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PHOSGENE

BACKGROUND INFORMATION

PHYSICAL AND CHEMICAL PROPERTIES

Chemical formula:

COCl2

Molecular weight:

98.9

Chemical name:

Carbonyl chloride, carbon oxychloride, chloroformyl chloride

CAS number:

75–44–5

Freezing point:

−127.8°C

Boiling point:

7.5°C

Density, liquid:

1.4187 (20°C)

Density gas:

4.39 (20°C)

Specific gravity, gas:

3.4 (2°C) (air=1)

pecific gravity, liquid:

1.392 (19°C/4°C)

Solubility:

Slightly soluble in water (hydrolyzes to HC1 and CO2); soluble in carbon tetrachloride, chloroform, acetic acid, and toluene

General characteristics:

Easily liquified, colorless, nonflammable gas; odor, sweet at low concentrations and pungent at higher concentrations

Conversion factors:

1 ppm=4 mg/m3

1 mg/m3 =0.25 ppm

OCCURRENCE AND USE

Phosgene was first prepared in 1812 by the photochemical reaction of carbon monoxide and chlorine; it is now commercially prepared by passing chlorine and excess carbon monoxide over activated carbon. Depending on the quantity required and the availability of the raw material, numerous variations of the basic synthetic process are used. Continuous processing and a high degree of automation are required for phosgene purification, condensation, and storage.

In its first application, phosgene was the most heavily used chemical-warfare agent during World War I (Moore and Gates, 1946; Stavrakis, 1971). Its utility as a reactive chemical intermediate is of relatively recent origin (Chadwick and Hardy, 1967; Chadwick and Cleveland, 1981; Hardy, 1982; NIOSH, 1976). It is now an important and widely used intermediate; the majority of its production is captive, e.g., in the manufacture of other chemicals within the same plant. The principal use of phosgene is in the polyurethane industry, which consumes over 85% of the world’s phosgene output. It is also used in polycarbonate resins, dyes, and pharmaceutical intermediary products (Chadwick and Cleveland, 1981; Hardy, 1982; NIOSH, 1976).



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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 PHOSGENE BACKGROUND INFORMATION PHYSICAL AND CHEMICAL PROPERTIES Chemical formula: COCl2 Molecular weight: 98.9 Chemical name: Carbonyl chloride, carbon oxychloride, chloroformyl chloride CAS number: 75–44–5 Freezing point: −127.8°C Boiling point: 7.5°C Density, liquid: 1.4187 (20°C) Density gas: 4.39 (20°C) Specific gravity, gas: 3.4 (2°C) (air=1) pecific gravity, liquid: 1.392 (19°C/4°C) Solubility: Slightly soluble in water (hydrolyzes to HC1 and CO2); soluble in carbon tetrachloride, chloroform, acetic acid, and toluene General characteristics: Easily liquified, colorless, nonflammable gas; odor, sweet at low concentrations and pungent at higher concentrations Conversion factors: 1 ppm=4 mg/m3 1 mg/m3 =0.25 ppm OCCURRENCE AND USE Phosgene was first prepared in 1812 by the photochemical reaction of carbon monoxide and chlorine; it is now commercially prepared by passing chlorine and excess carbon monoxide over activated carbon. Depending on the quantity required and the availability of the raw material, numerous variations of the basic synthetic process are used. Continuous processing and a high degree of automation are required for phosgene purification, condensation, and storage. In its first application, phosgene was the most heavily used chemical-warfare agent during World War I (Moore and Gates, 1946; Stavrakis, 1971). Its utility as a reactive chemical intermediate is of relatively recent origin (Chadwick and Hardy, 1967; Chadwick and Cleveland, 1981; Hardy, 1982; NIOSH, 1976). It is now an important and widely used intermediate; the majority of its production is captive, e.g., in the manufacture of other chemicals within the same plant. The principal use of phosgene is in the polyurethane industry, which consumes over 85% of the world’s phosgene output. It is also used in polycarbonate resins, dyes, and pharmaceutical intermediary products (Chadwick and Cleveland, 1981; Hardy, 1982; NIOSH, 1976).

