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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
1
Bromine1
Acute Exposure Guideline Levels
PREFACE
Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.
AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs have been defined as follows:
AEGL-1 is the airborne concentration (expressed as parts per million [ppm] or milligrams per cubic meter [mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory
1
This document was prepared by the AEGL Development Team composed of Sylvia Talmage (Oak Ridge National Laboratory) and Chemical Manager Ernest Falke (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guideline reports (NRC 1993, 2001).
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.
AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects, or an impaired ability to escape.
AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening health effects or death.
Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsensory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGLs represent threshold levels for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL.
SUMMARY
The halogen bromine (Br2) is a dark reddish-brown volatile liquid at room temperature. Its oxidizing potential lies between that of chlorine and iodine. Bromine is used as a water disinfectant, for bleaching fibers, and in the manufacture of medicinal bromine compounds, dyestuffs, flame retardants, agricultural chemicals, inorganic bromide drilling fluids, and gasoline additives.
Bromine is a skin, eye, and respiratory-tract irritant. Inhalation causes respiratory-tract irritation and pulmonary edema. Although accidental human exposures have occurred, concentrations were either not reported or were judged unreliable. The data on the inhalation toxicity of bromine are sparse and, at times, conflicting. Aside from old and anecdotal information, the database is limited to one study with human subjects and two lethality studies with the mouse as the test species. One of the lethality studies (Bitron and Aharonson 1978) provided data sufficient for derivation of the relationship between concentrations that result in lethality (LC50 values [concentration with 50% lethality]) and exposure duration: C2.2 × t = k (chemical concentration in air with a chemical-specific exponent applied to a specific end point × exposure time = response).
The AEGL-1 was based on exposures of 20 healthy human subjects to concentrations of 0.1 to 1.0 ppm for at least 30 min (Rupp and Henschler 1967). Eye irritation, but not nose or throat irritation, occurred during a 30-min exposure at 0.1 ppm. At concentrations of ≥0.5 ppm, there was a stinging and burning sensation of the conjunctiva. The 30-min exposure to 0.1 ppm, which caused
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mild irritation, was chosen as the basis for the AEGL-1. The 0.1-ppm concentration was divided by an intraspecies uncertainty factor of 3 to protect susceptible individuals. An intraspecies uncertainty factor of 3 was considered sufficient because workers have been occupationally exposed to 1 ppm with no symptoms other than “excess irritation” (Elkins 1959). The resulting 0.033-ppm concentration is 30-fold lower than the 1-ppm concentration that induced excess irritation in healthy workers. Effects at this low concentration appear to be limited to the eyes and upper respiratory tract; there is likely to be little penetration to the lower respiratory tract. Compared with the 0.5-ppm AEGL-1 concentration for chlorine, a chemical that more readily penetrates to the lower respiratory tract, the intraspecies uncertainty factor of 3 for bromine is considered adequate. An intraspecies uncertainty factor of 1 was applied to the 0.5-ppm test value for chlorine because this concentration failed to elicit an asthmatic response in atopic and asthmatic individuals. The resulting 30-min AEGL-1 value of 0.033 ppm was used for all AEGL-1 exposure durations, as adaptation to mild sensory irritation occurs.
The AEGL-2 was based on the exposure to approximately 1 ppm for 30 min, which the subjects in the above study (Rupp and Henschler 1967) found irritating (stinging and burning sensation of the conjunctiva and nose and throat irritation). The 30-min 1-ppm value was divided by an intraspecies uncertainty factor of 3 to protect susceptible individuals and time-scaled to the other AEGL-2 exposure durations by using the concentration-exposure duration relationship of C2.2 × t = k from the mouse lethality study. An intraspecies uncertainty factor of 3 was considered sufficient, as the symptoms may be below those defining the AEGL-2. Furthermore, compared with the 30-min AEGL-2 value of 2.8 ppm for chlorine, this value may be conservative. The 30-min value for the less well-scrubbed chlorine was based on transient changes in pulmonary parameters (without respiratory symptoms) in asthmatic and atopic individuals. No reliable studies with exposures to higher concentrations were located.
Both lethality studies with the mouse described the inhalation toxicity of both chlorine and bromine. However, both studies reported lower LC50 values for chlorine than those reported in more recent well-conducted studies. Nevertheless, the study that reported the lower lethal concentrations for chlorine was used for derivation of the AEGL-3 values for bromine (Schlagbauer and Henschler 1967). The data in this study showed a clear concentration-response relationship; the exposure duration was 30 min. Using probit analysis, a 30-min LC50 value of 204 ppm and a 30-min LC01 of 116 ppm were calculated. The 30-min LC01 of 116 ppm was used as the basis for calculation of AEGL-3 values. The 116-ppm LC01 was divided by a combined uncertainty factor of 10 (3 for interspecies differences [the mouse was the most sensitive species for lethal effects in tests with other halogens] and 3 for intraspecies differences [at high concentrations, bromine is corrosive to the mucous membranes of the respiratory system; effects are not expected to differ greatly among individuals]) and
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scaled across time using the relationship C2.2 × t = k, derived from the Bitron and Aharonson (1978) study.
The calculated values are shown in Table 1-1.
1.
INTRODUCTION
Bromine, a halogen, is a dark reddish-brown volatile liquid that vaporizes readily to a red vapor at room temperature. The diatomic state persists in the liquid, gas, and solid phases. Chemically, the electronegativity and oxidizing potential of halogens decrease as the atomic weight increases, thus making bromine intermediate in oxidizing potential between chlorine and iodine. All the halogens form an acid in water, and the reactivity of these acids shows the same relationship as the elemental halogens. The water solubility of bromine is greater than that of chlorine (O’Neil et al. 2001; Teitelbaum 2001). Additional chemical and physical properties are listed in Table 1-2.
