4
Chlorine
This chapter reviews the physical and chemical properties and toxicokinetic, toxicologic, and epidemiologic data on chlorine. The Subcommittee on Submarine Escape Action Levels used this information to assess the health risk to Navy personnel aboard a disabled submarine from exposure to chlorine gas and to evaluate the submarine escape action levels (SEALs) proposed to avert serious health effects and substantial degradation in crew performance from short-term exposure (up to 10 d). The subcommittee also identifies data gaps and recommends research relevant for determining the health risk attributable to exposure to chlorine.
BACKGROUND INFORMATION
Chlorine is an abundant, naturally occurring halogen gas that does not occur in nature in its elemental state (Table 4–1). However, chlorine combines readily with inorganic and organic substances, with the exception of rare gases other than xenon), and nitrogen (Budavari 1989). When formed, chlorine is a diatomic gas with a pungent, suffocating odor. Chlorine can be formed if seawater makes contact with submarine batteries, and it therefore poses a health (survival) risk in a disabled submarine. To protect the health of submarine personnel until they can be rescued submarine escape action levels (SEALs) are needed to avoid
TABLE 4–1 Chemical and Physical Properties
|
CAS number |
7782–50–5 |
|
Molecular formula |
Cl2 |
|
Molecular weight |
70.9 |
|
Color |
Greenish-yellow |
|
Odor |
Suffocating |
|
Odor threshold |
0.2–0.4 ppm |
|
Boiling point |
–34.05°C |
|
Melting point |
–101.00°C |
|
Density (water=1) |
1.5649 at boiling point |
|
Vapor density |
1.4085 at 20°C |
|
Solubility |
Water, alkalies |
|
Conversion factors 25°C, 1 atm |
1 ppm=2.9 mg/m3 1 mg/m3=0.34 ppm |
|
Abbreviations: CAS, Chemical Abstract Service. Source: Budavari (1989) |
|
adverse health effects or degradation in crew performance following short-term exposures to chlorine. This chapter presents the available toxicity information on chlorine and the subcommittee’s evaluation of the Navy’s proposed SEALs.
Chlorine is used in the manufacture of many products, as a bleaching compound for residential and commercial use, and as a biocide for municipal water and waste treatment (i.e., purifying and disinfecting water, detinning and dezincing iron) (Budavari 1989). It also was used as chemical-warfare agent in World War I (Withers and Lees 1987).
TOXICOKINETIC CONSIDERATIONS
There are few toxicokinetic studies of chlorine inhalation, and there have been no toxicokinetic studies on dermal exposure to chlorine.
Absorption
Absorption of chlorine is primarily via the upper respiratory tract. Chlorine is moderately soluble and, thereby, considered a Category I gas (EPA 1994). Because of its reactivity at localized sites, chlorine is not readily absorbed systemi-
cally. Dermal absorption is possible, but that constitutes a secondary and minor route of exposure. Chlorine reacts with moisture in tissue, resulting in a release of hydrochloric and hypochlorous acids (Budavari et al. 1996; Perry et al. 1994). Nodelman and Ultman (1999a, b) used a bolus inhalation method to study the absorption and distribution of inhaled chlorine during a single breath. Five male and five female volunteers were exposed to chlorine by nose and mouth separately at a concentration of 3 ppm (parts per million). Chlorine was predominantly absorbed in the upper respiratory system (nasal passages, mouth, pharynx), regardless of administration route, with less than 5% of the inspired chlorine found beyond the upper airway and none found in the respiratory air spaces.
Distribution
Inhaled chlorine is predominantly retained in the upper respiratory tract (Nodelman and Ultman 1999a, b), and is a known irritant. At low doses (≤2.5 ppm for up to 2 h), approximately 95% of chlorine is effectively scrubbed in the upper respiratory tract. At higher concentrations, it reaches the lungs and can exert toxic effects (EPA 1994).
Metabolism and Disposition
There are no studies on the metabolism of chlorine after inhalation or dermal exposure. Chlorine gas reacts at the localized site, resulting in little absorption into the systematic blood system (Eaton and Klaassen 1996).
HUMAN TOXICITY DATA
There have been many studies of the toxicity of chlorine in exposed human populations. The subject was of interest during World War I, when chlorine was used as a weapon and the lethality of exposure was widely documented. But lethal concentrations in accidental exposures often are not documented so experimental animal studies must be used. Chlorine is detectable at low, nonlethal concentrations. It is an irritant to eyes, nose, and throat at concentrations less than 0.5 ppm for 4 h.
Data sources regarding the toxicity of chlorine include experimental studies with human volunteers and animals; accidentally exposed cohorts of workers, communities, or individuals; warfare studies; and epidemiologic occupational investigations. Each of these data sources is reviewed below and summarized in
the accompanying tables (Tables 4–2 to 4–5). The information in the tables reflects the spectrum of chlorine gas exposure signs and symptoms (ranging from localized irritation to pulmonary edema and death).
Experimental Studies
Studies of chlorine exposure in humans are detailed in Tables 4–2 and 4–3. Table 4–2 presents early attempts to determine thresholds for irritant effects, and it is restricted to studies that focused on the irritant effects of chloride. The quality of these early data is questionable because some studies did not provide enough information to support their conclusions (Fieldner et al. 1921, as cited in NIOSH 1976), some used a small number of test subjects (Matt 1889, as cited by NIOSH 1976), and some reported difficulties in maintaining constant concentrations of chlorine within the exposure chambers (Rupp and Henschler 1967, as cited in NIOSH 1976).
Table 4–3 presents findings from more recent studies that quantified exposure. Overall, they indicate that chlorine can be detected at concentrations as low as 0.5 ppm (possibly even lower) for 4 h and that it causes slight irritation of the eyes, nose, and throat (Anglen 1981). At higher concentrations, irritant effects are more pronounced, and there are effects on pulmonary function at 1 ppm, which can increase with duration (Rotman et al. 1983). The effects appear to be transient, resolving after exposure ceased.