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 In 1978, demand for phosgene was an estimated 1,630 million pounds. The growth in U.S. demand for phosgene from 1970 to 1979 was 9.2%/yr; future growth in demand is forecast at 7.0%/yr through 1984 (Anonymous, 1980). The capacity for the production of phosgene in the United States (12 producers at 15 sites) in 1983 was estimated to be < 2,101 million pounds (SRI International, 1983). In 1973, the pattern of phosgene use was as follows: production of toluene diisocyanate (TDI), 61.7%; production of polymethylene polyphenylisocyanate (PMPPI), 23.6%; production of polycarbonate resins, 3.9%; and other uses (including production of acyl chlorides, chloroformate esters, diethylcarbonate, dimethylcarbamylchloride, isocyanates other than TDI and PMPPI, dyes, biocides and pharmaceuticals and use as a chlorinating agent), 10.7% (SRI International, not dated). In 1977, the polycarbonate industry consumed approximately 6% of the phosgene produced and herbicide manufacture and processing used 9% (Hardy, 1982). World production of isocyanates in 1978 has been estimated as 635,000 metric tons of TDI and 454,000 metric tons of diphenyl methane-4,4’-diisocyanate (MDI) products. The estimated 1981 capacities of U.S. manufacturers of isocyanates amounted to 318,000 and 444,000 metric tons for TDI and polymeric isocyanates, respectively (Chadwick and Cleveland, 1981). TDI is a precursor of polyurethane resins, which are widely used to make foams, elastomers, and coatings. Polycarbonate resins based on phosgene find use in appliance and electric-tool housings, electronic parts, and break-resistant glazing. A rapidly growing use of phosgene is in the preparation of PMPPI for the production of rigid polyurethane foams (SRI International, not dated). The reaction of phosgene with primary alkyl and aryl amines, referred to as phosgenation, yields carbamoyl chlorides, which can be dehydrohalogenated readily to isocyanates: RNH2+COCl2 → RNHCOCl → RN=C=O+HCl. This procedure is used almost exclusively for the production of isocyanates (Chadwick and Cleveland, 1981). All commercial manufacturing processes for aromatic isocyanates currently in use appear to have the following steps: A solution of an amine in an aromatic solvent—such as xylene, monochlorobenzene, or o-dichlorobenzene—is mixed with a solution of phosgene in the same solvent at a temperature below 60°C. The resulting mixture slurry is digested in one to three stages for several hours at progressively increasing temperatures up to 200°C; digestion is accompanied by the injection of additional phosgene. The final solution of reaction products is fractionated to recover hydrogen chloride, unreacted phosgene, and solvent for recycling, isocyanate product, and distillation residue.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 In addition to commercial production, phosgene can be produced by the thermal decomposition of chlorinated hydrocarbons (Spolyar et al., 1951) and by the photooxidation of chlorinated hydrocarbons in the atmosphere (NIOSH, 1976; Singh, 1976). For example, Singh (1976) demonstrated by field monitoring at four California sites (urban and nonurban) that chloroethylenes (primarily C2Cl4 and C2HCl3), which are emitted worldwide in extremely large quantities (1.5 million metric tons in 1975), photodecompose to form highly toxic species, such as phosgene and chloroacetylchlorides. On the basis of estimates from recent laboratory studies, present C2Cl4 and C2HCl3 emission could result in the formation of about 0.3 million metric tons of phosgene per year (Gay et al., 1976). Because these solvents are typically emitted in urban areas and are relatively reactive (the tropospheric half-lives of C2HCl3 and C2Cl4 are 2 and 4 days, respectively), high concentrations of phosgene could be encountered during adverse meteorologic conditions in and around urban centers. The atmospheric sinks of phosgene have not been fully delineated. Simulated tropospheric irradiation in the presence of water vapor suggests negligible tropospheric loss through photolysis and gas-phase hydrolysis. The two important sinks of phosgene appear to be heterogeneous decomposition and slow liquid-phase hydrolysis (Singh, 1976). NIOSH estimated that about 10,000 workers have potential occupational exposure to phosgene during its manufacture and use (NIOSH, 1976). Their occupations include those involved in the production of phosgene itself, chlorinated compounds, dyes, glass, herbicides, insecticides, isocyanates, organic chemicals, and resins and firefighting, welding, and brazing (Gafafer, 1966; NIOSH, 1976). Long-term exposure at low concentrations may occur in submarines. The potential source of phosgene in submarines could be leaked Freon undergoing thermal decomposition. SUMMARY OF TOXICITY INFORMATION EFFECTS ON HUMANS Three sources of exposure to phosgene in air are readily identifiable: direct emission of phosgene during manufacture, handling, and use (ACGIH, 1980; Polednak, 1980); thermal decomposition of polyvinyl-chloride (PVC) (Brown and Birky, 1980) and chlorinated hydrocarbons (Cucinell, 1974; NIOSH, 1976), such as chloroform, carbon tetrachloride, and trichloroethylene—solvents, paint removers, and nonflammable dry-cleaning fluids containing chlorinated hydrocarbons may decompose to phosgene in the presence of fire or heat (Diller, 1978); and photooxidation of chloroethylenes in air (Gross et al., 1965). The first two sources might result in serious indoor hazard (Diller, 1978; NIOSH, 1976; Spolyar et al., 1951), but their contribution to the total ambient phosgene content is minimal (Spolyar et al., 1951), whereas segments of the general population could be exposed at higher concentrations from atmospheric pollution, e.g., from fuel emission of municipal incinerators (Carotti and Kaiser, 1972).

