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Neurotoxicity

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Description of key information

The findings in a neutrotoxicological screening battery performed as part of the 90-day repeat oral dose study with ammoniumm bromide indicates that effects observed are probably reversible as evidenced in the four week recovery period at doses ≥225 mg/kg bw/day in both sexes.
Studies with sodium bromide give an NOAEL = 80 mg/kg bw/day (equivalent to 62.1 mg (Br-) /kg bw/day).

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
neurotoxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Principles of method if other than guideline:
other
GLP compliance:
no
Species:
mouse
Strain:
other: C1300 mouse neuroblastoma cells, clone Neuro-2a
Sex:
not specified
Route of administration:
other: in vitro study
Vehicle:
water
Duration of treatment / exposure:
Exposure period: 2 day(s)

Frequency of treatment:
Continuous exposure

Remarks:
Doses / Concentrations:
0, 10-4, 10-5 and 10-6 M
Basis:

Control animals:
yes, concurrent vehicle
Details on study design:
Type: other
Observation period: 2 day exposure period

Basis for effect level:
other: see 'Remark'
Remarks on result:
not measured/tested
Remarks:
Effect level not specified
Conclusions:
A concentration of 10-6 M sodium bromide produces no noticeable effect light microscopically even after prolonged application (longer than 2 days). After a 2 day exposure to higher concentrations of sodium bromide and subsequent fixation of the mouse neuroblastoma cells, a pronounced increase in the length and branching of the processes or neurites is revealed. In addition there is an increase in the number of differentiated neuron-like mouse neuroblastoma cells treated with lower concentrations of sodium bromide. The length of processes, the number of branching and the cell number per area is significantly dependent on the concentration of the applied substances. The degree of branching per length of neuronal processes shows a slightly more pronounced effect when higher concentrations of sodium bromide are used.
Endpoint:
neurotoxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Principles of method if other than guideline:
other
GLP compliance:
no
Species:
mouse
Strain:
NMRI
Sex:
male
Route of administration:
other: oral
Vehicle:
water
Duration of treatment / exposure:
Exposure period: 36 day(s)

Frequency of treatment:
Daily

Remarks:
Doses / Concentrations:
0, 400, 1200, 3600 and 10800 ppm
Basis:

No. of animals per sex per dose:
100

Control animals:
yes, concurrent vehicle
Details on study design:
Type: other
Observation period: 42 days pre-exposure, 36 days during exposure, 50 days post-exposure

Details on results:
result is equivalent to: NOAEL = 310 ppm for the bromide ion
Dose descriptor:
NOAEL
Effect level:
400 ppm
Basis for effect level:
other: based on behavioural activityTest
Remarks on result:
other:
Dose descriptor:
LOAEL
Effect level:
1 200 ppm
Basis for effect level:
other: based on behavioural activityTest
Remarks on result:
other:

Result: NOAEL = 400 ppm. LOAEL = 1200 ppm based on behavioural activity
Test result is equivalent to: NOAEL = 310 ppm for the bromide ion
Conclusions:
Result: NOAEL = 400 ppm. LOAEL = 1200 ppm based on behavioural activityTest result is equivalent to: NOAEL = 310 ppm for the bromide ion


Doses of 1200 ppm and above causes statistically significant decreases in body weights during the dosing period and continuing after.The motility in the two highest dose groups rose after the beginning of sodium bromide administration, passed a maximum and developed a plateau. A sudden decrease in motility followed the end of the treatment but the group on the highest dosage did not return to the original level of activity. These motility differences were only statistically significant for the highest two dose regimes.All bromide diets caused a decrease in evasion time, with the highest dosage group showing the most obvious change. All but the lowest dose group reached the range of significance.Only the highest dose group had a significant effect on the behaviour on the treadmill, reducing the number of revolutions observed in a 10 minute period.Multivariate analysis of all 11 variables measured indicate that no significant effects were noted for the 400 ppm dose group while for the 1200ppm dose group significant changes were noted at a small range of time points. Higher dosages gave clear and statistically significant changes in many variables over a larger range of time points, both during and after sodium bromide administration. The effect limit based on behavioural variables and body weight therefore lies between 400 and 1200 ppm NaBr in mice.The effects of the 10800 ppm are not completely reversible but, on the basis of the results of the statistics, this seems to be largely due to the influence of the retardation on body weight.
Endpoint:
neurotoxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
GLP compliance:
no
Species:
rat
Strain:
other: Wistar experimental strain
Sex:
male/female
Route of administration:
other: gavage
Vehicle:
not specified
Frequency of treatment:
Daily

