Bromine

Endpoint summary

Description of key information

The exposure to low doses of bromine vapour (0.2 - 0.5 ppm) induces symptoms of irritation in human subjects after 30 minutes. The reported odour threshold for bromine is 0.01 ppm. A threshold for irritaition of the repiratory tract and eyes of 0.1 ppm has been proposed by SCOEL  for both acute and chronic exposures (Dir. 2006/15/EC). 
All recorded incidental acute exposures to bromine vapour of humans result in varying levels of effect related to irritation/corrosive effects of the respiratory tract. It is notable that after higher inhalation exposures, lung effects with reversible obstruction occurred only after several hours post exposure. In most cases the effects were reversible after several weeks of treatment. However where acute high exposure occurred mortalities occurred. 
The available human data supports the concentration effect data found in animal studies. The available data suggest that the iritation threshold is not dependent on the exposure duration. Recent mechanistic studies using RNA expression techniques  (Price et al., 2008 and 2011, Rogers et al., 2011) support this observation for dermal exposure. 

Additional information

1.      Mode of action considerations

Bromine is a corrosive liquid and forms corrosive vapors. Its corrosive activity is due to its reactivity and oxidizing potential at the site of first contact following hydrolysis to HOBr and HBr. The reactive HOBr or hypobromite ion will react with organic material at the site of first contact and is, together with the acid (HBr, HOBr), responsible for the local effects. In dilute aqueous environments the reaction half- life can be derived from the kinetic constant (k1 = 97 s^-1) (Beckwith et al., 1996) (see CSR chapter 4.1.1.1) of reaction (1) assuming first order kinetics with a surplus of water as ln2/k1 = 0.007 seconds.

Reaction 1

Br₂+ H₂O ---> HOBr + Br^-+ H⁺

Any systemic effects will be due to the bromide ion that is formed in the reaction. The bromide ion will initially be present as hydrogen bromide that can be neutralized at physiological pH to form bromide salts. However, due to its highly corrosive properties, the tolerable exposure concentration of bromine will be driven by the concentration leading to local irritation and corrosion.

2.      Available historical human data

Several publications on accidental exposure of humans to bromine vapors are available in the literature and have been reviewed in chapters 5.2.2, 5.3.1.2, 5.3.2.2, 5.3.3.2, 5.3.4 and 5.10.4 of the CSR.

As bromide salts were historically used in medicine, systemic side effects, such as neurological disturbances ,are also known from human experience. Some publications were reviewed in chapter 5.10.4. For more information on bromide toxicity in humans, we refer to the REACH dossier of sodium, bromide. Key animal studies on sodium bromide have been included in this REACH dossier.

The Data Table below provides the nature and severity of local effects after a human inhalation exposure and the corresponding exposure information

Kind of study	Reported effects	Exposure concentration	Exposure duration	Reference
Report on accidental exposure, general population	99 individuals showed mild symptoms of conjunctivitis, irritation of the upper respiratory tract, coughing,and headache. Symptoms lasted up to 3 days in 20 to 30% of the cases, while one case lasted up to 1 month	0.2 to 0.5 ppm	Maxiumum of 4 h	Morabia et al., 1988
Case report poisoning	Death from accidental bromine vapour inhalation. Burns on 20% of the body, including pulmonary and tracheal damage.	Estimaten > 10 ppm	Unknown	Champeix et al., 1970
Volunteer study, exposure of 20 individuals to randomly varying concentrations for 30 min	Odour threshold: 0.01 ppm. Subjective irritation to eyes and mucous membranes of nose and throat	0.2 ppm (1.3 mg/m3)	30 min	Rupp and Henschler, 1967

The available data suggest an irritation threshold for bromine after inhalation exposure is slightly below 0.2 ppm (1.3 mg/m³) which can lead to mild subjective irritation in humans. From the data of Kelsal and Sim (2001) and Woolf and Shannon (1999), it seems that the dose response is relatively steep with regard to delayed pulmonary irritation effects; once the irritation threshold is reached.