The uses of bromine include water disinfection, bleaching fibers and silk, and the manufacture of medicinal bromine compounds and dyestuffs (O’Neil et al. 2001). The global market for bromine-containing compounds includes flame retardants, agricultural chemicals (principally methyl bromide), inorganic bromide drilling fluids such as calcium bromide, and gasoline additives (Glauser 2009). Production of ethylene dibromide, a gasoline antiknock agent for leaded fuels has decreased substantially over the past years. Likewise, the use of brominated fumigants and pesticides, such as ethylene dibromide and methyl bromide, has been restricted in the United States (Teitelbaum 2001). Commercially, bromine is recovered from soluble bromide salts in salt lakes, inland seas, brine wells and seawater. Seawater contains bromine at a concentration of 65 ppm (Teitelbaum 2001).
In 2005, world production was estimated at 587,000 metric tons, most of the bromine being used for brominated flame retardants ((Glauser 2009). Several production plants are located near natural brine sites in Arkansas (Jackisch 1992). Bromine is shipped in bulk quantities in 7,570-liter (L) and 15,140-L lead-lined pressure tank cars or 6,435- to 6,813-L nickel-clad pressure tank trailers filled to at least 92% capacity (Jackisch 1992). Bromine is also shipped in 600-, 1,200-, and 1,800-gallon tank trucks and 2,300- and 4,400-gallon tank cars (Great Lakes Chemical Corporation 1996).
Bromine is a skin, eye, and respiratory tract irritant (Teitelbaum 2001). All of the exposure data on humans and many of the experimental data on animals are extremely old, provide few experimental details, or conflict with more recent information. Therefore, many of the data are considered unreliable. Two inhalation studies with the mouse as the test species and using several concentrations and exposure durations were located. However, both of these studies report values for chlorine that are much lower than those of other researchers.
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TABLE 1-1 Summary of AEGL Values for Bromine
Classification
10 min
30 min
1 h
4 h
8 h
End Point (Reference)
AEGL-1 (Nondisabling)
0.033 ppm (0.22 mg/m3)
0.033 ppm (0.22 mg/m3)
0.033 ppm (0.22 mg/m3)
0.033 ppm (0.22 mg/m3)
0.033 ppm (0.22 mg/m3)
Eye irritation in humans (Rupp and Henschler 1967)
AEGL-2 (Disabling)
0.55 ppm (3.6 mg/m3)
0.33 ppm (2.2 mg/m3)
0.24 ppm (1.6 mg/m3)
0.13 ppm (0.85 mg/m3)
0.095 ppm (0.62 mg/m3)
Conjunctiva and nose and throat irritation in humans (Rupp and Henschler 1967)
AEGL-3 (Lethal)
19 ppm (124 mg/m3)
12 ppm (78 mg/m3)
8.5 ppm (55 mg/m3)
4.5 ppm (29 mg/m3)
3.3 ppm (21 mg/m3)
30 min LC01 in mice (Schlagbauer and Henschler 1967)
TABLE 1-2 Chemical and Physical Data for Bromine
Parameter
Data
Reference
Synonyms
Dibromine
HSDB 2008
CAS registry number
7726-95-6
O’Neil et al. 2001
Chemical formula
Br2
O’Neil et al. 2001
Structure
Br-Br
O’Neil et al. 2001
Molecular weight
159.9 (Br2)
O’Neil et al. 2001
Physical state
Dark, reddish-brown fuming liquid, vaporizes rapidly at room temperature
O’Neil et al. 2001
Melting and boiling point
−7.25ºC/59.47ºC
O’Neil et al. 2001
Solubility
17 g/L in water at 20ºC
Teitelbaum 2001
Vapor pressure
175 mmHg at 20ºC
AIHA 2001
Vapor density (air = 1)
3.5
AIHA 2001
Liquid density (water = 1)
3.1
O’Neil et al. 2001
Flammability
Not flammable; may cause fire on contact with combustibles
DOT 1985
Conversion factors (Br2)
1 ppm = 6.5 mg/m3
1 mg/m3 = 0.15 ppm
AIHA 2001
2.
HUMAN TOXICITY DATA
2.1.
Acute Lethality
Champeix et al. (1970) described the case of a worker exposed to an unknown concentration of vapor during an industrial accident. A postmortem examination revealed bromine burns to 20% of the body, extensive pulmonary and
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tracheal damage, and effects on the kidneys and liver. In another industrial accident, eight workers were exposed to an unknown concentration of bromine vapor (Suntych 1953). Three workers developed bronchopneumonia, one developed blepharospasm, and the remainder developed laryngitis. One worker died as the result of sudden circulatory failure associated with bronchopneumonia.
Carel et al. (1992) reported a transportation accident involving a semi-trailer truck carrying liquid bromine on an isolated stretch of highway in the Negev Desert, Israel. The driver was pinned in the cabin of the truck and was unable to free himself or reach his protective equipment. He died of bromine intoxication 3 h after the accident occurred.
Using primarily the database on chlorine, the relationship between the toxicity of chlorine and bromine, and the relationship between concentration and time from animal lethality data, Withers and Lees (1986) calculated an LC50 for humans exposed to bromine. Their model incorporates the effects of physical activity, inhalation rate, the effectiveness of medical treatment, and the lethal toxic load function (the relationship between lethality, concentration, and time). Concentrations were based on the estimate that bromine is 1.5 times less toxic than chlorine. The estimated 30-min LC50 at a standard level of activity (inhalation rate of 12 L/min) for the regular, vulnerable, and average (regular + vulnerable) populations were 375, 150, and 315 ppm, respectively. Estimated LC10 values for a 10-min exposure were 325, 130, and 208 ppm, respectively.
2.2.
Nonlethal Toxicity
2.2.1.
Odor Threshold
The odor threshold for bromine has been variously reported at approximately 0.01 to 3.8 ppm (Rupp and Henschler 1967; Billings and Jonas 1981; Amoore and Hautala 1983; Ruth 1986). Ruth (1986) reported the threshold for irritation at 0.3 ppm, but the source of the data was not stated. Rupp and Henschler (1967) reported that healthy subjects had difficulty distinguishing between the odor of chlorine and the odor of bromine at concentrations up to 1 ppm, the highest concentration tested. The odor has been reported as suffocating by O’Neil et al. (2001) and bleachy and penetrating by Ruth (1986).