Experimental data support the conclusion that chlorine has both lethal and nonlethal effects in humans. Death can occur at high doses, and various effects, such as choking, coughing, and reactive airway dysfunction are seen at intermediate concentrations. Lower, nonlethal doses are associated with symptoms such as localized irritation of the eyes, nose, and throat. There are no data available where people have been exposed to chlorine gas at concentrations of 1–5 ppm or greater for more than 8 h.
Accidental Exposures
Numerous studies have examined the effects of accidental exposure to chlorine, and reviews of those studies have been published as well (e.g., NIOSH 1976; NRC 1976; WHO 1982) and will not be repeated here. In most of those studies, exposure to chlorine was high albeit not quantified. Overall, the studies indicate that exposure to high concentrations of chlorine causes effects in the respiratory tract (e.g., pulmonary edema, pneumonia, and tracheobronchitis) that can result in death (Römcke and Evensen 1940, as cited in WHO 1982; Baader 1952, as cited in NIOSH 1976; Dixon and Drew 1968; Adelson and Kaufman 1971).
TABLE 4–2 Threshold Data on Chlorine from Older Experimental Studies Using Human Subjects
|
Odor Detection (ppm) |
Ocular Irritation (ppm) |
Nasal Irritation (ppm) |
Throat Irritation (ppm) |
Cough (ppm) |
Reference |
|
1.3 |
1.3–2.5 |
3.5 |
2.5 |
3.5 |
Matt 1889 (as cited in NIOSH 1976) |
|
3.5 |
— |
— |
15.1 |
30.2 |
Fieldner et al. 1921 (as cited in NIOSH 1976) |
|
3.3 |
— |
— |
6.6 |
— |
Vedder and Sawyer 1924 (as cited in NRC 1976) |
|
0.044 |
— |
0.09 |
0.09 |
0.09 |
Beck 1959 (as cited in NIOSH 1976) |
|
0.2 |
0.2 |
0.2 |
0.2 |
0.2 |
Beck 1959 (as cited in NIOSH 1976) |
|
0.3 |
1 |
1 |
1 |
1 |
Takhiroy 1960a,b (as cited in NRC 1976) |
|
0.28–0.45 |
— |
— |
— |
— |
Ryazanov 1962 |
|
|
0.45 |
0.06 |
0.058 |
0.5 |
Rupp and Henschler 1967 (as cited in NIOSH 1976) |
Withers and Lees (1985) used lethality data from animal and human studies in a probit analysis to estimate concentrations that would be lethal to 50% (LC50) or to 10% (LC10) of a human population. They estimated a 30-min LC50 of 250 ppm for a normal population, 100 ppm for a susceptible population, and 210 ppm for the average population (combining normal and susceptible groups). The estimated LC10 for each population was 125 ppm, 50 ppm, and 80 ppm, respectively.
Immediate effects of exposure to chlorine include choking, coughing, dyspnea, nausea, vomiting, anxiety, loss of consciousness, and eye and nasal irritation (Abhyankar et al. 1989; Beach et al. 1969; Chasis et al. 1947; Moulick et
al. 1992; Shroff et al. 1988). Subjects who survive exposure to high concentrations (>100 ppm) or who are exposed to lower concentrations (30–60 ppm) exhibit labored breathing, airway obstruction, pulmonary edema, impaired pulmonary function, tracheobronchitis, pneumonia, cyanosis, and cough (Chasis et al. 1947; Colardyn et al. 1976; Joyner and Durel 1962, as cited in WHO 1982; Kaufman and Burkons 1971; Kowitz et al. 1967; Ploysongsang et al. 1982). Some investigators have found that the effects can persist for months or years (Kaufman and Burkons 1971; Kowitz et al. 1967; Schwartz et al. 1990; Sessa et al. 1970, as cited in WHO 1982); others have found no significant permanent damage (Faure et al. 1970, as cited in WHO 1982; Jones et al. 1986; Weill et al. 1969).
There also are case reports of reactive airways dysfunction syndrome (RADS) associated with chlorine exposure (Alberts and do Pico 1996; Donnelly and FitzGerald 1990; Schönhofer et al. 1996). RADS is persistent hyper-reactivity of the airways that occurs after a single exposure to a high concentration of an irritant gas (Brooks et al. 1985). All reported RADS cases have resulted from accidental exposures in which exposure concentrations can be presumed to have been high.
Schwartz et al. (1990) followed 20 accidentally exposed individuals for 12 yr and reported an increasing prevalence of low residual volume over time and an increase in airway reactivity. These findings suggest that acute exposure has long-term pulmonary sequella and that the presence of air trapping indicates long-term injury. Unfortunately, the chlorine exposure was not quantified.
Other effects that have been reported after accidental exposure to chlorine, include palpable and painful liver (Tatarelli 1946, as cited in WHO 1982); anxiety, phobias, or hysteria (Chasis et al. 1947; Segaloff 1961, as cited in WHO 1982); electrocardiographic abnormalities (Leube and Kreiter 1971, as cited in WHO 1982); leukocytosis and elevated glutamate-pyruvate-transaminase (Leube and Kreiter 1971, as cited in WHO 1982); and brain hemorrhages (Baader 1952, as cited in NIOSH 1976).
Table 4–3 summarizes some studies for which there are quantitative data on accidental exposure.
The data from accidental chlorine exposure support the conclusion that dose is related to type and severity of health effect, which can range from localized irritation of the eyes, nose, and throat; to life-threatening respiratory symptoms that include pulmonary edema and pneumonia; to death.