Remarks:
Doses / Concentrations:
0, 40, 80, 120 mg/kg bw/day
Basis:

No. of animals per sex per dose:
127

Control animals:
yes, concurrent no treatment
Details on study design:
Type: other
Observation period: Until pups were aged 85 days

Dose descriptor:
NOAEL
Effect level:
ca. 80 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: based on maze navigation speed
Remarks on result:
other:
Dose descriptor:
LOAEL
Effect level:
ca. 120 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: based on maze navigation speed
Remarks on result:
other:

Result: NOAEL = 80 mg/kg bw/day. LOAEL = 120 mg/kg bw/day (based on maze  navigation speed)
Test result is equivalent to: NOAEL = 62 mg(Br-)/kg bw/day for the bromide ion
Endpoint:
neurotoxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Principles of method if other than guideline:
other
GLP compliance:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
other: Microinfusion
Vehicle:
other: ethanol (0.2 %) and distilled water
Duration of treatment / exposure:
Exposure period: 30 minute(s)

Frequency of treatment:
Single exposure

Remarks:
Doses / Concentrations:
10 µL of 500 mM solution
Basis:

No. of animals per sex per dose:
10
Control animals:
other: control animals were given mock cerebrospinal fluid
Details on study design:
Type: other
Observation period: 1 month

Basis for effect level:
other: see 'Remark'
Remarks on result:
not measured/tested
Remarks:
Effect level not specified

Axons and synapsing terminals were frequently seen in the experimental as in control ganglia. After sodium bromide treatment, plastic changes were seen in dendrites which were similar in their main characteristic to those described for GABA. These consisted mostly of the formation of non-inervated post synaptic thickenings, accumulation of microvesicles and changes in shape of dendrites.

Endpoint:
neurotoxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
GLP compliance:
no
Species:
other: Bullfrog, Rana catesbiana
Strain:
not specified
Sex:
not specified
Route of administration:
other: in vitro study
Vehicle:
other: Ringer's solution.
Remarks:
Doses / Concentrations:
112 mM sodium bromide
Basis:

Control animals:
no
Details on study design:
Type: other

Observations and clinical examinations performed and frequency:
The ganglion was bathed in solution
Basis for effect level:
other: Equimolar replacement of sodium chloride by sodium bromide in Ringer's solution caused hyperpolarization of ganglion cells and antidromically evoked spikes showed increased rates of rise as well as prolonged post spike positivity.
Remarks on result:
not measured/tested
Remarks:
Effect level not specified
Endpoint:
neurotoxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
GLP compliance:
no
Species:
rat
Strain:
other: CFN
Sex:
female
Route of administration:
other: Intraperitoneal injection
Vehicle:
water
Frequency of treatment:
Behavioural studies: administration once daily for 6 weeks
Bromide excretion assessment: once daily for 6 days
Brain chemistry studies: administration once daily for 6 weeks

Remarks:
Doses / Concentrations:
Behavioural studies: 100, 200 or 300 mg Br-/kg in H2O, 1 mL/kg i.p. Bromide excretion assessment: 300 mg Br-/kg in H2O, 1 mL/kg i.p. Brain chemistry studies: 0, 100, 200 or 300 mg Br-/kg in H2O, 1 mL/kg i.p.
Basis:

No. of animals per sex per dose:
21
Control animals:
other: Behavioural studies: control data was obtained from all animals prior to sodium bromide dosing; bromide excretion assessment: None; brain chemistry studies: animals dosed with vehicle only
Details on study design:
Type: other
Observation period: Behavioural studies: 4 weeks
Bromide excretion assessment: 4, 38, 76 and 100 hours
Brain chemistry studies: 24 hours
Dose descriptor:
NOAEL
Effect level:
ca. 129 mg/kg bw/day
Basis for effect level:
other: worst case assumption from behavioural changes
Remarks on result:
other:
Dose descriptor:
LOAEL
Effect level:
ca. 258 mg/kg bw/day
Basis for effect level:
other: worst case assumption from behavioural changes
Remarks on result:
other:

Result: NOAEL = 100 mg Br-/kg bw/day (equivalent to 129 mg NaBr/kg bw/day) LOAEL  = 200 mg Br-/kg bw/day (equivalent to 258 mg NaBr/kg bw/day) (worst case  assumption from behavioural changes).
Endpoint:
neurotoxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
GLP compliance:
no
Species:
mouse
Strain:
other: murine C1300 neuroblastoma cells
Sex:
not specified
Route of administration:
other: in vitro study
Vehicle:
other: Eagle's minimum essential medium supplemented with 10% calf serum
Remarks:
Doses / Concentrations:
0, 10-4, 10-5 or 10-6 M sodium bromide
Basis:

Control animals:
yes, concurrent vehicle
Details on study design:
Type: other

Basis for effect level:
other: see 'Remark'
Remarks on result:
not measured/tested
Remarks:
Effect level not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
80 mg/kg bw/day
Study duration:
subacute
Species:
rat

Effect on neurotoxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Effect on neurotoxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

A neurotoxicologigal screening battery was performed as part of the 90 -day repeat oral dose study (Barton et al 2007) on ammonium bromide. The findings noted during the detailed neurotoxicity examination (included viability, clinical signs, detailed functional observations) consisted of increased limpness, decreased alertness, increases in landing foot splay and decreases in fore and hind limb grip strength. At the low dose (100 mg/kg bw/day) the findings were limited to slight limpness in 3 males; of these, only one showed the finding on more than one occasion. Functional alterations were noted in both sexes at ≥225 mg/kg bw/day. All of these effects had reversed following the 4 week recovery period, except for hind limb grip strength in females at 750 mg/kg bw/day. It was considered that all neurotoxicological effects were probably reversible.

Ammonium 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 ammonium bromide.

Sodium bromide neurotoxicity in the mouse.

Motility was increased and evasion time decreased upon administration of sodium bromide while treadmill activity was decreased. Bodyweight decreases were noted for the highest three dose groups.

Multivariate analysis of all 11 variables measured indicate that no significant effects were noted for the 400 ppm dose group while for the 1200 ppm dose group significant changes were noted at a small range of time points. Higher dosages gave clear and statistically significant changes in many variables over a larger range of time points, both during and after sodium bromide administration. The effect limit based on behavioural variables and body weight therefore lies between 400 and 1200 ppm sodium bromide in mice.

Sodium bromide neurotoxicity in the rat.

The criterion of errors shows a positive relationship between the number of errors and the strength of the bromide-dosage. The criterion of time shows that the 120 mg/kg bw/day group which received the largest dose of bromide was significantly slower than each of the other groups but the other groups did not differ among themselves. All groups reached the same level of performance before the 25thday of the test. The fact suggested that in the maze-test the deleterious effects of the bromide appear in the rate of learning rather than in the performance finally attained.

 LOAEL: 120 mg/kg bw/day - significantly slower navigation of the maze for rats (equivalent to 93.1 mg (Br-)/kg bw/day)

NOAEL: 80 mg/kg bw/day (equivalent to 62.1 mg (Br-) /kg bw/day)

Justification for classification or non-classification

Based on a NOAEL of 80 mg/kg bw/day, Sodium bromide is not classified as neurotoxic.