2.2.2.
General Toxic Effects
The signs and symptoms associated with human exposure to low concentrations include upper airways irritation, inflammation of the eyelids, lacrimation, coughing, nosebleed, and a feeling of oppression, dizziness, and headache (Flury and Zernik 1931; Alexandrov 1983; Teitelbaum 2001). After several hours these symptoms may be followed by abdominal pain and diarrhea and a measles-like eruption on the trunk and extremities. Inhalation of “larger quantities” results in brown coloration of the eyes, tongue, and mucous membranes of
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the mouth, catarrh, salivation, coughing, feeling of suffocation, glottis cramps, hoarseness, bronchitis, and bronchial asthma (Flury and Zernik 1931). Bromine was reported to produce a stinging and burning sensation of the conjunctiva at exposures of ≥0.5 ppm (Rupp and Henschler 1967). Chronic exposure to bromine resulting in excessive tissue levels of bromide ions (bromism) may lead to slowing of cerebration, impaired memory, anorexia, skin rash, headache, slurring of speech, confusion, weakness, disturbed reflexes, drowsiness, and mild conjunctivitis (EPA 1988).
Irritant levels for bromine have been reported in several sources. Many of the data are extremely old and are compromised by inadequate descriptions of vapor-generation methods, analytic-measurement methods, and exposure durations. These data and reviews are cited here for completeness.
Henderson and Haggard (1943), relying on older data including Matt (1889) and Flury and Zernik (1931) who cite Lehmann (1887), stated that 40-60 ppm is dangerous for brief exposures, 4 ppm is the maximum concentration that can be tolerated for 0.5 to 1 h, and 0.1 to 0.15 ppm can be tolerated for prolonged periods of time. Flury and Zernik (1931) and Withers and Lees (1986) cited the data of Matt (1889) who exposed human volunteers to bromine vapor (bromine was poured into a room) for 16 min to 7.67 h. Under this exposure scenario, Matt (1889) stated that 1-2 ppm could be tolerated by workers indefinitely, 3.5 ppm is tolerable for 30 min to 1 h, and 4 ppm is intolerable for work conditions.
Workers regularly exposed to bromine concentrations at approximately 0.3 to 0.6 ppm for 1 year experienced headache; pain in the joints, stomach, and chest; irritability; and loss of appetite (Alexandrov 1983). Long-term exposure can lead to nervous system disorders, myocardial degeneration, and thyroid hyperplasia. The source of the Alexandrov (1983) data was not given. Elkins (1959), citing a personal communication, reported that 1 ppm in a Massachusetts plant handling liquid bromine was judged to be excessively irritating. Flury and Zernik (1931) cited the data of Lehmann (1887) who reported that exposure to 0.75 ppm in a workroom caused no symptoms in 6 h. OSHA (unpublished material, 1997) monitoring data taken from January 1, 1985, to January 1, 1997, and involving 22 samples from 10 area offices, showed that workers are currently exposed to concentrations between 0.00 and 0.18 ppm. “Total times” for the 0.18-ppm exposures ranged from 15 min to 7.5 h.
2.2.3.
Clinical Study
In a clinical study, Rupp and Henschler (1967) determined the odor threshold and subjective irritation concentrations of both chlorine and bromine. These authors subjected 20 healthy students to “low concentrations” of bromine or chlorine in an 8 m3 exposure chamber. Bromine gas was generated directly from a heated 2-L flask containing 50 mL of the liquid; dilutions were made
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with fresh air. Analytic determinations were made titrimetrically with thiosulfate solution (higher concentrations) or spectrophotometrically (concentrations below 0.1 ppm). Samples were collected in potassium iodide solution (higher concentrations) or by absorption by o-toluidine hydrochloride (lower concentrations). The odor threshold for bromine was tested at concentrations of 0.01, 0.02, 0.05, 0.1, 0.2, 0.5, and 1.0 ppm over a 30-min duration. Odor intensity was evaluated with the descriptors: minimal, medium strong, strong, and very strong. Subjective eye, nose, and throat irritation was evaluated as concentrations increased from 0 to 0.9 ppm over a 1-h duration.
A total of 20 students were tested, with 3-4 entering the exposure chamber at one time. Upon chamber entry, odor of bromine was noted by all 20 individuals at a concentration of 0.01 ppm, with an intensity of minimal to medium strong. At 0.2 ppm, most subjects rated odor intensity between medium strong and very strong. In the second part of the study, the subjects recorded their irritation every 5 min over a 60-min period. Eye irritation was first noted at a bromine concentration of 0.1 ppm and occurred within the first 30 min of exposure. At concentrations of 0.2 ppm and higher, distinct nose, eye, and throat irritation occurred, with a rapidly increasing concentration response. Between 0.5 and 0.9 ppm, a 5-min exposure was perceived as uncomfortable (concentrations of 0.5 to 0.9 ppm were irritating to the conjunctiva, nose, and throat.); however, the intensity of effect did not increase above 0.5 ppm. Irritation appeared to be limited to the eyes, nose, and throat; a “compelling cough stimulus” was not attained at concentrations up to 0.9 ppm. At similar concentrations, bromine was found to be more irritating than chlorine. In evaluating their own experiment, the authors noted that the actual concentrations were approximately 40% (range 17-57%) less than the nominal concentrations reported above. Measurements were taken in the vicinity of a wall and not in the immediate area of the subjects. In evaluating the experimental results, Henschler considered the threshold for subjective discomfort to be 0.5 ppm (D. Henschler, Institut for Toxicology, Wurzburg, Germany, personal commun., Dec. 21, 1999).