TABLE 4–3 Human Toxicity Data, Exposure to Chlorine
|
Sample (n) |
Route |
Concentration (ppm) |
Duration |
Effect |
Reference |
|
EXPERIMENTAL STUDIES: Volunteers |
|||||
|
3 |
Whole body |
0.21–0.52 |
NR |
Investigators examined chlorine’s effect on chronaxie, the minimum time need to excite a tissue with a current twice the rheobasic strength, and on reactions to visual stimulus. Prolonged optical chronaxie was found at 0.52 ppm, but not between 0.21 and 0.34 ppm. Optical chronaxie values returned to baseline levels within 2–2.5 min after exposure ceased. Increased sensitivity to light was found at 0.52 ppm, but not at 0.28 ppm. NIOSH (1976) noted that this study measured fine alterations in physiology and their importance to human health is poorly understood. |
Takhirov 1960b (as cited in NRC 1976) |
|
8 |
Whole body |
0.5, 1, 2, 4.0 |
2 h |
No complaints at 0.5 or 1 ppm. At 2 ppm, subjects reported slight irritation of the eyes, nose, throat. At 4 ppm, subjects reported objectionable odor, irritation of the nose and throat, desire to cough. No effects on lung function between 0.5 and 2 ppm. Only 2–3 subjects exposed at 4 ppm remained in the exposure chamber for 2 h, so lung function was not reported for that group. |
Joosting and Verberk 1974 |
|
Sample (n) |
Route |
Concentration (ppm) |
Duration |
Effect |
Reference |
|
31 |
Whole body |
0.5, 1, 2.0 |
4 h |
At the two lower concentrations, subjects detected odor and reported throat irritation and an urge to cough. At 2 ppm, effects were reported to be more irritating. |
Anglen 1981 |
|
8 |
Whole body |
0.5, 1.0 |
8 h (with 30-min or 1-h break for testing after 4 h) |
Pulmonary function tests were performed at 4 and 8 h. At 4 h, small but statistically significant changes were observed at 1 ppm, including changes in FEV1, PEFR, FEF50, and FEF25, TLC, Raw, and difference in nitrogen concentration. At 8 h, there were alterations in forced vital capacity, FEV1, PEFR, FEF50, FEF25, and Raw. Most of these values returned to normal the next day. |
Rotman et al. 1983 |
|
WARFARE EXPOSURE STUDIES: Soldiers |
|||||
|
700 |
Whole body |
NR |
NR |
Review of medical records of soldiers gassed with chlorine. Acute effects included death, dyspnea, pulmonary edema, bronchitis, pneumonia, asthma. Long-term effects (4 yr after exposure) included “irritable heart” (condition not described). There appeared to be no correlation between acute pulmonary effects and health status 4 yr later. |
Meakins and Priestly 1919 |
|
838 (from 1,843 casualities) |
Whole body |
NR |
NR |
Review of medical records 8–10 yr after exposure. 4 deaths attributed to “later effect of chlorine gasing.” Subjects had bronchopneumonia, lobar pneumonia, purulent pleurisy, tubercular |
Gilchrist and Matz 1933 |
|
|
meningitis. Survivors exhibited pulmonary tuberculosis, bronchitis, pleurisy, neurocirculatory asethnia, tachycardia, dyspnea, nephritis, laryngitis, valvular heart disease, keratitis, conjunctivitis. Most subjects made complete recovery. 9 subjects had long-term effects, such as pulmonary tuberculosis, bronchitis, chronic adhesive pleurisy. |
||||
|
|
Whole body |
10–1,000 |
NR |
Investigators concluded that chlorine is subjectively identified at 10 ppm, produces slight effects at 20 ppm, and causes death at 1,000 ppm within 5 min. “Asphyxiating phase” occurs up to 36 hr after exposure and includes irritation of the throat, coughing, dyspnea, aphonia, bardycardia, pulsus tardus, cyanosis, subnormal temperature. Death during this phase was attributed to pulmonary edema. “Post-asphyxiating phase” occurs when pulmonary edema subsides and bronchitis develops. Other effects include headache, nausea, vomiting, weakness, diarrhea. |
Gerchik 1939 |
|
ACCIDENTAL EXPOSURE STUDIES |
|||||
|
85 |
Whole body |
30–60 (Estimated) |
NR |
Acute effects included cough, dyspnea, expectoration, respiratory problems. Some of the more severe effects were death, pulmonary edema, bronchopneumonia. Effects were more severe in individuals undergoing physical exertion. Most reported chronic effect was dyspnea. |
Römcke and Evensen 1940 (as cited in WHO 1982); Hoveid 1956 (as cited in NRC 1976) |
|
Sample (n) |
Route |
Concentration (ppm) |
Duration |
Effect |
Reference |
|
100 (65 casualties, with 15 hospitalized) |
Whole body |
10–400 |
NR |
1 death and 10 cases of pulmonary edema. Subjects exhibited dyspnea, coughing, vomiting, eye irritation, and burns of the face. Chest X-rays of hospitalized patients showed fine miliary mottling of the lungs. No evidence of pneumonitis, and findings disappeared 12 d after exposure. |
Joyner and Durel 1962 |
|
|
Hysteria after exposure reported, particularly among individuals with “slight tendencies toward neurosis.” 1 physician reported cases of congestive heart failure in elderly subjects; all responded to treatment. |
Segaloff 1961 (as cited in WHO 1982) |
|||
|
|
7-yr follow-up of the 12 most severely affected subjects indicated no permanent lung damage. |
Weill et al. 1969 |
|||
|
88 (25 with prior exposure at lower doses) |
Whole body |
66 ppm |
NR |
Immediate effects included dyspnea, coughing, irritation of the eyes and throat, headache, giddiness, chest pain, abdominal discomfort. Subjects also exhibited hilar congestion, bronchial vasculature markings, respiratory incapacitation, tracheobronchial congestion, chronic bronchitis, scattered hemorrhages, bronchial erosion. Bronchial smears taken from 28 subjects 5 d after exposure showed basal-cell and goblet-cell hyperplasia, acute inflammation, and chromatolysis |
Shroff et al. 1988 |
|
|
of columnar epithelial cells. 15 subjects exhibited columnar epithelial cell syncitia, nonpigmented alveolar macrophages, and proliferating fibroblasts and capillary fragments. Evidence of epithelial regeneration and repair by fibrosis 15–25 d after exposure. |
|
|||
|
14 |
Whole body |
30 ppm |
NR |
