5

Vinyl Chloride1

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-3—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 are defined as follows:

AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or 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 effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure

1This document was prepared by the AEGL Development Team composed of Fritz Kalberlah (Forschungs- und Beratungsinstitut Gefhtoffe GmbH), Chemical Manager Bob Benson (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). 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 guidelines reports (NRC 1993, 2001).



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5 Vinyl Chloride1 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 Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished 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-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or 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 effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. 1 This document was prepared by the AEGL Development Team composed of Fritz Kalberlah (Forschungs- und Beratungsinstitut Gefhtoffe GmbH), Chemical Manager Bob Benson (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). 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 con- cluded 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 guidelines re- ports (NRC 1993, 2001). 257

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258 Acute Exposure Guideline Levels 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 sus- ceptible 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 sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory 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 AEGL values 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 correspond- ing AEGL. SUMMARY Vinyl chloride (VC) is a colorless, flammable gas with a slightly sweet odor. It is heavier than air and accumulates at the bottom of rooms and tanks. Worldwide production of VC is approximately 27,000,000 tons. Most VC is polymerized to polyvinyl chloride. Combustion of VC in air produces carbon dioxide and hydrogen chloride. Odor thresholds of VC range from 10 to 25,000 ppm. Validated studies that provide quantitative data on odor recognition and detection are not available; therefore, a level of odor awareness (LOA) could not be derived. VC is an anesthetic compound. After a 5-min exposure to VC at 16,000 ppm, volunteers experienced dizziness, lightheadedness, nausea, and visual and auditory dulling (Lester et al. 1963). Mild headache and some dryness of the eyes and nose were the only complaints of volunteers exposed at 491 ppm for several hours (Baretta et al. 1969). No data on the developmental or reproduc- tive toxicity of VC in humans after acute exposure are available. Chromosomal aberrations in human lymphocytes were associated with accidental exposure to VC. After chronic occupational exposure, VC is a known human carcinogen that induces liver angiosarcoma, possibly hepatocellular carcinoma, and brain tu- mors. Evidence of tumors at other sites is contradictory. Two epidemiologic studies (Mundt et al. 2000; Ward et al. 2001) found no increase in standardized mortality ratios (SMRs) after 5 years of occupational exposure to VC, whereas a third study suggested an increase after 1-5 years of exposure (Boffetta et al. 2003).

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Vinyl Chloride 259 Acute exposure to VC results in narcotic effects (Mastromatteo et al. 1960), cardiac sensitization (Clark and Tinston 1973, 1982), and hepatotoxicity (Jaeger et al. 1974) in laboratory animals. Prodan et al. (1975) reported 2-h LC50 values (lethal concentration, 50% lethality) for mice, rats, rabbits, and guinea pigs of 117,500, 150,000, 240,000, and 240,000 ppm, respectively. No studies of reproductive or developmental toxicity after a single exposure are available. In repeated-exposure studies, developmental toxicity (e.g., delayed ossification) in mice, rats, and rabbits was observed only at maternally toxic concentrations. Embryo-fetal development of rats was not affected by VC at concentrations up to 1,100 ppm for 2 weeks (6 h/day) (Thornton et al. 2002). Positive results for genotoxicity after in vitro and single and repeated in vivo treatment have been reported for VC. Elevated etheno-adducts were observed after single and short- term exposure and were associated with mutational events (Barbin 2000; Swen- berg et al. 2000). Adduct levels in young animals were greater than in adult animals after identical treatment (Laib et al. 1989; Ciroussel et al. 1990; Fedtke et al. 1990; Morinello et al. 2002). A study of adult rats exposed to VC at 45 ppm for 6 h found no increase in relevant etheno-adducts above background (Watson et al. 1991). Induction of liver tumors has been reported in rats after short-term (5 weeks and 33 days) exposure (Maltoni et al. 1981, 1984; Froment et al. 1994). VC induces lung tumors in mice after a single exposure to high concentrations of VC (Hehir et al. 1981). Short-term exposure experiments by Drew et al. (1983), Maltoni et al. (1981), and Froment et al. (1994) indicated newborn and young animals are more susceptible to tumor formation than adult animals. The cancer risk from exposure to VC for 30 min to 8 h was estimated on the basis of laboratory animal data. However, there is great uncertainty in those estimates, and they conflict with epidemiologic data on occupational ex- posure to VC. AEGL-1 values are based on a study of four to seven volunteers exposed to VC (Baretta et al. 1969). Two individuals experienced mild headache when exposed to VC at 491 ppm for 3.5 h and 7.5 h (two exposures for 3.5 h, with a 0.5 h break between exposures). The time of onset of headaches was not speci- fied, so it was assumed to be after 3.5 h. A total uncertainty factor of 3 was used. Because the AEGL-1 values are based on human data no interspecies uncer- tainty factor was used. The effects are probably from VC in the blood and not a metabolite. Only small interindividual differences in the pharmacokinetics of VC are expected, as the concentration of VC required to elicit the AEGL-1 ef- fect is greater than that required for saturation of the metabolic pathways. An intraspecies uncertainty factor of 3 is used to account for toxicodynamic differ- ences among individuals. The other exposure duration-specific values were de- rived by time scaling according to the dose-response regression equation Cn × t = k, using the default of n = 3 for shorter exposure periods and n = 1 for longer exposure periods; there were no suitable experimental data for deriving the value of n. The default values were used because the mechanism for the induc- tion of headache is unknown, but is unlikely to be a simple function of VC in the

