Ammonium bromide

Endpoint summary

Description of key information

NOAEL=60mg/kg/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

60 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Klimisch 1 according to appropriate OECD testing guidleine and GLP

System:

respiratory system: upper respiratory tract

Organ:

liver

lungs

skin

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

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 short term oral toxicity of ammonium bromide was investigated in rats (90-day toxicity study with neurotoxicity screening battery; 4-week dose range finding study). In addition, short term oral toxicity of sodium bromide was investigated in rats and dogs. The nervous system and the endocrine system were the main target organs in rats. In dogs, the nervous system was the main target organ. In both species, effects on bodyweight growth were noted (reduced bodyweight/bodyweight gain). Gastrointestinal toxicity (bloody stool, vomiting, diarrhea) and skin lesions were other effects noted in dogs.

 

No repeated dose toxicity studies performed with sodium bromide in animals by the dermal and inhalation routes are available. A subchronic dermal toxicity study conducted on sodium bromide is not considered necessary since the potential dermal absorption rate of sodium bromide is expected to be low and the systemic dose is not expected to be higher than the doses used in the available oral 90 day rat study. Nor is a subchronic inhalation toxicity study conducted on sodium bromide considered necessary since sodium bromide is not a volatile substance with a particle size that precludes inhalation.

Ammonium bromide

A 4-week dose-range finding study was performed in rats with ammonium bromide concentrations of 100, 500 and 1000 mg/kg bw/day mixed with the diet. In this study clinical signs were noted in male and female rats at a dose level of 500 mg/kg bw/day and above. The observed clinical signs consisted of agitated, nervous and hyperactive behaviour, subdued behaviour, rolling gait, hunched posture, piloerection and eyes partially closed. To a lesser extent unkempt coat and irregular breathing were noted. Statistically significant reduced body weight gains (males:-49%; females:-31%), reduced food consumption (males: 29%) and increased rel. liver weight (females) were noted in addition in animals of the high dose group (1000 mg/kg bw/day). The NOEL for male and female rats was determined at 100 mg/kg bw/day (corresponding to 82 mg bromide/kg bw/day). The NOAEL for male and female rats was determined at 100 mg/kg bw/day based on clinical signs indicating neurotoxicity and subdued behaviour (both sexes at ≥500 mg/kg bw/day), reduced body weight gain (both sexes at 1000 mg/kg bw/day) and increased liver weight (females at 1000 mg/kg bw/day) (Willerton and Robins, 1999).

 

A 90-day feeding study which included also a neurotoxicity screening battery was performed with ammonium bromide in rats following administration of 100 and 225 mg/kg bw/day in both sexes and500 mg/kg bw/day (males) as well as 750 mg/kg bw/day (females), respectively. Main study and neuropathology animals were treated continuously for at least 13 consecutive weeks. Recovery animals were fed treated diet for 13 weeks, and were then fed untreated diet for a period of at least 4 weeks. Clinical signs of subdued behaviour and neurotoxic effects (abnormalities of gait) were noted during the routine daily clinical examination (in males at ≥225 mg/kg bw/day; in females at 750 mg/kg bw/day). Additional findings included hunched posture, unkempt coat and claws that were longer than normal. The signs generally became apparent after approximately 8 weeks of treatment, and persisted until necropsy (main study animals) or at least the third week of the recovery period. Clinical signs of neurotoxicity were also noted during the detailed neurotoxicity examination (in males at ≥100 mg/kg bw/day; in females at ≥225 mg/kg bw/day). 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. In the absence of histopathological findings it was considered that all neurotoxicological effects were probably reversible. Other effects noted in the study consisted of: reduced bodyweight gain (males at ≥225 mg/kg bw/day; females at 750 mg/kg bw/day), reduced food consumption (males at 500 mg/kg bw/day), minor changes in haematology parameters (males at 500 mg/kg bw/day; females at 750 mg/kg bw/day), minor changes in biochemical parameters (males at ≥225 mg/kg bw/day; females at ≥100 mg/kg bw/day), decreased urine pH (females at 750 mg/kg bw/day) and reduced epididymides weight (males at 500 mg/kg bw/day). No treatment related necropsy or histopathological findings were observed. No NOEL was determined for male and female rats. The NOAEL for female rats was determined at 100 mg/kg bw/day (corresponding to 82 mg bromide/kg bw/day) based on clinical signs of neurotoxicity (noted at ≥225 mg/kg bw/day), clinical signs of subdued behaviour (noted at 750 mg/kg bw/day), reduced bodyweight gain (noted at 750 mg/kg bw/day), changes in haematological parameters (noted at ≥225 mg/kg bw/day), changes in biochemical parameters (noted at 750 mg/kg bw/dag) and decreased pH urine (noted at 750 mg/kg bw/day). No NOAEL was determined for male rats but the NOAEL was considered to be close to the dose level of 100 mg/kg bw/day (Bartonet al., 2000).

 

Sodium bromide supporting data

Observations in a 4-week oral study in female rats (Van Logten M.J.et al., 1973) and a 90-day oral study in male and female rats (Van Logten M.J.et al., 1974) demonstrated that sodium bromide caused behavioural changes, growth reduction, increased thyroid and adrenals weights, and a dose-related disturbance of the endocrine system. The NO(A)EL for rats was 15 mg (Br^-)/kg bw/day from the 90-day oral study. The results of an additional 90-day repeat dose study with sodium bromide (Van Logten M.J.et al., 1976) and a 90-day study with a similar salt, ammonium bromide (Barton S.J.et al., Inveresk Research, Report No. 18612) 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. Repeat dose studies in dogs were performed according to non-standard tests in which animals received 78 rising to 312 mg (Br^-)/kg bw/day for 400 days (Rosenblum I., 1958). Signs of toxicity noted were stated as being comparable with signs noted in human after suffering bromide intoxication. Although no NO(A)EL was determined, the study author states that dogs receiving 78 mg (Br^-)/kg/day showed no mortalities and only minimal signs of toxicity.

Conclusion

The NO(A)EL from sub-chronic toxicity studies is 95 mg/kg bw/day (modified for sodium bromide) from the 90-day oral study with ammonium bromide in rats.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The ion of concern for systemic toxicity is bromide. The study by Barton et al on ammonium bromide gives the lowest reliable NOAEL for bromide salts = 100 mg/kg bw/day. The NOAEL has been extrapolated to NaBr giving a final NOAEL for inorganic bromide salts of 95 mg/kg bw/day.

Justification for classification or non-classification

The substance should not be classified based on NOAEL 60 mg/kgbw/day in 90 day of oral repeated dose exposure.