5 subjects had pre-existing COAD. Immediate effects in all subjects included lacrimation, sneezing, coughing, sputum, retrostenal burning, dyspnea, apprehension, vomiting. Among non-COAD subjects, all effects disappeared within 2 wk and pulmonary function was normal at 6 mo. Among COAD subjects, effects persisted and there was no improvement in pulmonary function at 6 mo. |
Abhyankar et al. 1989 |
|
82 |
Whole body |
66 ppm (found 2 h after leak) |
<1 h |
All subjects exhibited dyspnea, cough, bronchospasm. Other effects included irritation of the eyes and throat, headache, abdominal pain, vomiting, giddiness. 5 subjects had cyanosis, X-rays showed cases of patchy infiltrates, hilar congestion. Pulmonary function was affected in most subjects; bronchoscopy revealed tracheobronchial mucosal irritation. Some subjects had hemorrhagic spots, erosions, ulcers. In a follow-up of 16 patients for 1 yr, 4 reported |
Moulick et al. 1992 |
|
Sample (n) |
Route |
Concentration (ppm) |
Duration |
Effect |
Reference |
|
|
persistent cough 4–6 wk after discharge from the hospital. No symptoms were found in any subject after 1 yr, chest X-rays and pulmonary function tests were normal. In a follow-up of 5 subjects for 3 yr, no residual symptoms were found. |
|
|||
|
OCCUPATIONAL EPIDEMIOLOGY STUDIES |
|||||
|
15 |
Whole body |
NR |
NR |
Pregnancy outcome of 15 female workers tracked between 1932 and 1933. 2 subjects had miscarriages (1 appeared to be induced). The others had normal births. Investigators concluded the chlorine exposure had no effect on pregnancy, delivery, lactation. |
Skljanskaja et al. 1935 (as cited in WHO 1982) |
|
35 |
Whole body |
NR |
6.4 yr (average employment) |
Subjects reported suffering from respiratory diseases; no X-ray changes found. |
Evans 1940 (as cited in NIOSH 1976) |
|
49 |
Whole body |
NR |
12 yr (average employment) |
No statistically significant differences in measurements of hemoglobin, red blood cell counts, leukocyte counts between exposed workers and 39 non-exposed workers. |
Tawast et al. 1956 (as cited in NIOSH 1976) |
|
52 Workers in mercury |
Whole body |
<0.37 |
10 yr (mean employ |
All subjects had periodic short-term exposure to high concentrations of chlorine. Respiratory function and prevalence of chronic lung disease |
Capodaglio et al. 1969 (as cited in WHO 1982) |
|
cell chlorine production unit |
|
ment) |
not statistically different from 27 unexposed employees. |
|
|
|
139 Chlorine gas workers |
Whole body |
<1.0 (average) |
NR |
Short-term exposure to high concentrations of chlorine combined with occasional long-term exposure to low concentrations might be associated with decreased maximum midexpiratory flow; long-term exposure to low concentrations of chlorine did not appear to have such an association. |
Chester et al. 1969 |
|
332 Chlorine plant workers (382 control workers) |
Inhalation and dermal |
0.006–1.42 |
10.9 yr (average employment) |
No statistically significant signs or symptoms observed on a dose-response basis, compared with 382 control workers, for abnormal chest X-rays, electrocardiograms, pulmonary function. Controls were age matched. |
Patil et al. 1970 |
|
147 Pulp mill workers |
Whole body |
7.4, trace, and <0.001 in 1958, 1962, and 1963 |
NR |
Pulp mill workers potentially exposed to chlorine, sulfur dioxide, chlorine dioxide, and/or hydrogen sulfide. 2 subgroups were exposed predominantly to chlorine/chlorine dioxide or sulfur dioxide. No significant differences observed between the subgroups and a nonexposed group of workers (paper mill). |
Ferris et al. 1967 |
|
Sample (n) |
Route |
Concentration (ppm) |
Duration |
Effect |
Reference |
|
271 Workers (mortality study), 200 (morbidity study), pulp and paper mill |
Whole body |
7.4, trace, and <0.001 in 1958, 1962, and 1963 |
NR |
10-yr follow-up mortality and morbidity study. No increased mortality, incidence of specific cause of death, respiratory symptoms, prevalence of chronic nonspecific respiratory disease. Some suggestion that exposure to chlorine or sulfur dioxide might have a slight adverse effect on pulmonary function. |
Ferris et al. 1979 |
|
Abbreviations: COAD, chronic obstructive airway disease; FEF50, forced expiratory flow rate at 50% vital capacity, FEF25, forced expiratory flow rate at 25% vital capacity, FEV1, forced expiratory volume at 1s; NR, not reported; PEFR, peak expiratory flow rate; Raw, airway resistance; TLC, total lung capacity. |
|||||
Warfare Exposures
During World War I, chlorine gas was used as a weapon that was associated with a range of symptoms that depended upon concentration and duration of exposure. The spectrum of signs and symptoms reported varied from localized irritation to death.
Retrospective studies (see Table 4–3) of soldiers exposed to chlorine gas indicate that chlorine initially causes dyspnea, pulmonary edema, bronchitis, and pneumonia, which can result in death (Gilchrist and Matz 1933, as cited in Das and Blanc 1993; Meakins and Priestly 1919). Some subjects continued to suffer respiratory problems for years after exposure (Gilchrist and Matz 1933, as cited in Das and Blanc 1993).
Occupational and Epidemiological Studies
Table 4–3 presents details from occupational and epidemiologic studies of chlorine. In a review of the prevalence of chronic obstructive pulmonary disease among chlorine gas workers, Chester et al. (1969) reported that short-term exposure to high concentrations of chlorine combined with occasional long-term exposure to low concentrations might be associated with decreased maximum mid-expiratory flow; long-term exposure to low concentrations of chlorine did not appear to have such an association. However, the investigators did not provide any quantitative data on what constituted low or high concentrations. Another study found some evidence that chronic exposure to chlorine might have reduced pulmonary function in workers (Ferris et al. 1967, 1979), but others have not found differences between exposed and non-exposed workers (Capodaglio et al. 1969, as cited in WHO 1982; Patil et al. 1970).