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260 Acute Exposure Guideline Levels blood. The extrapolation from a 3.5 h exposure to 10 min is justified because humans exposed at 4,000 ppm for 5 min did not experience headaches (Lester et al. 1963). The AEGL-2 values are based on prenarcotic effects observed in human volunteers. After exposure to VC at 16,000 ppm for 5 min, five of six persons experienced dizziness, lightheadedness, nausea, and visual and auditory dulling. At 12,000 ppm, one of six persons experienced dizziness and “swimming head, reeling.” No effects were reported at 4,000 ppm. A single person reported slight effects (“slightly heady”) of questionable meaning at 8,000 ppm (this volunteer also felt slightly heady when given a sham exposure and reported no response when exposed at 12,000 ppm) (Lester et al. 1963). VC at 12,000 ppm was con- sidered the no-effect level for impaired ability to escape. An intraspecies uncer- tainty factor of 3 was used to account for toxicodynamic differences among in- dividuals. The effects are probably from VC in the blood and not a metabolite. Only small interindividual differences in pharmacokinetics of VC are expected, as the concentration of VC required to elicit AEGL-2 effects is greater than that required for saturation of the metabolic pathways. By analogy with other anes- thetics, the effects are assumed to be solely concentration dependent. Thus, after reaching steady state after about 2 h, no increase in effect is expected. The other exposure duration-specific values were derived by time scaling according to the dose-response regression equation Cn × t = k, with n = 2, based on a study by Mastromatteo et al. (1960). This study reported various time-dependent prenar- cotic effects in mice and guinea pigs after less than steady-state exposure condi- tions. Time extrapolation was performed from 5 min to 10-min, 30-min, 60-min, and 2-h exposures. The steady state concentration at 2 h is used for the 4- and 8- h values. The AEGL-3 values are based on cardiac sensitization and the no-effect level for lethality. Short-term exposure (5 min) to VC induced cardiac sensitiza- tion in dogs (effective concentration producing 50% response [EC50] was 50,000 and 71,000 ppm in two independent experiments) (Clark and Tinston 1973, 1982). Severe cardiac sensitization is a life-threatening effect, but at 50,000 ppm no animals died. The cardiac-sensitization model with the dog is considered an appropriate model for humans and is highly sensitive because the response is optimized by the exogenous administration of epinephrine (Brock et al. 2003; ECETOC 2009). This protocol is conservative and has built-in safety factors; thus, no additional uncertainty factors were considered necessary (ECETOC 2009). Accordingly, an interspecies uncertainty factor of 1 was applied. Only small interindividual differences in pharmacokinetics of VC are expected, as the concentration of VC required to elicit the effect is greater than that required for saturation of the metabolic pathways. An intraspecies uncertainty factor of 3 is used to account for toxicodynamic differences among individuals. By analogy with other halocarbons (e.g., Halon 1211, HFC 134a) that are cardiac sensitizer, the effects are assumed to be solely dependent on the concentration of VC in the blood. Thus, after reaching steady state after about 2 h, no increase in effect is expected. The other exposure duration-specific values were derived by time