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 Human exposure to gaseous phosgene reported in the literature is generally limited to episodes of acute exposure (Diller, 1978). The acute toxicity of phosgene is both dose- and time-dependent. Phosgene, at concentrations of 3–5 ppm causes irritation of the eyes and throat with coughing; exposure at 25 ppm for 30–60 min is dangerous; and brief exposure at 50 ppm may be rapidly fatal (Henderson and Haggard, 1943; Hygienic Guide Series, 1968; Patty, 1963; Sax, 1968). The symptoms of moderate exposure to phosgene are often dryness or a burning sensation in the throat, vomiting, pain in the chest, and dyspnea (Patty, 1963). Phosgene poisoning is characterized by a symptom-free latent period of 2–24 h followed by chest pain, shortness of breath, and increasing difficulty in breathing. Severe respiratory distress may be delayed for up to 72 h; the latent interval depends on the concentration and duration of exposure (Hygienic Guide Series, 1968). The distress is caused by pulmonary edema and is characterized by cough, production of foamy sputum, progressive dyspnea, and severe cyanosis (Patty, 1963). Pulmonary edema may progress to pneumonia, and cardiac failure may intervene. In nonfatal cases, no permanent residual damage is believed to occur (Patty, 1963; Sax, 1968). The mortality among two groups of workers exposed to phosgene gas at the same uranium-processing plant in 1943–1945 has been described by Polednak (1980). One group consisted of 699 white men with daily exposure at low concentrations or at concentrations above 1 ppm; the second group consisted of 106 men with definite acute exposures and symptoms at exposures equal to or greater than 50 ppm/min. A control group included 9,352 white men who worked at the same plant. Of the group of 106 men, 25 had x-ray evidence of acute pneumonitis, and one death from pulmonary edema due to phosgene occurred less than 24 h after exposure. A total of 30 deaths had occurred in this group as of 1974 (SMR=113); there were no deaths from lung cancer, but three deaths (vs. 1.37 expected) were due to respiratory disease. Mortality ratios (SMRs) for most causes of death among the 699 chemical workers were similar to those among 9,352 controls employed at the same plant but not exposed to phosgene (or uranium dust). Table 7 lists a number of cases of human phosgene inhalation exposure (NIOSH, 1976). Splashes of liquid phosgene into the eye may produce severe irritation, and skin contact may cause severe burns (Hygienic Guide Series, 1968). Fatal exposure to phosgene has resulted in extensive degenerative changes in the epithelium of the trachea, bronchi, and bronchioli and hemorrhagic edematous focal pneumonia (Gerritsen and Buschmann, 1960). Most fatalities due to acute phosgene exposure occur during the first 24–48 h (Chadwick and Hardy, 1967). Most patients who died within the first 72 h died of pulmonary edema or cardiac problems; those who died later had such complications as pulmonary infection, thrombosis, and embolism. The clinical course has also been described by NIOSH (1976), Boyd and Perry (1960), Delephine (1923), Gerritsen and Buschmann (1960), Glass et al. (1971), Long and Hatch (1961), Spolyar et al. (1951), Stavrakis (1971), and Underhill (1920). No effects other than odor detection were reported (NIOSH, 1976) in 56 military personnel (without upper respiratory problems) who were exposed to phosgene at increasing concentrations until they could all smell it. Of “technically trained” personnel, 50% detected phosgene

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 at 1.5 ppm, 39% detected it at 1.2 ppm, and none below 0.4 ppm (Wills et al., 1938). EFFECTS ON ANIMALS Acute overexposure to phosgene for short periods has generally produced the same symptoms in all animal species tested (NIOSH, 1976). The lungs appear to be the principal target organ for phosgene, and the characteristic pathologic feature is the development of pulmonary edema of unknown pathogenesis. Survivors of an acute episode exhibit various degrees of bronchopneumonia, benign pneumonia, bronchial plugging, lung collapse, pulmonary consolidation, pneumonia, and emphysema; animals that die after exposure show severe pulmonary edema. For example, Cameron et al. (1942a) exposed mice, rats, guinea pigs, rabbits, cats, monkeys, and goats to phosgene at 0.86 ppm for 5 h. Within 24 h, 10% of the rats and 60% of the mice died. Microscopic examination of the lungs showed severe effects in 39% of the animals, mild effects in 31%, and slight effects in 30%; pulmonary edema was the most common finding. Cameron et al. (1942b) also exposed mice, rats, guinea pigs, rabbits, cats, and goats to phosgene at 0.2 ppm, 5 h/d for 5 d. No deaths occurred from the acute exposure, and few animals showed any evidence of distress. Necropsy disclosed pulmonary lesions in 67% of the animals; an estimated 4–11% displayed moderate to severe lesions. Pulmonary edema was noted in 41% of the animals, but was usually slight. It was concluded that repeated exposure to phosgene at low concentrations induced lung damage, although rarely to a severe degree. However, Cucinell (1974), in reviewing the latter study, stressed the extensive lung lesions present in 4% of the animals. Exposure of the same species at 1 ppm, 5 h/d for 5 d caused pulmonary lesions that were considered “likely to give rise in man to serious clinical symptoms” (Cameron and Foss, 1941). Exposure of cats at the same concentration caused hemoconcentration and leukocytosis (Cucinell, 1974). Gross et al. (1965) demonstrated chronic pneumonitis in rats as early as 4 h after exposure to phosgene. The sensitivity of the alveolar epithelium to phosgene is such that the pulmonary reaction can be identified after exposures at concentrations as low as 0.5 ppm for 120 min. The lowest exposure that produced a recognizable typical pulmonary lesion had a Ct value (concentration of the gas, in parts per million, multiplied by the time of exposure, in minutes) of 15 (e.g., 3 ppm for 5 min). Ct values producing pneumonitis are summarized in Table 8. The chronic pneumonitis is initially centered in the respiratory bronchiole and its evaginating alveoli. There is cellular thickening of these structures with the elaboration of new reticulin fibers. In addition to having thickened walls, the alveoli are often filled with desquamated cells (Gross et al., 1965). Table 9 lists a number of additional phosgene inhalation studies conducted in animals (NIOSH, 1976). Phosgene is reportedly responsible for the development of long-term lung disease in man, as well as emphysema and obliterative bronchiolitis in dogs (Cucinell, 1974; Galdston et al., 1947; Rossing, 1964). Although no quantitative data are available on the dosage that