The findings on the long-term effect of exposure—in particular, RADS and neurophysiologic and neuropsychologic effects—are equivocal. Clinical changes have been observed on x-rays, but not all studies have addressed other potential causes, such as cigarette smoking or unrelated occupational exposures.
EXPERIMENTAL ANIMAL TOXICITY DATA
Acute Exposures
Acute inhalation exposure to chlorine has been shown to cause lethal and nonlethal toxic effects in a variety of tests involving laboratory animals. Table 4–4
lists LC50 data for chlorine in rats and mice. Table 4–5 describes acute toxicity studies. In those studies, consistent effects were observed in the respiratory tract, including irritation of the mucosa of the respiratory passages, dyspnea, reduction in respiratory rate, and pulmonary edema. Chlorine can cause immediate or delayed death (Underhill 1920; Zwart and Woutersen 1988), and some investigators have shown that duration of exposure, as well as concentration, affects survival (Bitron and Aharonson 1978).
There are no animal toxicity studies specifically on dermal exposure to chlorine gas, but most of the inhalation studies involved whole-body exposures. Those studies reported irritation of the mucous membranes of the respiratory tract and the eyes.
Repeated Exposure
Repeated or continuous exposure to chlorine has been studied in several animal species (Table 4–5). As in acute studies, the primary effects are irritation of the respiratory tract (nasal passages, nasopharynx, larynx, trachea, lungs) and the eyes. In general, the severity of the effects was related to concentration and duration of exposure. No mortality or histopathologic effects in the respiratory tract below the nose have been observed in studies where rats, mice, or monkeys were exposed at concentrations of 2 to 3 ppm for 6 h/d, 5 d/wk for 6 wk (Barrow et al. 1979; Klonne et al. 1987; Wolf et al. 1995). However, 3 of 20 rats died in a group of rats exposed to 9 ppm, 6 h/d, 5 d/wk for 6 wk All of the rats in this group also had marked histopathologic lesions in larynx, trachea, and lung (Barrow et al. 1979). Jiang et al. (1983) reported that rats exposed at a concentration of 9.1 ppm for 6 h/d for 1, 3, or 5 d had lesions in the nasal passages and minor changes to the nasopharynx, larynx, trachea, and lungs.
MECHANISM OF ACTION
The irritation of the respiratory tract caused by chlorine is thought to be due to its strong oxidizing capacity. Chlorine oxidizes water in the surface tissues of the respiratory tract to form hydrochloric and hypochlorous acids, which break into hydrochloric acid (HCl) and free oxygen. When combined with water, oxygen radicals are released, resulting in tissue destruction enhanced by the presence of HCl (Perry et al. 1994; Stokinger 1981; Wolf et al. 1995). Nascent oxygen is a potent protoplasmic poison.
TABLE 4–4 LC50 for Exposure to Chlorine
|
Species |
Duration |
LC50 (ppm) |
Reference |
|
Rat |
5min |
5,500 |
Zwart and Woutersen 1988 |
|
|
10 min |
1,946 |
Zwart and Woutersen 1988 |
|
|
30min |
700 |
Zwart and Woutersen 1988 |
|
|
53 min |
1,000 |
Weedon et al. 1940 (as cited in WHO 1982) |
|
|
60 min |
455 |
Zwart and Woutersen 1988 |
|
|
60 min |
293 |
Vernot et al. 1977 |
|
|
408 min |
250 |
Weedon et al. 1940 (as cited in WHO 1982) |
|
Mouse |
10 min |
523 |
Silver and McGrath 1942 (as cited in WHO 1982) |
|
|
10 min |
594 |
Silver and McGrath 1942 (as cited in WHO 1982) |
|
|
10 min |
626 |
Geiling and McLean 1941 (as cited in WHO 1982) |
|
|
10 min |
674 |
Silver et al. 1942 (as cited in WHO 1982) |
|
|
10 min |
1,057 |
Zwart and Woutersen 1988 |
|
|
11 min |
290 |
Bitron and Aharonson 1978 |
|
|
28 min |
1,000 |
Weedon et al. 1940 (as cited in WHO 1982) |
|
|
30 min |
504 |
Zwart and Woutersen 1988 |
|
|
30 min |
127 |
Schlagbauer and Henschler 1967 (as cited in WHO 1982) |
|
|
55 min |
170 |
Bitron and Aharonson 1978 |
|
|
60 min |
137 |
Vernot et al. 1977 |
|
|
408 min |
250 |
Weedon et al. 1940 (as cited in WHO 1982) |
|
Abbreviations: LC50, median lethal concentration. |
|||
NAVY’S RECOMMENDED SEALS
The Navy proposed a SEAL 1 of 2 ppm and a SEAL 2 of 5 ppm for chlorine. These values appear to be based primarily on information presented in a
TABLE 4–5 Experimental Animal Toxicity Data, Exposure to Chlorine
|
Species: No. per Group |
Route |
Concentration (ppm) |
Duration |
Effect |
NOAEL, LOAEL (ppm) |
Reference |
|
ACUTE EXPOSURE |
||||||
|
Rat: 4 |
Whole body |
50, 100, 200, 500, 1,500 |
2–10min |
At concentrations ≤500 ppm, no significant histologic changes in airway mucosa or lungs. At 1,500 ppm for 2 min, slight perivascular edema, occasional small clusters of polymorphonuclear leukocytes in mucosa of large airways. For 10-min exposure, airspace and interstitial edema 1 h after exposure, decreased edema and appearance of mucosa polymorphonuclear leukocytes at 5–24 h, and epithelial regeneration at 72 h. |
NOAEL: 500 |
Demnati et al. 1995 |
|
Rat: 10 |
Whole body |
322–5,793 |
5 min-1 h |
Clinical effects observed in this study to determine the LD50 included restlessness, eye and nasal irritation, dyspnea, reduced respiratory rate. At 5,793 ppm for 5 min and 2,248 ppm for 10 min, pathologic changes observed in nose, larynx, trachea. No deaths at 547 ppm for 30 min or at 322 ppm for 60 min. |