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Vinyl Chloride 261 scaling according to the dose-response regression equation Cn × t = k, with n = 2, based on data from Mastromatteo et al. (1960). Time extrapolation was per- formed from 5 min to 10-min, 30-min, 60-min, and 2-h exposures. The steady state concentration at 2 h is used for the 4- and 8-h values. The AEGLs values for VC are presented in Table 5-1. 1. INTRODUCTION VC is a colorless, flammable gas with a slightly sweet odor. It is heavier than air and accumulates at the bottom of rooms and tanks. Its worldwide pro- duction is approximately 27,000,000 tons. Most VC is polymerized to polyvinyl chloride, which subsequently is used to produce packaging materials, building materials, electric appliances, medical-care equipment, toys, agricultural piping and tubing, and automobile parts. The largest single use of polyvinyl chloride is in the building sector (WHO 1999). About 10,000 tons are used in the produc- tion of 1,1,1-trichloroethane and other chlorinated solvents on an annual basis (Kielhorn et al. 2000). TABLE 5-1 Summary of AEGL Values for Vinyl Chloridea End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 450 ppm 310 ppm 250 ppm 140 ppm 70 ppm Mild headaches (nondisabling) (1,200 (800 (650 (360 (180 in 2/7 humans mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (Baretta et al. 1969); no-effect level for notable discomfort. AEGL-2 2,800 ppm 1,600 ppm 1,200 ppm 820 ppm 820 ppm Mild dizziness (disabling) (7,300 (4,100 (3,100 (2,100 (2,100 in 1/6 humans mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (Lester et al. 1963); no-effect level for impaired ability to escape. 12,000 ppmb 6,800 ppmb 4,800 ppmb 3,400 ppm AEGL-3 3,400 ppm Cardiac (lethal) (31,000 (18,000 (12,000 (8,800 (8,800 sensitization mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (Clark and Tinston 1973, 1982); no-effect level for lethality. a Derivation of the AEGL values excludes potential mutagenic or carcinogenic effects after a single exposure, which might occur at lower concentrations based on laboratory animal data (see Appendix C). b The explosion limits for VC in air range from 38,000 ppm to 293,000 ppm. The 10-min, 30-min, and 1-h AEGL-3 values exceed 10% of the lower explosion limit. Therefore, safety considerations against explosion should be taken into account.

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262 Acute Exposure Guideline Levels Most VC is produced either by hydrochlorination of acetylene, mainly in Eastern European countries, or by thermal cracking of 1,2-dichloroethane. VC is stored either under pressure at ambient temperature or refrigerated at atmos- pheric pressure (WHO 1999). Since it does not polymerize readily, VC is stored without additives. Combustion of VC in air produces carbon dioxide and hydro- gen chloride (WHO 1999). The chemical and physical properties of VC are presented in Table 5-2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Danziger (1960) describes two worker deaths from accidental exposure to VC. The concentration and exposure duration were not specified, but circum- stances suggest inhalation of very high concentrations of VC. Autopsy results show cyanosis, congestion of lung and kidneys, and failure of blood coagulation. Citing results from Schaumann (1934), 12% VC (120,000 ppm) is reported as “dangerous concentrations” (Danziger 1960; Oster et al. 1947). At very high concentrations, VC causes asphyxia, probably from narcosis- induced respiratory failure (HSDB 2005). TABLE 5-2 Chemical and Physical Properties of Vinyl Chloride Parameter Value Reference Synonyms Vinyl chloride monomer, monochlorethene, WHO 1999 monochlorethylene, 1-chloroethylene, chlorethylene, chloroethene CAS Reg. No. 75-01-4 WHO 1999 Chemical formula C2H3Cl WHO 1999 Molecular weight 62.5 g/mol WHO 1999 Physical state Gaseous (at room temperature) WHO 1999 Color Colorless WHO 1999 Melting point -153.8°C WHO 1999 Boiling point -13.4°C WHO 1999 0.910 g/cm3 at 20°C Density WHO 1999 Solubility in water Soluble in almost all organic solvents, slightly WHO 1999 soluble in water Vapor pressure 78 kPa at -20°C WHO 1999 165 kPa at 0°C 333 kPa at 20°C Odor Slightly sweet WHO 1999 Explosion limits in air 3.8-29.3 vol% in air at 20°C; WHO 1999 4-22 vol% 1 ppm = 2.59 mg/m3 at 20°C, 101.3 kPa Conversion factors WHO 1999 1 mg/m3 =0.386 ppm