In the same study, Rupp and Henschler (1967) reported sensory irritation for chlorine at concentrations that proved to be nonirritating in later well-conducted studies (reviewed in 54 Fed. Reg. 2455[1989]). For example, Rupp and Henschler (1967) reported conjunctival pain in several subjects after 15 min of exposure to chlorine at 0.5 ppm, whereas, in a study by Rotman et al. (1983), healthy subjects reported no serious subjective symptoms of irritation from chlorine at a concentration of 1 ppm for 8 h. The lack of controls in the Rupp and Henschler (1967) study as well some methodologic shortcomings in the chlorine part of the study are discussed by OSHA (54 Fed. Reg. 2455 [1989]). The more recent studies of odor thresholds reported higher concentrations than those reported in the Rupp and Henschler (1967) study. It should also be noted that concentration and exposure-duration data reported in the text and figures of the Rupp and Henschler study are conflicting.
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2.2.4.
Accidents
On the morning of November 8, 1984, an accident at a chemical plant in Geneva, Switzerland, resulted in the release of 550 kg of liquid bromine (Morabia et al. 1988). Bromine in gaseous form was released via the ventilation system with sufficient force to form a dense brown cloud that drifted into the neighborhood. The cloud remained low over the ground and drifted through the center of the town before reaching Lake Geneva where it dissipated. The time elapsed from the release to disappearance of the cloud over the lake was approximately 5 h. An ozone analyzer located at the Ecotoxicological Centre of the Canton of Geneva (location not given) detected an oxidizing substance between 10 and 12 o’clock that morning. At an undefined time, the centre measured bromine concentrations (Draeger tubes equipped with chlorine reactive tubes) to define the outside limits of the potentially contaminated zone. These concentrations were between 0.2 and 0.5 ppm; concentrations were not measured initially or in the vicinity of the plant.
Ninety-one patients were admitted to the casualty, outpatient, and ophthalmology departments of the University Hospital at Geneva (Morabia et al. 1988). These patients reported signs and symptoms of eye irritation (90%), upper airways irritation (68%), cough (47%), expectoration (34%), and headache (46%). One patient, a worker at the plant, was treated for severe acute bronchitis; following hydrocortisone treatment, he rapidly recovered and was discharged the next day. In the remainder of the patients, symptoms were considered moderate and self-limiting. A 1-month follow-up of 62 of the patients indicated that there were no serious late complications.
Following the transportation accident described by Carel et al. (1990, 1992) in Section 2.1 above, several motorists were exposed to bromine vapor when they stopped to assist the driver of the truck. These exposures produced only mild respiratory symptoms and first and second degree burns to exposed areas of the skin. Four persons were treated with steroids because of shortness of breath; one, a heavy smoker, had diffuse lung wheezes. Six to eight weeks after the accident, four of the exposed motorists complained of cough, shortness of breath, chest tightness, eye irritation, headache, dizziness, fatigue, memory disturbances, and sleep and sexual disturbances. Clinical and laboratory examinations, however, revealed no abnormal findings.
2.3.
Developmental and Reproductive Effects
No data concerning developmental and reproductive effects of bromine exposure in humans by the inhalation route were identified in the available literature. Chronic bromism has been associated with two cases of developmental problems (EPA 1988). The bromism was a result of ingestion of bromide salts.
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2.4.
Genotoxicity
No data concerning the genotoxicity of bromine in humans were identified in the available literature.
2.5.
Carcinogenicity
No data concerning the carcinogenicity of bromine in humans were identified in the available literature.
2.6.
Summary
No inhalation studies on the developmental and reproductive toxicity, genotoxicity, or carcinogenicity of bromine in humans were located in the available literature. Human exposures may cause eye, skin, and mucous membrane irritation as well as headache, abdominal pain, and dyspnea (Teitelbaum 2001). Incidences of human exposures were found, but few clear concentration-exposure durations were reported. Some of these data indicate that concentrations of ≤1.0 ppm are irritating (Elkins 1959; Rupp and Henschler 1967; Alexandrov 1983; Ruth 1986). Other data are quoted from secondary and tertiary sources. A study using human subjects reported eye irritation at a concentration of 0.1 ppm and additional sensory irritation at concentrations of ≥0.2 ppm (Rupp and Henschler 1967). The results of parts of this study do not agree with data or statements of other, more recent investigators (Rotman et al. 1983; Ruth 1986; 54 Fed. Reg. 2455 [1989]).
3.
ANIMAL TOXICITY DATA
3.1.
Acute Lethality
Several recent sources cited the data of Flury and Zernik (1931), who cited the data of Lehmann (1887). These data are so old that they should be considered unreliable but are reported here for completeness. Lehmann (1887) reported that inhalation exposure of three animal species at 180 ppm (duration not reported) caused severe irritation and corneal clouding, the 7-h LC10 was 140 ppm for both the cat and guinea pig, and exposure at 300 ppm for 3 h caused deaths in rabbits and guinea pigs. Observations at the latter concentration-exposure time revealed pulmonary edema, deposits on the trachea and bronchi, and gastric hemorrhage.
Henderson and Haggard (1943) reported that a concentration of 1,000 ppm is rapidly fatal. Their source of data appears to be Hill (1915) who experimented with guinea pigs. The original data were not located.
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3.1.1.
Rats
Ivanov et al. (1976) reported an LC50 of 415 ppm for the rat. Neither the exposure time nor the original citation were stated.
3.1.2.
Mice
Ivanov et al. (1976) reported an LC50 of 4,46 ppm for the mouse. Neither the exposure time nor the original citation was stated.