NA |
Zwart and Wourtersen 1988 |
|
Rat: 40– 50 |
Whole body |
25 |
10 min |
50% reduction in respiratory rate. |
NA |
Barrow and Steinhagen 1982 |
|
Rat: 14 |
Whole body |
10.9 |
6 h |
50% reduction in respiratory rate. |
NA |
Chang and Barrow 1984 |
|
Mouse: 8 |
Whole body |
1,500 |
5 min |
Lung resistance increased up to 3 d after exposure. Responses to methacholine enhanced for up to 7 d after exposure. Effects persisted in some rats for a month or more. Histopathologic changes included epithelial flattening, necrosis, increase in smooth muscle mass, epithelial regeneration. Bronchoalveolar lavage revealed increased number of neutrophils. The most damage to the epithelium occurred within 1–3 d of exposure, corresponding with maximal functional changes. |
LOAEL: 1500 |
Demnati et al. 1998 |
|
Mouse: 4 |
Whole body |
0.7–38.4 |
10 min |
50% reduction in respiratory rate at 9.3 ppm. |
NA |
Barrow et al. 1977 |
|
Mouse: 10 |
Whole body |
579–1,654 |
10 min |
Deaths during second week of observation, suggesting that they might have been due to secondary infection. No deaths at 754 ppm. |
NA |
Zwart and Woutersen 1988 |
|
Mouse: 10 |
Whole body |
458–645 |
30 min |
Some deaths occurred during second week of observation, suggesting that they might have been due to secondary infection. |
NA |
Zwart and Woutersen 1988 |
|
Species: No. per Group |
Route |
Concentration (ppm) |
Duration |
Effect |
NOAEL, LOAEL (ppm) |
Reference |
|
Mouse: 10 |
Whole body |
3.5 |
60 min |
50% reduction in respiratory rate occurred within 10 min of exposure. |
NA |
Gagnaire et al. 1994 |
|
Mouse: 28–84 |
Whole body |
170, 290 |
15–160 min and 5–30 min, respectiv ely |
Duration of exposure affected survival. At 290 ppm, mortality was 100% at 25 min, 80% at 15 min, 40% at 9 min, and 0% for 6 min. At 170 ppm, mortality was 80% at 120 min, 50% at 52 min, and 10% at 22 min. Consistent delay of 5–10 d before substantial mortality. |
NA |
Bitron and Aharonson 1978 |
|
Mouse: 10 |
Whole body |
10 |
3 h |
8 deaths within 4 d. Pathologic examinations revealed pulmonary edema and necrosis, inflammation of the respiratory epithelium. |
NA |
Schlagbauer and Henschler 1967 (as cited in WHO 1982) |
|
Guinea pig: NR |
Whole body |
NR |
15–30 min |
No data on mortality presented. Animals reported to have pulmonary edema, hemorrhages. |
NA |
Faure et al. 1970 (as cited in WHO 1982) |
|
Rabbit: 4 |
Whole body |
50, 100, 200 |
30 min |
Lung measurements of volume-pressure relationships and inspiratory-expiratory flow rate taken periodically between 30 min and 60 d after exposure. No effects observed at 50 ppm. Alterations in flow rate ratios observed at 100 ppm and 200 ppm, recovered after 14 and 60 d, |
NOAEL: 50 LOAEL: 100 |
Barrow and Smith 1975 |
|
|
respectively. Pulmonary compliance compromised throughout the study. Pathologic changes of lungs included hemorrhages, pneumonitis, anatomic emphysema at 3 and 14 d after exposure, but not after 60 d. |
|
||||
|
Dog: <100 |
Whole body |
50–2,000 |
30 min |
“Minimum acute lethal toxicity” for 3-d observation, 800–900 ppm. At 50–250 ppm, some delayed deaths occurred after the 3-d period. At the higher concentrations, immediate effects included respiratory arrest and bronchoconstriction. After exposure ceased, gradual increase in respiratory rate for 1 h, subsided after 17 h. Pulse rate declined initially, but doubled over the normal rate after 10 h. Animals that died had pulmonary edema. Other clinical effects included ocular irritation, sneezing, salivation, retching, vomiting, general excitement, dyspnea, respiratory distress. Pathologic examination revealed necrosis of the epithelial lining of the respiratory tract, pneumonia, bronchitis, bronchiolitis, and fibrosis. |
NA |
Underhill 1920 (as cited in WHO 1982); Winternitz et al. 1920 (as cited in WHO 1982) |
|
Pig: 2–6 |
Trach. tube |
110, 140 (50 or 100 L) |
6 h |
Pigs were anesthetized and mechanically ventilated. At 140 ppm (100 L), severe |
LOAEL: 110 |
Gunnarsson et al. 1998 |
|
Species: No. per Group |
Route |
Concentration (ppm) |
Duration |
Effect |
NOAEL, LOAEL (ppm) |
Reference |
|
|
pulmonary dysfunction occurred after 10 min. 5 of 6 died within 6 h. Pigs exhibited rapid drop in arterial oxygen tension, biphasic decline in lung complance, gradual increase in cardia output. Similar but milder effects observed at the lower concentration; evidence of improvement in those effects at the end of the study. Microscopic examinations revealed epithelial sloughing of the bronchi and bronchioles, infiltration with leukocytes. |
|
||||
|
REPEATED EXPOSURE |
||||||
|
Rat: 9–10 |
Whole body |
9.1 |
6 h/d for 1, 3, or 5 d |
Pathologic exams performed immediately after exposure revealed lesions in the nasal passages, including epithelial degeneration with epithelial cell exfoliation, erosion, ulceration (respiratory epithelium) and epithelial erosion and ulceration of the olfactory epithelium of the dorsal meatus. Less severe changes were observed in the nasopharynx, larynx, trachea, lungs. |