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Vinyl Chloride 263 2.2. Nonlethal Toxicity A summary of the acute effects in humans after exposure to VC is pre- sented in Table 5-3. TABLE 5-3 Summary of Acute Effects in Humans after Inhalation of Vinyl Chloride Concentration Duration Effects Reference Very high Unknown Ocular irritation Danziger 1960 25,000 ppm 3 min Dizziness, disorientation with regard to Patty et al. 1930 space and size, burning sensation in feet, persistent headache. 20,000 ppm 5 min 6/6 dizziness, lightheadedness, nausea, Lester et al. visual and auditory dulling, 1/6 persistent 1963 headache. 16,000 ppm 5 min 5/6 dizziness, lightheadedness, nausea, Lester et al. visual and auditory dulling; no effects in 1963 one volunteer. 12,000 ppm 5 min 1/6 “swimming head, reeling,” 1/6 “unsure” Lester et al. of effects (somewhat dizzy in the middle of 1963 exposure). 8,000 ppm 5 min 1/6 “slightly heady” (volunteer also felt Lester et al. slightly heady at sham exposure and 1963 reported no effects at 12,000 ppm). 4,000 ppm 5 min No effects. Lester et al. 1963 3,000 ppm Unknown Odor threshold (geometric averages of Amoore and three studies, omitting extreme points and Hautala 1983 duplicate quotations). High, Unknown Prenarcotic and narcotic effects; repeated Suciu et not specified exposure caused headaches, asthenovegetative al. 1975 syndrome, cardiovascular effects, hepatomegaly. 491 or 3.5 h 2/7 reported mild headache and dryness Baretta et 459 ppm of the eyes and nose. al. 1969 261 ppm Unknown Detection of VC odor by 4/4 subjects. Baretta et al. 1969 20 ppm Unknown Odor threshold in polyvinyl chloride Hori et al.1972 production workers. 10 ppm Unknown Odor threshold in workers from a polyvinyl Hori et al. 1972 chloride facility not working in polyvinyl chloride production.

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264 Acute Exposure Guideline Levels 2.2.1. Neurotoxicity VC was considered a potential anesthetic. A narcotic limit concentration for man is 7-10% (70,000-100,000 ppm) (Lehmann and Flury 1938; Oster et al. 1947; Danziger 1960). Schauman (1934) reported narcosis at somewhat higher concentrations. Exposure to unknown, high concentrations of VC (e.g., during cleaning of autoclaves) also resulted in narcotic effects (Suciu et al. 1975). Acute Exposure Lester et al. (1963) exposed six volunteers (three men and three women) to VC at 0, 0.4, 0.8, 1.2, 1.6, or 2% (0, 4,000, 8,000, 12,000, 16,000, or 20,000 ppm, nominal concentration) for 5 min using a plastic breathing mask that cov- ered the mouth and nose. The total gas flow was 50 liters per minute (L/min). The desired concentrations were obtained by metering air and VC (gas chroma- tography of the liquid phase indicated more than 99% VC) through flow meters and passing the appropriate flows through a 2-L mixing chamber. The concen- tration was continuously monitored by a thermal conductivity meter (less than 5% deviation from the desired concentration). All volunteers were exposed to every concentration in a randomized fashion, separated by a 6-h interval. Dizzi- ness (“slightly heady”) was experienced by one volunteer at 8,000 ppm (the sub- ject also reported slight dizziness at sham exposure and reported no response at 12,000 ppm). At 12,000 ppm, four people reported no response, one subject re- ported reeling and swimming head, and another subject was unsure of some ef- fects. The latter person had a somewhat dizzy feeling in the middle of exposure. Dizziness, nausea, headache, and dulling of visual and auditory cues were re- ported by five people exposed to VC at 16,000 ppm and by all subjects exposed at 20,000 ppm. All symptoms disappeared shortly after termination of exposure; headache persisted for 30 min in one subject after exposure at 20,000 ppm. Two experimenters were exposed to VC at 25,000 ppm (nominal concen- tration) for 3 min by entering an exposure chamber. They reported dizziness, slight disorientation with regard space and size of surrounding objects, and a burning sensation in the feet. The subjects immediately recovered on leaving the chamber and complained only of a slight headache that persisted for 30 min. No further details were presented (Patty et al. 1930). Baretta et al. (1969) exposed four to six volunteers to VC at 59, 261, and 491 ppm (analytic concentrations) for 7.5 h (including a 0.5 h lunch period). The corresponding time-weighted average concentrations were 48, 248, and 459 ppm over 7.5 h. Seven people were exposed at 491 ppm for only 3.5 h. The subjects were exposed in an exposure chamber (41 feet × 6 feet, 7.5 feet high) with a continuous positive air supply and exhaust system. Air was recirculated with a squirrel cage fan through a series of inlet and outlet ducts spanning the length of the chamber. VC concentration was monitored by an infrared spectrophotome- ter. The vapors were introduced from a pressurized storage cylinder through 6 feet of 1/8 inch in diameter stainless-steel tubing into a rotometer prior to enter-