Two other acute lethality studies, both using the mouse as the test species, provided details of the exposures. Bitron and Aharonson (1978) exposed 1-month-old male albino mice (28 to 126 mice/group) to concentrations of 240 or 750 ppm for four exposure times at each concentration and calculated 50% mortality as a function of exposure time (median lethal exposure time, or Lt50). Bromine vapor was generated from the liquid, collected in an aqueous solution of potassium iodide, and determined by standard iodometry. Mice were restrained in cylindrical glass exposure chambers. Postexposure observations were made over a 30-day period. The data displayed a clear dose-response relationship and Lt50 values for the 240 and 750 ppm exposures were 100 and 9 min, respectively. Mortality at each concentration-exposure duration is listed in Table 1-3. Dose-response curves were presented graphically, and the values listed in Table 1-3 were estimated from the graph. The results of this work were unusual in that many of the deaths were delayed, occurring during the second week of the observation period, rather than during and immediately following exposure. The authors exposed similar groups to chlorine, and it was noted that chlorine is considerably more toxic to mice than bromine.
Using the method of Litchfield and Wilcoxon (1949), Bitron and Aharonson (1978) also computed 0 or 100% mortalities, which they presented graphically. For the 240-ppm concentration, no deaths were calculated to occur following an exposure for 20 min. For the 750-ppm concentration, no deaths were calculated to occur following approximately 5 min of exposure (same as the experimental value).
TABLE 1-3 Mortality in Mice Exposed to Bromine at 240 or 750 ppm
Concentration (ppm)
Exposure Duration (min)
Mortality (%)
240
24
7
65
27
120
50
215
90
750
5
0
7
44
13
73
24
95
Source: Bitron and Aharonson 1978. Reprinted with permission; copyright 1978, American Industrial Hygiene Association.
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escape within 30 min would be possible without any escape-impairing symptoms or any irreversible health effects.
cREL-TWA (recommended exposure limits–time-weighted average, National Institute for Occupational Safety and Health ) (NIOSH 2005) is analogous to the ACGIH TLV-TWA.
dPEL-TWA (permissible exposure limits–time-weighted average, Occupational Safety and Health Administration, OSHA) (29 CFR 1910.1000 [2003]) is analogous to the ACGIH TLV-TWA but is for exposures of no more than 10 h/d, 40 h/wk.
eTLV-TWA (Threshold Limit Value–time-weighted average, American Conference of Governmental Industrial Hygienists) (ACGIH 1996) is the time-weighted average concentration for a normal 8-h workday and a 40-h workweek to which nearly all workers may be repeatedly exposed, day after day, without adverse effect.
fREL-STEL (recommended exposure limits–short-term exposure limit, National Institute for Occupational Safety and Health) (NIOSH 2005) is analogous to the ACGIH TLV-TWA.
gTLV-STEL (Threshold Limit Value–short-term exposure limit, American Conference of Governmental Industrial Hygienists) (ACGIH 1996) is defined as a 15-min TWA exposure that should not be exceeded at any time during the workday even if the 8-h TWA is within the TLV-TWA. Exposures above the TLV-TWA up to the STEL should not be longer than 15 min and should not occur more than four times per day. There should be at least 60 min between successive exposures in this range.
hMAK (maximale argeitsplatzkonzentration [maximum workplace concentration], Deutsche Forschungsgemeinschaft [German Research Association]) (DFG 2007) is analogous to the ACGIH TLV-TWA. The MAK for bromine was withdrawn in 2007, and bromine was placed in category IIB, substances for which no MAK value can be established at present.
iMAC (maximaal aanvaarde concentratie [maximum accepted concentration], SDU Uitgevers [under the auspices of the Ministry of Social Affairs and Employment, The Hague, The Netherlands]) is analogous to the ACGIH TLV-TWA (MSZW 2004).
8.3.
Data Adequacy and Research Needs
The data on the toxic effects of bromine are sparse. Because of the sparse-data, lower values were chosen for the AEGL-1 and AEGL-2 than might have been used in the presence of extensive data. No recent reliable human studies were available. Some of the studies that are quoted and requoted in toxicology books were performed as early as the 1880s; vapor generation and analytic techniques have improved since that time. The clinical study by Rupp and Henschler (1967) tested both bromine and chlorine and reported irritant values for chlorine that are lower than those in other studies. The values for bromine may be correspondingly low. Two lethality studies with the mouse as the test species were available for calculation of the AEGL-3 values. Both the key study, Schlagbauer and Henschler (1967), and the study by Bitron and Aharonson (1978) were noted to have lower lethality values for chlorine than those of many other investigators, and their values for bromine may be correspondingly low. Although bromine is less toxic than chlorine, the interim AEGL-3 values for bromine are less than those for chlorine (NRC 2004).
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In the absence of reliable studies that address the end point of irritation, a study to determine the exposure concentration producing a 50% decrease in the respiratory rate (RD50) in the mouse would be of value, particularly as it would confirm the irritation potential of bromine relative to that of chlorine.
9.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 1996. Supplements to the Sixth Edition Documentation of the Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs). American Conference of Governmental Industrial Hygienists, Cincinnati, OH.
AIHA (American Industrial Hygiene Association). 2001. The AIHA 2001 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides. Fairfax, VA: AIHA Press.
Alexandrov, D.D. 1983. Bromine and compounds. Pp. 326-329 in Encyclopaedia of Occupational Health and Safety, 3rd. Ed, Vol.1, L. Parmeggiani, ed. Geneva: International Labour Organization.
Amoore, J.E., and E. Hautala. 1983. Odor as an aid to chemical safety: Odor thresholds compared with Threshold Limit Values and volatilities for 214 industrial chemicals in air and water dilution. J. Appl. Toxicol. 3(6):272-290.
Anglen, D.M. 1981. Sensory response of human subjects to chlorine in air. Ph.D. Dissertation, University of Michigan, Ann Arbor, MI.
Billings, C.E., and L.C. Jonas. 1981. Odor thresholds in air as compared to Threshold Limit Values. Am. Ind. Hyg. Assoc. J. 42:479-480.
Bitron, M.D., and E.F. Aharonson. 1978. Delayed mortality of mice following inhalation of acute doses of CH2O, SO2, Cl2, and Br2. Am. Ind. Hyg. Assoc. J. 39(2):129-138.
