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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

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 including effects on reproduction or development 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. Therefore data on reproductive and developmental toxicity of sodium bromide have been included in this dossier as supporting information for a weight of evidence approach to assess possible reproductive and developmental toxicity of bromine.

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.

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). With an expsoure duration of 6 h/day repiratory volume of 0.0002 m3/min (0.072 m3/6h) for the rat the NOAEL would correspond to a dose of 0.012 mg/day, with a body weight of 250g for the rat this would correspond to 0.046 mg/kg/day and the LOEL to 0.4 mg/kg bw/day.

Data on bromide are summarized below.

Sodium bromide reproductive toxicity in the rat:

No treatment-related effects on the breeding results were observed up to 1200 ppm. Fertility was nil in the 19200 ppm group and was markedly reduced in the 4800 ppm group. These effects were found to be reversible. In the latter group, the viability of the offspring was lower than in the other groups.Microscopic examinations of all pups born during the entire experimental period provided no evidence of anomalies.The lowest LO(A)EL was for female parental toxicity at 1200 ppm sodium bromide in feed (dose related effects on female adrenal weights first become significant at this dose). The NOAEL was 12 mg (Br-)/kg bw/day (300 ppm in feed). 

Due to bromine's highly corrosive properties, the tolerable exposure concentration of bromine will be driven by the concentration leading to local irritation and corrosion and systemic dose levels that would lead to fertility impairment cannot be reached by exposure to bromine.

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. Therefore 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.

4. Technical feasibility

A reproductive toxicity 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).

This maximum attainable dose level is clearly below the NOAEL of for reproductive or systemic effects of bromide.

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 including posible effects on reproduction and dvelopment, 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. This value is also considered to be protective against possible effects to reproduction and development and is higher than the DNEL 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 including developmental toxicity and toxicity to reproduction. Further testing of bromine with regard to these endpoints is therefore not scientifically justified.


Short 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 including effects on reproduction and development, due to the rapid reactivity in water (see above), the moiety of concern for systemic toxicity after bromine exposure is the bromide ion and respective data have been included.
However, 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 for local irritation effects of bromine.This value is also considered to be protective against possible effects to reproduction and development and is higher than the DNEL 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 including developmental toxicity and toxicity to reproduction.

Effects on developmental toxicity

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 including effects on reproduction and development, due to the rapid reactivity in water (see above), the moiety of concern for systemic toxicity after bromine exposure is the bromide ion and respective data have been included.
However, 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 for local irritation effects of bromine.This value is also considered  to be protective against possible effects to reproduction and development and is higher than the DNEL 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 including developmental toxicity and toxicity to reproduction.
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 1Br2+ H2O --> HOBr + Br-+ H+. Any systemic effects including effects on reproduction or development 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. Therefore data on reproductive and developmental toxicity of sodium bromide have been included in this dossier as supporting information for a weight of evidence approach to assess possible developmental toxicity of bromine.

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.

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).

With an expsoure duration of 6 h/day repiratory volume of 0.0002 m3/min (0.072 m3/6h) for the rat the NOAEL would correspond to a dose of 0.012 mg/day, with a body weight of 250g for the rat this would correspond to 0.046 mg/kg/day and the LOEL to 0.4 mg/kg bw/day.

The bromide data are summarized below.

Sodium bromide reproductive toxicity in the rat:No treatment-related effects on the breeding results were observed up to 1200 ppm. Fertility was nil in the 19200 ppm group and was markedly reduced in the 4800 ppm group. These effects were found to be reversible. In the latter group, the viability of the offspring was lower than in the other groups.Microscopic examinations of all pups born during the entire experimental period provided no evidence of anomalies.The lowest LO(A)EL was for female parental toxicity at 1200 ppm sodium bromide in feed (dose related effects on female adrenal weights first become significant at this dose).NOAEL is 12 mg (Br-)/kg bw/day (300 ppm in feed). 

Sodium bromide developmental toxicity in the rat:

Maternal toxic effects:Treatment at 1000 mg/kg bw/day was associated with unsteady gait, feet falling through cage grid floor, poorly coordinated movements, reduced bodytone and hair loss. There was one mortality at this dose level. Lower bodyweight gains were observed during days 6 to 12 and 16 to 20 of pregnancy. Increased food consumption was observed during days 6-9 and 14-15, followed by lower food consumption during days 18-19.Treatment at 300 mg/kg bw/day was associated with lower bodyweight gains during days 16-20 of pregnancy.Treatment at 100 mg/kg bw/day was not associated with any observable maternal responses.Embryotoxic effects:

There were no adverse effects on any of the litter parameters recorded for any of the dose groups.

Detailed examination of foetal morphology from dams treated at 1000 mg/kg bw/day revealed higher incidences of foetuses/litters showing absent left kidney, absent left ureter, absent/narrow left uterine horn, distorted ribs, shortened/absent 13thribs, irregular ossification of the thoracic vertebral centra, reduced and/or unossified sternebrae and reduced ossification of one or more cranial centres than in controls.

In the 300 mg/kg bw/day dose group, detailed examination of the foetal morphology revealed a higher incidence of foetuses showing reduced ossification of various components of the skeleton compared with controls.

Treatment at 100 mg/kg bw/day was not associated with any observable adverse effects on or in utero development of the conceptus.

A LOAEL: 300 mg/kg bw/day based reduced body weight gains in dams and foetal skeletal anomalies and variants (equivalent to 233 mg (Br-)/kg bw/day) and a NOAEL: 100 mg/kg bw/day (equivalent to 77.6 mg (Br-) /kg bw/day) was derived from this study.

Due to bromine's highly corrosive properties, the tolerable exposure concentration of bromine will be driven by the concentration leading to local irritation and corrosion and systemic dose levels that would lead to developmental cannot be reached by exposure to bromine.

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. Therefore 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. Technical feasibility

A developmental toxicity 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).

This maximum attainable dose level is clearly blow the NOAEL or LOAEL for developmental toxicity of bromide.

6.      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 including posible effects on reproduction and development, 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. This value is also considered to be protective against possible effects to reproduction and development and is higher than the DNEL 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 including developmental toxicity and toxicity to reproduction. Further testing of bromine with regard to these endpoints is therefore not scientifically justified.

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 symbol C, R35 (causes severe burns) and very toxic by inhalation (T +, R26). Human data from accidental exposure (Section 8.6.4; oral, dermal and inhalation exposure) indicate that primary toxic effects from exposure, i.e. local irritation and corrosion will occur at levels below which secondary effects on development and reproductive effects could occur. Therefore no classification for other than the corrosive and acute effects die to the corrosive nature of the substance is regarded appropriate.

Additional information