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Vinyl Chloride 265 ing the circulating air duct. A heating tape wrapped around the stainless-steel tubing prevented condensation of VC. Subjective and neurologic responses of the volunteers, as well as clinical parameters, were measured. Two subjects re- ported mild headache and some dryness of their eyes and nose after exposure to the highest concentration. The time of onset of headaches is not clearly stated, so it was assumed that headaches occurred in both experiments after 3.5 h and during or after 7.5 h. According to a literature review, acute human exposure to VC at 1,000 ppm for 1 h leads to fatigue and vision disturbances (Lefaux 1966). Exposure at 5,000 ppm for 60 min has lead to nausea and disorientation (Oettel 1954), with similar effects reported at 6,000 ppm for 30 min (Patty et al. 1930). VC concen- trations of 6,000 to 8,000 ppm are reported to result in prenarcotic symptoms (von Oettingen 1964). Examination of the primary literature did not show how those values were derived. No experimental background or observational data were provided. Thus, the referred results might not be used for risk assessment. Occupational Exposure Suciu et al. (1975) reported acute effects after 1,684 workers from two factories were exposed to VC. When air concentrations of VC were high (1963- 1964), acute and subacute poisonings occurred. After the first breaths of “a high concentration of VC,” pleasant taste in the mouth, euphoric conditions, slow movements, giddiness, and inebriety-like condition were reported. Continued exposure caused more pronounced symptoms of somnolence and complete nar- cosis. After repeated exposures to unknown high concentrations, workers com- plained of headaches, irritability, diminution of memory, insomnia, general as- thenia, paresthesia, tingling, and loss of weight. In addition to an “onset of an asthenovegetative syndrome,” other systemic and local effects included cardio- vascular effects, hepatomegaly, digestive responses, and respiratory changes. Workplace concentrations of VC in the factory were 2,300 mg/m3 (about 890 ppm) in 1963 and decreased in subsequent years. This VC concentration may have been an average exposure (not specified in the report). No information on peak concentrations and duration of episodes with short-term high concentra- tions of VC exposure was provided. Some of the reported activities, such as cleaning autoclaves, are associated with very high exposures. Several authors have reported headache in workers chronically exposed to VC. Exposure concentration and duration were not specified, but always were characterized as “high” (Lilis et al. 1975; Suciu et al. 1975; EPA 1987). 2.2.2. Odor A wide range of odor thresholds (10-25,000 ppm [26-65,000 mg/m3]) have been reported in the literature. Hori et al. (1972) reported a threshold of 20 ppm in production workers and 10 ppm in workers from other departments of