Carel, R.S., I. Belmaker, G. Potashnik, M. Levine, R. Blau, and H. Eden. 1990. Late health sequelae of accidental bromine exposure [in Hebrew]. Harefuah 119(9):259-262.
Carel, R.S., I. Belmaker, G. Potashnik, M. Levine, and R. Blau. 1992. Delayed health sequelae of accidental exposure to bromine gas. J. Toxicol. Environ. Health 36(3):273-277.
Champeix, J., P. Catilina, G. Andraud, P. Penel, and N. Lagarde. 1970. Clinical and experimental study of poisoning by bromide vapors [in French]. Pouman Coeur 26(8):895-903.
D’Alessandro, A., W. Kuschner, H. Wong, H.A. Boushey, and P.D. Blanc. 1996. Exaggerated responses to chlorine inhalation among persons with nonspecific airway hyperreactivity. Chest 109(2):331-337.
DFG (Deutsche Forschungsgemeinschaft). 2007. List of MAK and BAT Values 2007. Maximum Concentrations and Biological Tolerance Values at the Workplace Report No. 43. Weinheim, Federal Republic of Germany: Wiley VCH.
DOT (U.S. Department of Transportation). 1985. Chemical Hazard Response Information System (CHRIS): Hazardous Chemical Data. U.S. Department of Transportation, U.S. Coast Guard, Washington, DC.
Downs, A.J., and C.J. Adams. 1973. Chemical properties of the halogens. Pp. 1188-1232 in Comprehensive Inorganic Chemistry, J.C. Bailar, H.J. Emeleus, R. Nyholm, and A.F. Trotman-Dickenson, eds. New York: Pergamon Press.
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Elkins, H.B. 1959. Inorganic compounds: Bromine. P. 89 in Chemistry of Industrial Toxicology, 2nd Ed. New York: John Wiley and Sons.
EPA (U.S. Environmental Protection Agency). Office of Pesticide Programs/Health Effects Division Tox One-liners.
EPA (U.S. Environmental Protection Agency). 1988. Reportable Quantity Document for Bromine. Environmental Criteria and Assessment Office, U.S. Environmental Protection Agency, Cincinnati, OH.
EPA (U.S. Environmental Protection Agency). 2005. Bromine/Bromide. Docket EPA-HQ-OPP-2006-0143-0005 Office of Pesticide, U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/pesticides/reregistration/bromine/ accessed Mar. 11, 2010].
Flury, F., and F. Zernik. 1931. Brom. Pp. 121-123 in Schädliche gase dämpfe, nebel, rauch- und staubarten. Berlin: Springer.
Glauser, J. 2009. Bromine. CEH Report No. 719.1000. SRI Consulting’s Chemical Economics Handbook Program [online]. Available: http://www.sriconsulting.com/CE H/Public/Reports/719.1000/ [accessed Feb. 19, 2010].
Great Lakes Chemical Corporation. 1996. Bromine Safety and Handling Guide. Great Lakes Chemical Corporation, West Lafayette, IN.
Henderson, Y., and H.W. Haggard. 1943. Bromine. P. 133 in Noxious Gases, 2nd Ed. New York: Reinhold Publishing Company.
Hill, L. 1915. Gas poisoning. Br. Med. J. (Dec. 4, 1915):801-804.
HSDB (Hazardous Substances Data Bank). 2008. Bromine (CASRN 7726-95-6). TOXNET, Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen? HSDB [accessed Feb. 23, 2010].
Ivanov, N.G., A.M. Kliachkina, and A.L. Germanova. 1976. Experimental data for hygienic standardization of bromine and hydrogen bromide content in the air of working areas [in Russian]. Gig. Tr. Prof. Zabol. 20(3):36-39.
Jackisch, P.F. 1992. Bromine. Pp. 536-560 in Kirk-Othmer Encyclopedia of Chemical Technology, 4th Ed., Vol. 4, J.I. Kroschwitz, and M. Howe-Grant, eds. New York: John Wiley & Sons.
Keplinger, M.L., and L.W. Suissa. 1968. Toxicity of fluorine short-term inhalation. Am. Ind. Hyg. Assoc. J. 29(1):10-18.
Kurokawa, Y., A. Maekawa, M. Takahashi, and Y. Hayashi. 1990. Toxicity and carcino-genicity of potassium bromate - a new renal carcinogen. Environ. Health Perspect. 87:309-335.
Kusewitt, D.F., D.M. Stavert, G. Ripple, T. Mundie, and B.E. Lehnert. 1989. Relative acute toxicities in the respiratory tract of inhaled hydrogen fluoride, hydrogen bromide and hydrogen chloride. Toxicologist 9:36 [A 144].
Lehmann, K.B. 1887. Arch. Hyg. 7:335 (as cited in Flury and Zernik 1931).
Litchfield, J.T., and F. Wilcoxon. 1949. A simplified method of evaluating dose-effect experiments. J. Pharmacol. Exp. Ther. 96(2):99-113.
Matt, L. 1889. Experimental Contributions to the Theory of the Effects of Poisonous Gases on Human Beings [in German]. Inaugural dissertation. Julius-Maximilliams-Universität, Würzburg.
Morabia, A., C. Selleger, J.C. Landry, P. Conne, P. Urban, and J. Fabre. 1988. Accidental bromine exposure in an urban population: An acute epidemiological assessment. Int. J. Epidemiol. 17(1):148-152.
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MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: Broom. Den Haag: SDU Uitgevers [online]. Available: http://www.lasrook. net/lasrookNL/maclijst2004.htm [accessed Oct. 24, 2008].
NIOSH (National Institute for Occupational Safety and Health). 1996. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLH): NIOSH Chemical Listing and Documentation of Revised IDLH Values (as of 3/1/95)-Bromine. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. August 1996 [online]. Available: http://www.cdc.gov/niosh/idlh/7726956.html [accessed Feb. 23, 2010].
NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket Guide to Chemical Hazards: Bromine. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Cincinnati, OH. September 2005 [online]. Available: http://www.cdc.gov/niosh/npg/npgd0064.html [accessed Feb. 23, 2010].
NRC (National Research Council). 1993. Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press.
NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press.
NRC (National Research Council). 2004. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 4 Washington, DC: The National Academies Press.
NRC (National Research Council). 2010. Fluorine. Pp. 230-273 in Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 8. Washington, DC: The National Academies Press.
O’Neil, M.J., A. Smith, P.E. Heckelman, J.R. Obenchain, Jr., J. Gallipeau, and M.A. D’Arecca, eds. 2001. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 13th Ed. Whitehouse Station, NJ: Merck.
Rotman, H.H., M.J. Fliegelman, T. Moore, R.G. Smith, D.M. Anglen, C.J. Kowalski, and J.G. Weg. 1983. Effects of low concentration of chlorine on pulmonary function in humans. J. Appl. Physiol. 54(4):1120-1124.
Rupp, H., and D. Henschler. 1967. Effects of low chlorine and bromine concentrations in man [in German]. Int. Arch. Arbeitsmed. 23(1):79-90.
Ruth, J.H. 1986. Odor thresholds and irritation levels of several chemical substances: A review. Am. Ind. Hyg. Assoc. J. 47(3):A142-A151.
Schlagbauer, M., and D. Henschler. 1967. Toxicity of chlorine and bromine with single and repeated exposures [in German]. Int. Arch. Arbeitsmed. 23(1):91-98.
Shusterman, D.J., M.A. Murphy, and J.R. Balmes. 1998. Subjects with seasonal allergic rhinitis and nonrhinitic subjects react differentially to nasal provocation with chlorine gas. J. Allergy Clin. Immunol. 101(6 Pt. 1):732-740.
Suntych, F. 1953. Bromine gassing. Prac. Lek. 5:86 (as cited in ACGIH 1996).
Teitelbaum, D.T. 2001. The Halogens. Pp. 731-826 in: Patty's Toxicology, 5th Ed., Vol. 3, E. Bingham, B. Cohrssen, and C.H. Powell, eds. New York: John Wiley & Sons.
ten Berge, W.F., A. Zwart, and L.M. Appleman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapors and gases. J. Hazard. Mater. 13(3):301-309.
Withers, R.M.J., and F.P. Lees. 1986. The assessment of major hazards: The lethal toxicity of bromine. J. Hazard. Mater. 13(3):279-299.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
APPENDIX A
DERIVATION OF AEGL VALUES FOR BROMINE
Derivation of AEGL-1
Key study:
Rupp and Henschler 1967
Toxicity end point:
Eye irritation in humans at 0.1 ppm for 30 min
Uncertainty factors:
3 for intraspecies variability
Time-scaling:
Not applied; adaptation to mild sensory irritation
Modifying factor:
None
Calculation:
0.1 ppm/3 = 0.033 ppm
Derivation of AEGL-2
Key study:
Rupp and Henschler 1967
Toxicity end point: for 30 min
Eye, nose, and throat irritation in humans at 1.0 ppm
Time-scaling:
C2.2 × t = k, based on mouse lethality study (Bitron and Aharonson 1978)
Uncertainty factors:
3 for intraspecies variability
Modifying factor:
None
Calculations:
(Concentration/uncertainty factors)2.2 × t = k
(1 ppm/3)2.2 × 30 min = k
2.676 ppm2.2 × min = k
10-min AEGL-2:
(2.676 ppm2.2 × min/10 min)1/2.2 = 0.55 ppm
30-min AEGL-2:
0.33 ppm
1-h AEGL-2:
(2.676 ppm2.2 × min/60 min)1/2.2 = 0.24 ppm
4-h AEGL-2:
(2.676 ppm2.2 × min/240 min)1/2.2 = 0.13 ppm
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8-h AEGL-2:
(2.676 ppm2.2 × min/480 min)1/2.2 = 0.095 ppm
Derivation of AEGL-3
Key study:
Schlagbauer and Henschler 1967
Toxicity end point: probit analysis
30-min LC01 of 116 ppm in the mouse, calculated by
Time-scaling:
C2.2 × t = k, based on mouse lethality study (Bitron and Aharonson 1978)
Uncertainty factors:
3 for intraspecies variability
3 for interspecies variability
Modifying factor:
None
Calculations:
(Concentration/uncertainty factors)2.2 × t = k
(116 ppm/10)2.2 × 30 min = k
6,590.66 ppm2.2 × min = k
10-min AEGL-3:
(6,590.66 ppm2.2 × min/10 min)1/2.2 = 19 ppm
30-min AEGL-3:
116/10 = 12 ppm
1-h AEGL-3:
(6,590.66 ppm2.2 × min/60 min)1/2.2 = 8.5 ppm
4-h AEGL-3:
(6,590.66 ppm2.2 × min/240 min)1/2.2 = 4.5 ppm
8-h AEGL-3:
(6,590.66 ppm2.2 × min/480 min)1/2.2 = 3.3 ppm
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APPENDIX B
CATEGORY GRAPH OF TOXICITY DATA AND AEGL VALUES
FIGURE B-1 Category graph for bromine.