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 might cause permanent lung damage in man, it has been shown experimentally that exposure of dogs at 80–160 mg/m3 for 30 min every other day for a week causes interferences in lower airway resistance and, with continued exposure, permanent pathophysiologic changes within the lung (Rossing, 1964). According to Cucinell (1974), these concentrations are toxic and are 10–20 times greater than the dosage needed to produce pneumonitis (Table 8). The exact relation of phosgene exposure at these concentrations to human disease is unknown. Histopathologic examination of rats exposed at 0.2 and 1.0 ppm, 4 h/d, 5 d/wk for 2 wk at Haskell Laboratory (1976) showed no effects. The Committee is unaware of any data on the carcinogenic effects of phosgene. However, exposure at high concentrations could conceivably lead to neoplasia related to scarring or regeneration of damaged lung tissue (NIOSH, 1976). Cucinell (1974) reviewed aspects of the development of tolerance to phosgene in several species. For example, guinea pigs treated with low doses of phosgene—1.5 ppm (6 mg/m3) for 10 min—for 7 d became relatively resistant to toxic concentrations—35 ppm for 10 min (Cordier and Cordier, 1953b). Repeated exposure of cats to phosgene at 1.5–3.8 ppm or 5–6 ppm for 10 min every day had caused no greater lung damage after 40 d than after 2 d (Cordier and Cordier, 1953a). These animals were able to tolerate a total Ct of 9,000 mg · min/m3 (total time, 400 min), even though the LCt50 for cats is about 2,000 mg min/m3 for 1 min (Cucinell, 1974). Tolerance to high doses of phosgene is believed by some to represent a manifestation of pathologic changes in the lungs (Cucinell, 1974). The Committee is unaware of any data on the development of tolerance to phosgene in man. PHARMACOKINETICS When phosgene (which is only slightly soluble in water) is inhaled at a moderate concentration, it does not react noticeably with the aqueous mucous film of the upper respiratory tract. Without decomposition, phosgene then reaches the alveolar region and interacts there with components of the blood-air barrier. Immediate and irreversible damage occurs (Potts et al., 1949)—e.g., the membrane function breaks down, and fluid leaks from the capillaries into the interstitial space and then into the alveolar space, finally spreading to the trachea. The duration of this process—the developmental phase or clinical latent period (Diller, 1978)—depends on the inhaled dosage; the higher the dosage, the shorter the latent period. After moderate dosage, the clinical latent period may be about 6–15 h (Diller, 1978). Much of the current information on the metabolism of phosgene has been gained indirectly through recent studies of the in vitro metabolism of chloroform (Cresteil et al., 1979; Mansuy et al., 1977; Pohl et al., 1977) and carbon tetrachloride (Shah et al., 1979); that shows the intermediary formation of phosgene from both chlorinated hydrocarbons. For example, cysteine can form a stable adduct with chloroform metabolites when added to the incubation mixture (Mansuy et al., 1977; Pohl et al., 1977) and carbon tetrachloride (Shah et al., 1979); that shows

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 the intermediary formation of phosgene from both chlorinated hydrocarbons. For example, cysteine can form a stable adduct with chloroform metabolites when added to the incubation mixture (Mansuy et al, 1977; Pohl et al., 1977); this adduct is 4-carboxythiazolidine-2-one, the reaction product of cysteine with phosgene. The reactions of phosgene as a chloroform metabolite depend on which nucleophiles are present in the incubation medium (Cresteil et al., 1979; see Figure 3). Direct reaction with water leads to CO2, which is the final chloroform metabolite (Lavigne and Marchand, 1974; Paul and Rubinstein, 1963). Nucleophilic groups of microsomal macromolecules or free amino acids could react with phosgene and generate unstable acyl chlorides—e.g., carbamyl chlorides, chloroformates, or thiochloroformates, depending on whether the reacting group is amine, hydroxyl, or thiol (Cresteil et al., 1979). The reaction of these electrophilic intermediate acyl chlorides with water yields CO2 and regenerates the starting amino acid (or nucleophilic group of macromolecules). Finally, in this pathway, the nucleophilic group of amino acids catalyzes the hydrolysis of phosgene to CO2. With the evidence that phosgene is the precursor of CO2 from carbon tetrachloride (Shah et al., 1979), it was suggested that it might also be one of the reactive species that bind to lipids and proteins. Reynolds (1967) reported that 14COCl2 given to rats was found in liver protein and to a smaller extent in lipids, but the pattern was quite different from that of 14CCl4. Cessi et al., (1966) also reported that [14C]phosgene administered to rats labeled the liver proteins. INHALATION EXPOSURE LIMITS In 1980, ACGIH recommended a TLV for phosgene of 0.1 ppm for an 8-h working day (ACGIH, 1980). This figure is based on data obtained by the Chemical Warfare Service before 1921 that indicated that at 1 ppm phosgene may be safe for prolonged exposure (Cucinell, 1974). It is also based on the studies of Gross et al. (1965) that showed that exposure to phosgene at concentrations as low as 0.5 ppm for 2 h caused definitive pathologic changes in the lungs of rats killed 96 h after exposure. (Some abnormalities were considered to be present 3 mo after rats had been exposed at 2 ppm for 80 min.) A safe concentration zone of 0.1–0.125 ppm was recommended for international adoption in 1968 by the Joint ILO/WHO Committee on Occupational Health (ILO/WHO, 1968). In 1980, ACGIH recommended a TLV of 0.1 ppm, on the basis of its irritating effects on the respiratory tract at slightly above 0.1 ppm, to which tolerance develops (ACGIH, 1980). Table 10 lists additional maximal allowable concentrations (MACs) for 15 countries (ACGIH, 1983, International Labour Office, 1970; Jpn. Assoc. Ind. Health, 1971; OSHA, 1983; Soc. Ital. Med. Lav., 1975; Winell, 1975). NIOSH recommended in 1976 that occupational exposure to phosgene not exceed 0.1 ppm, determined as a TWA concentration for up to a 10-h workday in a 40-h workweek, or 0.2 ppm, as a ceiling concentration for any 15-min period (NIOSH, 1976). Cucinell (1974) suggested that the current standard of 0.1 ppm may be too high for 8 h/d, 5 d/wk at room temperature. It is also