 

3.      Animal data

The limited 4 months inhalation study in rats reported in the literature (Ivanov et al., 1976b) suggests that the NOAEL for irritation of the respiratory tract and olfactory epithelium was 0.16 mg/m³(0.02 ppm) and the LOAEL was 1.4 mg/m³(0.2 ppm).

4.      Consideration of the chemical nature of the substance

Bromine is a halogen and has a very similar mode of action as chlorine with regard to human local effects. This is due to similar reactivity and hydrolysis reaction products of the two halogens, HOCl and HCl for chlorine, and HOBr and HBr for bromine. Therfore we consulted the the EU Risk Assessment Report for chlorine (EU, 2007)as a reference point. For chlorine a threshold for acute inhalation in humans of 0.5 ppm (1.5 mg/m³) was derived based on objective signs of irritation, while some subjective symptoms were still reported at this level. Rats exposed to 0.4 ppm (1.2 mg/m³) of chlorine for 4 h exhibited elevated neutrophils in the lung lavage indicating an inflammatory response. For chlorine, 2 year inhalation studies in rats and mice (6 h/day, 3d/week, for 2 years) at dose levels of 0.4, 1 and 2.5 ppm were performed. No NOAEL could be derived. At the lowest dose level of 0.4 ppm (1.2 mg/m³), inflammation of the nasal olfactory epithelium was observed. However, in monkeys exposed to 0.1, 0.5 and 2.3 ppm 6 h/d, 5d/ week for one year a NOAEL of 0.5 ppm was derived, because at 0.1 and 0.5 ppm no significant changes were observed.

The NOAEL used in the risk characterization for repeated inhalation exposure in humans was based on the human acute data, as the effects appear to be related to the concentration in air and not the duration of exposure. The same approach was taken by SCOEL (1998) in the derivation of the occupational exposure limit for chlorine.

 

5.      Weight of evidence considerations

For the irritation effects of bromine, the mode of action is comparable to that of chlorine. Although data are available on bromine, they have limitations. For chlorine it has been demonstrated that rodents were more sensitive than humans and monkeys with regard to local irritation after inhalation exposure. Furthermore it was concluded for chlorine that the irritation threshold is related to the concentration rather than the exposure duration. The NOAEL and LOAEL values for local irritation derived in a rat study with bromine, are very close to the human acute threshold. This would suggest a similarity to chlorine, and that also for bromine the irritation threshold is related to the concentration and not the exposure duration. This is also corroborated by recent mechanistic studies on skin irritation using RNA expression techniques by Price et. al., 2008, 2011 and Rogers et al., 2011. They demonstrated that exposure of porcine skin to corrosive concentrations of bromine for different durations did not change the genomic response pattern significantly.

Based on this weight of evidence, the available human information can be used to derive a DNEL value for repeated exposure of humans. This approach has also been used by SCOEL to derive an indicative occupational exposure limit for bromine that was published in Directive 2006/15/EC. The 8h IOLEV is 0.7 mg/m³or 0.1 ppm. This is consistent with half of the level that led to slight subjective irritation effects in humans.

 

With regard to systemic effects, due to the rapid reactivity in water (see above), the moiety of concern for systemic toxicity after bromine exposure is the bromide ion. However, due to the irritant and corrosive properties of bromine and the HOBr/OBr reaction products these properties are considered the lead effect and it is unlikely then that at concentrations below the irritation threshold absorbed bromide levels would reach toxic concentrations. For example, the lowest DNEL derived for workers in the registration dossier of sodium bromide corresponds to 3.65 mg/m³of bromide and is considerably higher than the DNEL of 0.7 mg/m³derived for local irritation effects of bromine.

Key studies used for the DNEL derivation of bromide ions were included in this REACH dossier. The DNEL derivation for bromide is included in Annex I of the CSR.