LOAEL: 9.1 |
Jiang et al. 1983 |
|
Rat (SPD): 10 |
Whole body |
16 |
1 h/d for 4 wk or 2 |
Animals exhibited inflammatory changes of the trachea and bronchi that resulted in |
|
Elmes and Bell 1963 (as cited |
|
|
h/d for 5 wk |
bronchitis and death. |
|
in WHO 1982) |
||
|
Rat: 20 |
Whole body |
1, 3, 9 |
6 h/d, 5 d/wk for 6 wk |
At 9 ppm: 3 deaths, irritation of the eyes and upper respiratory tract, dyspnea, decreased body weight gain, increased segmented neutrophils and hematocrit, increased specific gravity of the urine, increased serum enzymes and urea nitrogen. Pathologic changes included inflammatory responses in the upper and lower respiratory tract; ulceration, erosion, edema, hemorrhage of the gastric mucosa; minor renal tubular and hepatocellular cytoplasmic changes. At 3 ppm: Irritation of the eyes and upper respiratory tract, decreased body weight gain, increased urine specific gravity. Pathologic changes included inflammation of the respiratory tract, minor hepatocellular cytoplasmic changes. At 1 ppm: Slight irritation of the nasal mucosa and decrease in body weight in females; increased urine specific gravity. Less severe pathologic evidence of inflammation of the respiratory tract. |
LOAEL: 1 |
Barrow et al. 1979 |
|
Species: No. per Group |
Route |
Concentration (ppm) |
Duration |
Effect |
NOAEL, LOAEL (ppm) |
Reference |
|
Rat (SPF): 15 |
Whole body |
40 |
3 h/d for a total of 42 hr |
Clinical effects included coughing, sneezing, and runny and blood-stained noses. Histologic examinations 14 d after exposure revealed recovery. |
LOAEL: 40 |
Bell and Elmes 1965 |
|
Rat (SPF and SPD): 8 |
Whole body |
90,104 |
3 h/d for 6 or 20 d |
Mortality, pulmonary inflammation, emphysema, pneumonia. Effects were more severe in SPD rats. |
|
Bell and Elmes 1965 |
|
Rat: 140 |
Whole body |
0.4, 1.0, 2.5 |
6 h/d, 5 d/wk or 3 alternate d/wk for 2 yr |
Lesions in nasal passages of all animals (mainly the anterior nasal cavity) included respiratory and olfactory epithelial degeneration, septal fenestration, mucosa inflammation, respiratory epithelial hyperplasia, squamous metaplasia, goblet cell hypertrophy and hyperplasia, secretory metaplasia of the transitional epithelium of the lateral meatus. Severity of the lesions was concentration related. |
LOAEL: 0.4 |
Wolf et al. 1995 |
|
Mouse: NR |
Whole body |
2.5, 5.0 |
8 h/d for 3 d |
Animals exhibited loss of body weight. At 5.0 ppm, microscopic changes found in lungs. Investigators did not report examination of lungs of animals exposed to the lower concentration. |
LOAEL: 5.0 |
Schlagbauer and Henschler 1967 (as cited in WHO 1982) |
|
Mouse: 24–34 |
Whole body |
9.3 |
6 h/d for 5 d |
Lesions found in anterior respiratory epithelium adjacent to the dorsal meatus and in respiratory epithelium, included exfoliation, inflammation erosion, ulceration, necrosis. Tracheal lesions and terminal bronchiolitis, with occlusion of the affected bronchioles by serocellular exudate. Recovery minimal to moderate after 72 h. |
LOAEL: 9.3 |
Buckley et al. 1984 |
|
Guinea pig: NR |
Whole body |
1.7 |
5 h/d for 87 d |
Some animals pre-exposed to tubercle bacilli, others were not. Deaths occurred among pre-exposed animals. |
LOAEL: 1.7 |
Arloing et al. 1940 (as cited in WHO 1982) |
|
Dog: 4 |
Whole body |
24–30 |
30 min |
Clinical signs included lacrimation, salivation, retching, vomiting. Variable effects on pulse, respiratory rate, increases in body temperature. |
LOAEL: 24 |
Barbour 1919 (as cited in NIOSH 1976) |
|
Dog: 3 |
Whole body |
180–200 |
30 min |
Clinical signs included lacrimation, salivation, retching, vomiting, reduction in muscle activity, dyspnea. Slight decrease in body temperature. No evidence of bronchitis or pulmonary edema. |
LOAEL: 180 |
Barbour 1919 (as cited in NIOSH 1976) |
|
Dog: NR |
Whole body |
800–900 |
30 min |
85% mortality. Decreases in body temperature. Surviving animals unable to regulate body temperature when exposed to high or low external temperatures. |
NA |
Barbour 1919 (as cited in NIOSH 1976) |
|
Species: No. per Group |
Route |
Concentration (ppm) |
Duration |
Effect |
NOAEL, LOAEL (ppm) |
Reference |
|
Monkey: 4 |
Whole body |
0.1, 0.5, 2.3 |
6 h/d, 5 d/wk for 1 yr |
At the highest concentration, the only significant clinical effect observed was ocular irritation. Histopathologic examinations revealed changes in nasal passages and trachea of a few animals, including focal epithelial hyperplasia with loss of cilia, decreased number of goblet cells. A few of the animals exposed to 0.5 pm had mild lesions in the nasal passages. |
NOAEL: 0.5 LOAEL: 2.3 |
Klonne et al. 1987 |
|
Abbreviations: LD50, median lethal dose; LOAEL, lowest observable adverse effect level; NOAEL, no observed adverse effect level; NR, not reported; ppm, parts per million; SPD, spontaneous pulmonary disease; SPF, specific pathogen-free. |
||||||
review of the toxicity of chlorine (NRC 1976) which reported that men can work uninterrupted when exposed at 1–2 ppm, and that severe irritation of the eyes, nose, and respiratory tract is observed after a few minutes of exposure to 5 ppm.