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 believed that ambient concentrations of phosgene in Industrial situations in the United States are considerably below the TLV. Industrial intoxication by phosgene has been due primarily to accidental exposure at high concentration. Cucinell (1974) further suggested that some adjustments in the acceptable concentration for the general population must be made for a continuous 24-h/d exposure, as opposed to single or intermittent exposure; as noted previously, animals tolerate intermittent exposures to phosgene better than continuous exposure. It was further noted that, although high doses of phosgene can cause chronic lung disease in man and animals, it is not certain whether low doses can aggravate pre-existing conditions or cause lung disease (Cucinell, 1974). Because the lowest experimental values available for long-term exposure suggest that 0.2 ppm for 5 h/d for 5 d may cause slight changes in the lung (Cameron et al., 1942b), Cucinell (1974) suggests that a value of 0.1 ppm would not be safe enough. If a safety margin of a factor of 10 is used, the environmental concentration should be 0.02 ppm, and that should not be exceeded by working personnel during an 8-h/d, 5-d/wk exposure. In support of the suggested ceiling concentration of phosgene, it was suggested that a Ct of 10 ppm.min is safe and that this applicaton of Haber’s law—constant toxic effect=(concentration) (duration of exposure)—is valid. For an 8-h workday, the ceiling would be 0.02 ppm. Cucinell (1974) further proposed that, for a 24-h/d exposure, the ceiling should be lowered by about one-third to 0.006 ppm and an additional safety factor of 10 was recommended for situations in which the general population may be exposed (0.0006 ppm). Tentative EELs for phosgene were reviewed by Zielhuis (1970), who suggested that the most relevant animal exposures to consider were those of Rinehart and Hatch (1964) and Gross et al. (1965). For example, when rats were exposed at 0.5–4 ppm for 5–480 min, death occurred when the Ct exceeded 180; at a Ct of 300, the mortality was 60%. There were no respiratory-function effects or observable pathologic changes at autopsy at a Ct of 15 (3 ppm for 5 min). Accordingly, the above information suggests that the Ct for man should remain below 15 when t is less than 60 min. Zielhuis (1970) proposed the following exposure limits: Duration, min EEL, PPm EEL/TLV ratio 5 2.0 20 15 0.8 8 30 0.4 4 60 0.2 2 COMMITTEE RECOMMENDATIONS In 1966, the Committee on Toxicology recommended EELs and CEL for phosgene.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 On the basis of what appear to be the most relevant animal-exposure studies (Gross et al., 1965; Cameron et al., 1942a, b; Cameron and Foss, 1941; Rinehart and Hatch, 1964) and the rationale for lowered concentrations of phosgene as described by Cucinell (1974) and Zielhuis (1970), it appears prudent to propose lower EELs than the Committee recommended in 1966. The Committee has based its recommendations on studies done by Cameron and Foss (1941) and Cameron et al. (1942a, b) that show that animals do not tolerate phosgene at 0.2 ppm administered 5 h/d for 5 d (they developed slight pulmonary edema). The present Committee’s recommended EELs and CEL for phosgene and the limits proposed in 1966 are shown below.   1966 1984 60-min EEL 1.0 ppm 0.2 ppm 24-h EEL 0.1 ppm 0.02 ppm 90-d CEL 0.05 ppm 0.01 ppm

