Bromine

Endpoint summary

Description of key information

Bromine is a highly reactive substance which is well known to cause burns to skin and eyes. It is classified/labelled with the symbols "C" (corrosive) and "T+" (very toxic), as well as the risk phrases "R35" (causes severe burns) and "R26" (very toxic by inhalation).   There is sufficient human data available to indicate an appropriate level for hazard identification for the main route of possible exposure, inhalation. The available data has been used for indication of an EU Indicative Occupational Exposure Level value (IOELV) given in Directive 2006/15/EC (8hr IOELV = 0.7 mg/m3 or 0.1 ppm). ECHA Guidance states that an EU IOELV can be used in place of a derived DNEL. Additional routes of exposure (i.e. oral or dermal) are not considered as appropriate routes for determination of repeat dose toxicity. 
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. 
Therefore sodium and ammonium bromide data on repeated dose toxicity were included in this dossier as supporting information for the weight of evidence approach. The relevant NOAEL for repeated dose toxicity was from a 90-day oral study in rats was 95 mg/kg bw/day. Such internal doses could never be reached by exposure to Bromine because of its corrosive properties.
Due to the irritant and corrosive properties of bromine and the HOBr/OBr reaction products these properties are considered the lead effect.  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/m3 of bromide and is considerably higher than the DNEL of 0.7 mg/m3derived forlocal irritation effects of bromine.

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

1.4 mg/m³

Species:

other: human

Quality of whole database:

Weight of evidence approach.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

1.4 mg/m³

Species:

other: human

Quality of whole database:

The assessment is based on human data and a weight of evidence approach.

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. Exposure considerations

Bromine is only used as intermediate for chemical synthesis or modification of polymers in the chemical industry. Exposure to the general public does not normally occur, except under accidental circumstances. Relevant routes of exposure are, therefore, confined to the dermal and inhalation route.

3. Technical feasibility

A repeated dose study via the oral route is difficult to perform. Bromine cannot be dosed in the diet or drinking water, as it will react with components of the diet and almost instantly hydrolyze in diluted water (see above). Any gavage dosing will have to be made with concentrations close to the irritation limit to avoid corrosion of the mucous membranes. Starting with the concentration that led to slight dermal irritation in humans at 4 mg/L (Kelsall and Sim, 2001) will likely be too high for the more sensitive mucous membranes of the gastro-intestinal tract. The maximum volume that can be administered by gavage to a rat is 1 ml/100g bw in a non-aqueous vehicle or 2 ml/100g bw in water. (e. g. OECD TG 414) With a body weight of ca. 250 g this would limit the dose that can be administered to 20 µg/day (80 µg/kg bw/day in an aqueous solution (i. e. dosing the degradation products) or 10 µg/day (40 µg/kg bw/day) in a non-aqueous vehicle).

Data from repeated dose studies of sodium and ammonium bromide can be summarized as follows:

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 effect on thyroid hormone levels. 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 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.

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

This clearly shows that the maximum dose levels of bromine that can be given to animals without causing local corrosivity are likely to be too low to exert any systemic effect. The only other route of exposure that could be explored is the inhalation route. However, the exposure concentration is equally limited by the local corrosive and irritation effects of bromine and systemic bromide concentrations are to low to reach bomide effect levels.

4. 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.

The Data Table attached 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.

5. 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).

6. 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.

7. 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/m3 or 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/m3 of bromide (see appendix 1 of the CSR in this dossier) and is considerably higher than the DNEL of 0.7 mg/m3 derived for local irritation effects of bromine.

It is therefore concluded that the DNEL derived based on local effects, precludes exposure to concentrations that would lead to any bromide related systemic toxicity.

Further testing of bromine with regard to these endpoints is therefore scientifically not justified.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The evaluation is based on human data and the corrosive and irritant effect of the substance.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
The evaluation is based on human data and the corrosive and irritant effect of the substance.

Justification for classification or non-classification

Bromine is a highly reactive substance which is well known to cause burns to skin and eyes. It is classified/labelled with the symbols “C” (corrosive) and “T+”(very toxic), as well as the risk phrases “R35” (causes severe burns) and “R26” (very toxic by inhalation). as corrosivity is the lead effect, the current classification correctly covers the hazardous properties of bromine.