg bw/d for young and older rats, respectively).