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 TABLE 7 Phosgene Inhalation Exposure Effects on Humansa No. Casesa Exposure Variables Duration of Exposure Effects Reference 109 Unknown 1 mol of phosgene Unknownb Brief Brief 30 min Pulmonary edema Pulmonary edema Pulmonary edema, death Thiess and Goldmann, 1968 2 Unknownb Unknownb Indefinite 3 h Pulmonary edema Pulmonary edema Gerritsen and Buschmann, 1960 1 Unknown (15 ppm)b,c 3.5 h Pulmonary edema, death Spolyar et al., 1951 1 Unknownb 4.5 h Acute bronchitis Glass et al., 1971 2 Unknown Unknown Brief Brief Bronchial irritation, death Delephine, 1923 1 Unknownb Brief Pulmonary edema Seidelin, 1961 7 Unknown Brief Acute bronchitis, delirium, pulmonary edema Steel, 1942 a Data from NIOSH, 1976. b Simultaneous exposure to chlorinated hydrocarbons. c Recreated exposure and simulating accident.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 TABLE 8 Pneumonitis Caused by Phosgene in Ratsa Ct, ppm-min Conc., ppm Time, min Chronic Pneumonitisb 13 1.3 10 0 15 1.5 10 0 24 0.8 30 + 27 0.9 30 + 33 1.1 30 − 36 1.2 30 + 40 1.0 40 + 48 0.8 60 ++ 48 0.8 60 +, P 54 0.9 60 ++, P 60 0.5 120 + 84 1.4 60 +++, P 88 1.1 80 + 90 0.5 180 + 90 0.5 180 ++ 90 0.5 180 + 90 1.5 60 +++ 96 0.8 120 +++ 108 0.9 120 0, P 120 1.0 120 ++, P 120 1.0 120 + 120 1.5 80 + 180 0.5 360 + 180 0.5 360 + 180 1.0 180 + 180 1.5 120 +++, P 192 1.2 160 ++ 198 1.1 180 +++ 210 1.0 210 ++ 228 1.9 120 ++ 240 0.5 480 +++, P 240 0.5 480 ++ 240 0.5 480 +++, P 240 1.0 240 ++, P 342 1.9 180 ++, P 360 1.0 360 +, F a Data from Gross et al., 1965. b 0=no chronic pneumonitis; +=slight chronic pneumonitis; ++=moderate chronic pneumonitis ; +++=severe chronic pneumonitis; P=acute pneumonia; and F=fibrinous pneumonia.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 TABLE 9 Phosgene Inahalation Exposures and Effects in Animalsa Species Concentration, ppm Duration of Exposure Duration of Effects Reference Rat 55–100 10 min Reduction in death rate from 74% to 33% by previous challenge Box and Cullumbine, 1947 Rabbit 50–200 14–25 min Decrease in sympathetic tone Ivanhoe and Meyers, 1964 Rabbit 67 30 min Pulmonary edema Boyd and Perry, 1960 Dog 44–120 30 min Pulmonary edema, pneumonia, emphysema, death Underhill, 1920 Dog 72 30 min Pulmonary consolidation, death Durlacher and Bunting, 1947 Dog 24–40 30 min, 1 or 2 exposures, 1–3/week Acute bronchiolitis Clay and Rossing, 1964 Dog 24–40 30 min, 4–10 exposures, 1–3/week Chronic bronchiolitis Clay and Rossing, 1964 Dog 24–40 30 min, 30–40 exposures, 1–3/week Emphysema Clay and Rossing, 1964 Cat and guinea pig 2.5–6.25 10 min/d, 2–41 d Pulmonary edema, bronchitis, bronchopneumonia, death Cordier and Cordier, 1953b a Data from NIOSH, 1976. b Animals were pregassed at 20 ppm for 10 min to determine effect of pregassing on response to later challenge.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 TABLE 10 Maximum Allowable Concentrations (MACs) for Phosgene Country Yeara MAC, mg/m3 Reference United States 1974 0.4 ACGIH, 1983 United States (OSHA) 1974 0.4 OSHA, 1983 West Germany 1974 0.4 Winell, 1975 East Germany 1973 0.5 Winell, 1975 Sweden 1975 0.3 (ceiling) Winell, 1975 CSSR (Czechoslovakia) 1969 0.4 Winell, 1975 USSR 1972 0.5 (ceiling) Winell, 1975 Italy 1975 0.4 Soc. Ital. Med. Lav., 1975 Japan 1969 0.4 Jpn. Assoc. Ind. Hlth., 1971 Bulgaria NG 0.5 Inter. Lab. Off., 1970 Finland NG 4 Inter. Lab. Off., 1970 Hungary NG 0.5 Inter. Lab. Off., 1970 Poland NG 0.5 Inter. Lab. Off., 1970 Rumania NG 0.5 Inter. Lab. Off., 1970 United Arab Republic NG 4 Inter. Lab. Off., 1970 Yugoslavia NG 0.4 Inter. Lab. Off., 1970 a NG=Not given.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 REFERENCES American Conference of Governmental Industrial Hygiensts. 1980. Documentation of the Thresold Limit Values. 4th ed., Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists. pp. 336–337. American Conference of Governmental Industrial Hygienists. 1983. TLVsR. Threshold Limit Values for Chemical Substances and Physical Agents in the Work Environment with Intended Changes for 1983–1984. Cincinnati, Ohio: American Conference of Governmental Hygienists 93 p. Anonymous. 1980. Phosgene. Chem. Mark. Rep. 217(3):9. Box, G.E.P., and Cullumbine, H. 1947. The effect of exposure to sub-lethal doses of phosgene on the subsequent L(Ct)50 for rats and mice. Br. J. Pharmacol. 2:38–55. Boyd, E.M., and Perry, W.F. 1960. Respiratory tract fluid and inhalation of phosgene. J. Pharm. Pharmacol. 12:726–732. Brown, J.E., and Birky, M.M. 1980. Phosgene in the thermal decomposition products of poly(vinylchoride): Generation, detection and measurement. J. Anal. Toxicol. 