ADDITIONAL RECOMMENDATIONS FROM THE NRC AND OTHER ORGANIZATIONS
Table 4–6 presents exposure limits for chlorine recommended by other organizations. The 24-h emergency exposure guidance level (EEGL) is the most relevant guidance level to compare to the SEALs (NRC 1984). EEGLs were developed for healthy military personnel in emergency situations. An important difference between EEGLs and SEALs is that EEGLs allow mild, reversible health effects, whereas SEALs allow moderate, reversible health effects. That is, SEALs allow effects that are somewhat more intense or potent than those for EEGLs. Therefore, SEAL values are higher than the corresponding EEGL values.
SUBCOMMITTEE ANALYSIS AND RECOMMENDATIONS
Submarine Escape Action Level 1
On the basis of its review of human and experimental animal health-effects and related data, the subcommittee concludes that the Navy’s recommended SEAL 1 of 2 ppm for chlorine is too high. The subcommittee recommends a SEAL 1 of 1 ppm. The subcommittee recognizes that the dose-response curve for chlorine is steep and therefore, the margin of safety is narrow. The subcommittee’s conclusion is based on studies in which human volunteers exposed to chlorine at a concentration of 0.5–4 ppm for 2–8 h complained or irritation of the eyes, nose, and throat (Joosting and Verberk 1974; NRC 1976; Anglen 1981; Rotman et al. 1983). Volunteers exposed at a concentration of 1 ppm for 8 h had transient pulmonary function changes; however, volunteers exposed at a concentration of 0.5 ppm for 8 h had only trivial pulmonary function changes (Rotman et al. 1983). The SEAL 1 is further supported by a study in which monkeys exposed to chlorine at 2 ppm for 6 h/d, 5 d/wk for 1 yr exhibited no histopathologic lesions of the lower respiratory tract (Klonne et al. 1987). That study would indicate that the recommended SEAL 1 has some margin of safety even if the exposure to chlorine lasts for 10 d.
TABLE 4–6 Exposure Recommendations from Other Organizations
|
Organization |
Type of Exposure Recommendation |
Exposure Limit, ppm |
Reference |
|
ACGIH |
TLV-TWA (8 h/d during 40-h workweek) |
0.5 |
ACGIH 1999 |
|
|
TLV-STEL (15 min) |
1 |
|
|
AIHA |
ERPG-1 |
1 |
AIHA 2001 |
|
|
ERPG-2 |
3 |
|
|
|
ERPG-3 |
20 |
|
|
DFG |
MAK (8 h/d during 40-h workweek) Peak Limit (5 min maximum duration, 8 times per shift) |
0.5 1 |
DFG 1997 |
|
NAC |
Proposed 8-h AEGL-1 |
0.5 |
Federal Register |
|
|
Proposed 8-h AEGL-2 |
0.71 |
October 30, 1997. |
|
|
Proposed 8-h AEGL-3 |
7.1 |
62(210):58839–58851. |
|
NIOSH |
REL-TWA (10 h/d during 40-hr workweek) |
0.5 |
NIOSH 2001 |
|
|
IDLH |
10 |
|
|
NRCa |
EEGL (1 h) |
3 |
NRC 1984 |
|
|
EEGL (24 h) |
0.5 |
|
|
|
CEGL (90 d) |
0.1 |
|
|
OSHA |
PEL-TWA (ceiling value) |
1 |
OSHA 1999b |
|
aGuidelines were established for use by the military. bOccupational Safety and Health Standards. Code of Federal Regulations. Part 1910. 1000 Air Contaminants. Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AEGL, acute exposure guideline level; AIHA, American Industrial Hygiene Association; CEGL, continuous exposure guidance level; DFG, Deutsche Forschungsgemeinschaft; EEGL, emergency exposure guidance level; ERPG, emergency response planning guidelines; IDLH, immediately dangerous to life and health; MAK, maximum concentration values in the workplace; NAC, National Advisory Committee; NRC, National Research Council; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limit; REL, recommended exposure limit; STEL, short-term exposure limit; TLV, Threshold Limit Value; TWA, time-weighted average. |
|||
Submarine Escape Action Level 2
On the basis of its review of human and experimental animal health-effects and related data, the subcommittee concludes that the Navy’s proposed SEAL 2 of 5 ppm for chlorine is too high. The subcommittee recommends a SEAL 2 of 2.5 ppm for chlorine. That recommendation is supported by a study in which 3 human volunteers exposed to chlorine at a concentration of 4 ppm for 2 h were able to tolerate the exposure and volunteers exposed at a concentration of 2 ppm for 2 h did not have significant changes in lung function (Joosting and Verberk 1974). The subcommittee’s recommended SEAL 2 is also supported by the study by Klonne et al. (1987), which is described above. The subcommittee concludes that most crew members should be able to tolerate the irritant effects of chlorine exposure at concentrations below 2.5 ppm for 24 h.
DATA GAPS AND RESEARCH NEEDS
Additional studies on the toxicity of chlorine in experimental animals are needed to better define the health effects of exposure at concentrations of 0.5–4 ppm, 24 h/d for up to 10 d. These studies should include evaluation of short-term effects, on pulmonary function and on long-term effects such as inflammation of the respiratory tract and pulmonary fibrosis. Studies are also needed on the interactive effects of chlorine with other gases found in disabled submarines.
Additional studies on chlorine toxicity in animals and, possibly, on human volunteers are needed to better define the health effects of chlorine gas exposure at 0.5–5 ppm, 24 h/d up to 7–10 d. Long-term exposure data for humans and animals is needed to approximate a disabled submarine situation. These studies should include evaluation of short-term effects on pulmonary function and long term effects such as pulmonary fibrosis. As is the case for all irritant toxic gases reviewed in this report.
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