TABLE B-1 Data Used in Category Graph
Source
Species
ppm
Min
Categorya
AEGL-1
0.033
10
AEGL
AEGL-1
0.033
30
AEGL
AEGL-1
0.033
60
AEGL
AEGL-1
0.033
240
AEGL
AEGL-1
0.033
480
AEGL
AEGL-2
0.55
10
AEGL
AEGL-2
0.33
30
AEGL
AEGL-2
0.24
60
AEGL
AEGL-2
0.13
240
AEGL
AEGL-2
0.095
480
AEGL
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Source
Species
ppm
Min
Categorya
AEGL-3
19
10
AEGL
AEGL-3
12
30
AEGL
AEGL-3
8.5
60
AEGL
AEGL-3
4.5
240
AEGL
AEGL-3
3.3
480
AEGL
Bitron and Aharonson 1978
Mouse
240
24
SL
Mouse
240
65
SL
Mouse
240
120
SL
Mouse
240
215
SL
Mouse
750
5
2
Mouse
750
7
SL
Mouse
750
13
SL
Mouse
750
24
SL
Schlagbauer and Henschler 1967
Mouse
111
30
2
Mouse
140
30
SL
Mouse
199
30
SL
Mouse
236
30
SL
Mouse
252
30
SL
Mouse
268
30
SL
Mouse
290
30
3
Mouse
315
30
3
Rupp and Henschler 1967
Human
0.1
30
1
Human
0.2
30
1
Human
0.5
30
1
Human
0.9
30
1
aCategory 0, no effect; 1, discomfort; 2, disabling, 3, lethal; SL, some lethality.
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APPENDIX C
ACUTE EXPOSURE GUIDELINE LEVELS FOR BROMINE
Derivation Summary for Bromine
AEGL-1 VALUES
10 min
30 min
1 h
4 h
8 h
0.033 ppm
0.033 ppm
0.033 ppm
0.033 ppm
0.033 ppm
Key Reference: Rupp, H., and D. Henschler. 1967. Effects of low concentrations of chlorine and bromine on man [in German]. Int. Arch. Arbeitsmed. 23(1):79-90.
Test Species/Strain/Number: 20 human subjects
Exposure Route/Concentrations/Durations: Inhalation, concentrations of 0.1 to 1.0 ppm for at least 30 min
Effects:
0.1 ppm: eye irritation
0.50 to 1.0 ppm: eye, nose, and throat irritation
End Point/Concentration/Rationale: Eye irritation but not nose or throat irritation at 0.1 ppm for 30 min; meets the AEGL-1 definition of notable discomfort.
Uncertainty Factors/Rationale:
Total uncertainty factor: 3
Interspecies: Not applied, human data used
Intraspecies: 3, Workers have been exposed to concentrations up to 1 ppm with irritation being the only reported symptom. Compared with the 0.5 ppm AEGL-1 for the less well-scrubbed chlorine, the value may be conservative. Chlorine at 0.5 ppm for 4 h failed to elicit an asthmatic response in sensitive subjects.
Modifying Factor: Not applied
Animal to Human Dosimetric Adjustment: Not applied.
Time-Scaling: Not applied, adaptation to mild sensory irritation.
Data Adequacy: Compared with the irritancy data on chlorine, these values may be conservative. Based on the small database for bromine, extra protectiveness was considered appropriate.
AEGL-2 VALUES
10 min
30 min
1 h
4 h
8 h
0.55 ppm
0.33 ppm
0.24 ppm
0.13 ppm
0.095 ppm
Key Reference: Rupp, H., and D. Henschler. 1967. Effects of low concentrations of chlorine and bromine on man [in German]. Int. Arch. Arbeitsmed. 23(1):79-90.
Test Species/Strain/Number: 20 human subjects
Exposure Route/Concentrations/Durations: Inhalation, concentrations of 0.1 to 1.0 ppm for at least 30 min
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10 min
30 min
1 h
4 h
8 h
0.55 ppm
0.33 ppm
0.24 ppm
0.13 ppm
0.095 ppm
Effects:
0.1 ppm: eye irritation
0.5 to 1.0 ppm: eye, nose, and throat irritation
End Point/Concentration/Rationale: Throat irritation at the 1.0 ppm concentration.
Uncertainty Factors/Rationale:
Total uncertainty factor: 3
Interspecies: Not applied, human data used.
Intraspecies: 3. Symptoms are below those defining an AEGL-2, but no reliable studies with exposures to higher concentrations were located. Irritation appeared to be limited to the upper respiratory tract with likely little penetration to the lower respiratory tract. Compared with the 30-min AEGL-2 value of 2.8 ppm for chlorine (which was protective of sensitive subjects) the uncertainty factor of 3 is adequate.
Modifying Factor: Not applied.
Animal to Human Dosimetric Adjustment: Not applied.
Time-scaling: C2.2 × t = k, based on a mouse lethality study.
Data Adequacy: Compared with the irritancy data on chlorine, these values may be conservative. But, based on the limited data base for bromine, extra protectiveness was considered appropriate.
AEGL-3 VALUES
10 min
30 min
1 h
4 h
8 h
19 ppm
12 ppm
8.5 ppm
4.5 ppm
3.3 ppm
Key Reference: Schlagbauer, M., and D. Henschler. 1967. Inhalation toxicity of chlorine and bromine with single and repeated exposures [in German]. Int. Arch. Arbetsmed. 23(1):91-98.
Test Species/Strain/Number: Mouse/NMRI/10 per exposure group
Exposure Route/Concentrations/Durations: Inhalation, 110.5 to 315 ppm for 30 min
Concentration:
Mortality:
110.5 ppm:
0/10
139.7 ppm:
3/10
198.9 ppm:
6/10
236.0 ppm:
9/10
252.1 ppm:
10/10
267.6 ppm:
9/10
290.3 ppm:
10/10
315.0 ppm
10/10
End Point/Concentration/Rationale: LC01 calculated by probit analysis
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10 min
30 min
1 h
4 h
8 h
19 ppm
12 ppm
8.5 ppm
4.5 ppm
3.3 ppm
Uncertainty Factors/Rationale:
Total uncertainty factor: 10
Interspecies: 3; the mouse was the most sensitive species in other studies with halogens
Intraspecies: 3; at high concentrations, the corrosive action of irritants is not expected to differ greatly among individuals.
Modifying Factor: Not applied.
Animal to Human Dosimetric Adjustment: Not applied.
Time-scaling: C2.2 × t = k, based on a mouse lethality study.
Data Adequacy: Compared with the lethality data on chlorine, these values may be conservative, but based on the small database for bromine, extra protectiveness was considered appropriate.