4:166–174. Cameron, G.R., and Foss, G.L. 1941. Effects of low concentrations of phosgene repeated for 5 hours on 5 consecutive days in groups of different animals. Porton Report No. 2316, Serial No. 63. Washington, D.C.: British Defense Staff, British Embassy. Cameron, G.R., Courtice, F.C., and Foss, G.L. 1942a. Effect of exposing different animals to a low concentration of phosgene 1:1,000,000 for 5 hours. Section IX in First Report on Phosgene Poisoning. Porton Report No. 2349, Washington, D.C.: British Defense Staff, British Embassy. Cameron, G.R., Courtice, F.C., and Foss, G.L. 1942b. Effect of exposed different animals to a low concentration of phosgene 1:1,000,000 for 5 hours on 5 consecutive days. Section VIII in First Report on Phosgene Poisoning. Porton Report No. 2349, Washington, D.C.: British Defense Staff, British Embassy. Carotti, A.A., and Kaiser, E.R. 1972. Concentrations of twenty gaseous chemical species in the fuel gas of a municipal incinerator. J. Air Pollut. Control Assoc. 22:248–253. Cessi, C., Colombini, C., and Mameli, L. 1966. The reaction of liver proteins with a metabolite of carbon tetrachloride. Biochem. J. 101:46C-47C.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 Chadwick, D.H., and Cleveland, T.H. 1981. Isocyanates, organic. In G.J. Burkey, C.I.Eastman, A.Klingsberg, L.Spiro, and M.Wainwright, eds., Kirk-Othmer Encyclopedia of Chemical Technology. 3rd rev. ed., Vol. 13. New York: Interscience Publishers, p. 789–818. Chadwick, D.H., and Hardy, E.E. 1967. Isocyanates, organic. In E.A. Parolla, C.Coeman, C.Comiskey, A.Klingsberg, and P.van Reyen, eds., Kirk-Othmer Encyclopedia of Chemical Technology. 2nd rev. ed., Vol. 12. New York: Interscience Publishers p. 54–58. Clay, J.R., and Rossing, R.G. 1964. Histopathology of exposure to phosgene. Arch. Pathol. 78:544–551. Compressed Gas Association, Inc. 1981. Handbook of Compressed Gases. 2nd ed. New York: Van Nostrand Reinhold Co. p. 430–435. Cordier, D., and Cordier, G. 1953a [Do repeated inhalation of weak concentration of phosgene sensitize the organism to a stronger concentration?] Compt. Rend. Sco. Biol. 147:327–330. Cordier, D., and Cordier, G. 1953b. The toxicity of weak concentration of phosgene after repeated inhalations. J. Physiol. 45:421–428. Cresteil, T., Beaune, P., Leroux, J.P., Lange, M., and Mansuy, D. 1979. Biotransformation of chloroform by rat and human liver microsomes; in vitro effects on some enzyme activities and mechanism of irreversible binding to micromolecules. Chem. Biol. Interactions 24:153–165. Cucinell, S.A. 1974. Review of the toxicity of long-term phosgene exposure. Arch. Environ. Health 28:272–275. Delephine, S. 1923. Summary of notes on two fatalities due to inhaling phosgene (COCl2). J. Ind. Hyg. 4:433–440. Diller, W.F. 1978. Medical phosgene problems and their possible solution. J. Occup. Med. 20:189–193. Durlacher, S.H., and Bunting, H. 1947. Pulmoanry changes following exposure to phosgene. Am. J. Pathol. 23:679–693. Gafafer, W.M., ed. 1966. Occupational Diseases: A Guide to Their Recognition. Washington, D.C.: U.S. Department of Health, Education, and Welfare, Public Health Service, p. 201 [Public Health Service Publ. No. 1097] Galdston, M., Luetscher, J.A., Jr., Longcope, W.T., and Ballich, N.L. 1947. A study of the residual effects of phosgene poisoning in human subjects. II. After chronic exposure. J. Clin. Invest. 26:169–181. Gay, B.W., Jr., Hanst, P.L., Bufalini, J.J., and Noonan, R.C. 1976. Atmsopheric oxidation of chlorinated ethylenes. Environ. Sci. Technol. 10:58–67.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 Gerritsen, W.B., and Buschmann, C.H. 1960. Phosgene poisoning caused by the use of chemical paint removers containing methylene chloride in ill-ventilated rooms heated by kerosene stoves. Br. J. Ind. Med. 17:187–189. Glass, W.I., Harris, E.A., and Whitlock, R.M. 1971. Phosgene poisoning: Case report. N.Z. Med. J. 74:386–389. Gross, P., Rinehart, W.E., and Hatch, T. 1965. Chronic pneumonitis caused by phosgene. Arch Environ. Health 10:768–775. Hardy, E.E. 1982. Phosgene. In: C.I.Eastman, A.Klingsburg, L.Spiro, G.Wachsman, and M.Wainwright, eds. Kirk-Othmer Encyclopedia of Chemical Technology. 3rd rev. ed., Vol. 17. New York: Interscience Publishers, p. 416–425. Haskell Laboratory. 1976. Report No. 223–76. Newark, Delaware: E.I. DuPont de Nemours and Co. Henderson, Y., and Haggard, H.W. 1943. Noxious Gases and the Principles of Respiration Influencing Their Action. Phosgene. 2nd and rev. ed. New York: Reinhold Publishing Corp. p. 137–138. Hygienic Guide Series. 1968. Phosgene (carbonyl chloride). Am. Ind. Hyg. Assoc. J. 29:308–311. International Labour Office/World Health Organization. 1968. Permissible Levels of Occupational Exposure to Airborne Toxic Substances. Sixth Report of the Joint ILO/WHO Committee on Occupational Health. World Health Organization Technical Report Series No. 415. Geneva: World Health Organization. 16 p. International Labour Office. 1970. Permissible Levels of Toxic Substances in the Working Environment. Sixth Session of the Joint ILO/WHO Committee on Occupational Health. Occupational Safety and Health Series 20. Geneva: ILO. 405 p. Ivanhoe, F., and Meyers, F.H. 1964. Phosgene poisoning as an example of neuropralytic acute pulmonary edema: The symathetic vasomotor reflex involved. Dis. Chest 46:211–218. Japanese Association of Industrial Health. 1971. Recommendations for permissible concentrations, etc. Trans. of Sangyo Igaku (Jpn. J. Ind. Health 13:475–484). Lavigne, J.-G., and Marchand, C. 1974. The role of metabolism in chloroform hepatotoxicity. Toxicol. Appl. Pharmacol. 29:312–326. Long, J.E., and Hatch, T.F. 1961. A method for assessing the physiological impairment produced by low-level exposure to pulmonary irritants. Am. Ind. Hyg. Assoc. J. 22:6–13.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 Mansuy, D., Beaune, P., Cresteil, T., Lange, M., and Leroux, J.-P. 1977. Evidence for phosgene formation during liver microsomal oxidation of chloroform. Biochem. Biophys. Res. Commun. 79:513–517. Moore, S., and Gates, M. 1946. Phosgene. In: Summary Technical Report of Division 9, NDRC. Vol. 1 Chemical Warfare Agents, and Related Chemical Problems. Par 1. Washington, D.C.: Office of Scientific Research and Development, National Defense Research Committee, p. 17–20. National Institute for Occupational Safety and Health. 1976. NIOSH Criteria for a Recommended Standard...Occupational Exposure to Phosgene. Cincinnati, Ohio: U.S. Department of Health, Education and Welfare, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health. 129 p. [HEW Publ. No. (NIOSH) 76–137] Occupational Safety and Health Administration. 1983. Toxic and Hazardous Substances. Air Contaminants 29 CFR 1910.1000. Patty, F.A. 1963. Phosgene, COC1. In D.W.Fassett, and D.D.Irish, eds., Patty’s Industrial Hygiene and Toxicology. Vol. II Toxicology. 2nd rev. ed. New York: Interscience Publishers, p. 938–940. Paul, B.B., and Rubinstein, D. 1963. Metabolism of carbon tetrachloride and chloroform by the rat. J. Pharmacol. Exp. Ther. 141:141–148. Pohl, L.R., Bhooshan, B., Whittaker, N.F., and Krishna, G. 1977. Phosgene: A metabolite of chloroform. Biochem. Biophys. Res. Commun. 79:684–691. Polednak, A.P. 1980. Mortality among men occupationally exposed to phosgene in 1943–1945. Environ. Res. 22–357–367. Potts, A.M., Simon, F.P., and Gerard, R.W. 1949. The mechanism of action of phosgene and diphosgene. Arch. Biochem. 24–329–337. Reynolds, E.S. 1967. Liver parenchymal cell injury. IV. Pattern of incorporation of carbon and chlorine from carbon tetrachloride into chemical constituents of liver in vivo. J. Pharmcol. Exp. Ther. 155:117–126. Rinehart, W.E., and Hatch, T. 1964. Concentration-time product (CT) as an expression of dose in sublethal exposures to phosgene. Am. Ind. Hyg. Assoc. J. 25:545–553. Rossing, R.G. 1964. Physiologic effects of chronic exposure to phosgene in dogs. Am. J. Physiol. 207:265–272. Sax, N.I. 1968. Dangerous Properties of Industrial Materials. 3rd ed., New York: Reinhold Book Corp. 1251 p. Seidelin, R. 1961. The inhalation of phosgene in a fire extinguisher accident. Thorax 16:91–93.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 Shah, H., Hartman, S.P., and Winhouse, S. 1979. Formation of carbony1 chloride in carbon tetrachloride metabolism by rat liver in vitro. Cancer Res. 39:3942–3947. Singh, H.B. 1976. Phosgene in ambient air. Nature 264:428–429. Societa Italiani di Medicina de Lavoro, Associazione Italiana degli Igienisti Industriali, Valori Limite Ponderati degli Inquinanti Chimici e Particolati degli Ambienti di Laoro per i1. 1975. Med. Lav. 66:361–371. Spolyar, L.W., Harger, R.N. Keppler, J.F., and Bumsted, H.E. 1951. Generation of phosgene during operation of trichloroethylene degreaser. AMA. Arch. Ind. Hyg. 4:156–160. SRI International, (not dated). Chemical Economics Handbook (CEH). Menlo Park, CA: Standard Research Institute International. [33 vols. loose leaf] SRI International. 1983. 1983 Directory of Chemical Producers, USA, Menlo Park, CA: Stanford Research Institute International. Stavrakis, P. 1971. The use of hexamethylenetetramine (HMT) in treatment of acute phosgene poisoning. Ind. Med. Surg. 40:30–31. Steel, J.P. 1942. Phosgene poisoning. Report of two cases. Lancet 1:316–317. Theiss, A.M., and Goldmann, P.J. 1968. Ist die Phosgenvergiftung noch ein arbeitsmedizinisches Problem? Zentr. ARbeitsmed. Arbeitsschutz 18:132–141. Underhill, F.P. 1920. The Lethal War Gases: Physiology and Experimental Treatment. New Haven: Yale University Press, p. 1–21, 40–84. Weast, R.C., and Astle, M.J., eds. 1978–1979. CRC Handbook of Chemistry and Physics. A Ready-Reference Book of Chemical and Physical Data. 59th ed. West Palm Beach, Florida: CRC Press, p. C-434. Wills, W.J.H.B., McFarland, C.W., and Webster, R.E. 1938. The detection of phosgene by odor. EATR 250. Aberdeen Proving Ground, MD; Edgewood Arsenal, March. Winell, M. 1975. An international comparison of hygienic standards for chemicals in the work environment. Ambio 4:34–36. Zielhuis, R.L. 1970. Tentative emergency exposure limits for sulphur dioxide, sulphuric acid, chlorine and phosgene. Ann. Occup. Hyg. 13:171–176.