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266 Acute Exposure Guideline Levels polyvinyl-chloride facilities (number of workers not specified). VC odor was perceived by 50% of the “non-production” workers at 200 ppm and by 50% of the “production” workers at 350 ppm. Odor threshold was tested by two meth- ods. Polyvinyl chloride was diluted with air at fixed concentrations and was supplied from a glass injector to the subject’s nostrils at a rate of 100 mL over 5 to 10 seconds. This procedure was repeated using gradually higher concentra- tions of VC until the subject perceived an odor. The second method involved measuring atmospheric concentrations of VC. Production workers were less sensitive to VC than workers from other departments. When workers from dif- ferent facilities were compared, even greater ranges on odor threshold were ob- served. However, interindividual differences and measurement techniques were not strictly controlled. The odor thresholds reported by Hori et al. (1972) were reviewed by the American Industrial Hygiene Association and were rejected because there was no calibration of panel odor sensitivity, it was not clear whether the limit was based on recognition or detection, and the number of trials was not stated in the study (AIHA 1997). Baretta et al. (1969) reported that none of six subjects perceived odor after entering an exposure chamber with VC at 59 ppm, whereas at 261 ppm all four subjects detected a very slight odor. Five of seven subjects were able to detect the odor of VC at 491 ppm, but after 5 min the odor was no longer perceived (study details described earlier). Two people exposed to VC at 25,000 ppm (nominal concentration) for 3 min in an experimental exposure chamber reported a “fairly pleasant odor” (Patty et al. 1930). Amoore and Hautala (1983) reported an odor threshold for VC of 3,000 ppm. This value reportedly represents the geometric average of three literature studies (individual studies not mentioned); studies reporting extreme points and duplicate quotations were omitted. It was not stated whether the value was a detection or recognition threshold. 2.2.3. Irritation Acute Exposure Irritating effects of VC are only observed after exposure to very high con- centrations. Lesions of the eyes (wedge-shaped brown discoloration of the bul- bar conjunctiva, palpebral slits, and conjunctiva and cornea appeared dry) were observed at autopsy in a worker who died from inhalation of very high concen- trations of VC. Intensely hyperemic lungs, with desquamation of the alveolar epithelium also were observed (Danziger 1960). Chronic Exposure Tribukh et al. (1949) reported mucous irritation of the upper respiratory tract and chronic bronchitis in polyvinyl-chloride workers; however, Lilis et al. (1975) and Marsteller et al. (1975) did not mention these effects.

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Vinyl Chloride 267 Suciu et al. (1975) describe coughing and sneezing after exposure of workers to VC during one shift; no other acute pulmonary effects or irritation were mentioned. These workers had been regularly exposed to VC for an ex- tended duration. In chronically exposed VC workers, evidence for adverse respiratory dis- ease is conflicting. Lung function (respiratory volume, vital capacity, and oxy- gen and carbon dioxide transfer) deteriorates over time. Emphysema, chronic obstructive pulmonary disease (COPD), respiratory insufficiency, dyspnea, and pulmonary fibrosis have been described (Suciu et al. 1975; Walker 1976; Lloyd et al. 1984). Some of these observations have been attributed to smoking as a possible confounder. 2.2.4. Cardiovascular Effects A slight decrease in blood pressure in VC workers has been attributed to the narcotic effects of VC (Suciu et al. 1975). In older experiments in human volunteers, no cardiovascular parameters have been measured (Lester et al. 1963). Raynaud’s disease has been correlated with extended occupational expo- sure to high concentrations of VC (ATSDR 1997), with histologic alterations of small vessels (Veltman et al. 1975). Other symptoms observed in VC workers are splenomegaly, hypertension, portal hypertension, generally increased car- diovascular mortality, and vasospastic symptoms (Suciu et al. 1975; Byron et al. 1976; ATSDR 1997). According to Kotseva, elevated occupational exposure to VC increases the incidence of arterial hypertension, but there is no conclusive evidence that it is associated on its own with an increased risk of coronary heart disease (Beck et al. 1973). 2.2.5. Other End Points Hematology and Immunology Blood tests of two workers that died from exposure to VC indicated failure of blood coagulation (Danziger et al. 1960). Hepatotoxicity More or less pronounced hepatitis and enlargement of the liver have been reported in chronically exposed workers (Marsteller et al. 1975; ECB 2000). In another study, impaired liver function and periportal liver fibrosis was found in workers at a polyvinyl chloride producing plant (no further details presented) (Lange et al. 1974). Liver function disturbances have been reported in workers from polyvinyl chloride producing factories (Fleig and Thiess 1978). Focal

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328 Acute Exposure Guideline Levels A similar result is obtained if the tumor data from Froment et al. (1994) are used. Froment et al. exposed newborn animals to only one concentration of VC (500 ppm). Hence, fewer extrapolations were needed compared with the Maltoni et al. (1981) data (data and calculation not shown). For both calcula- tions, there is uncertainty about the influence of exposure to VC via mother’s milk. Because of metabolic saturation at high-level inhalation exposure, this influence might have been limited. However, no estimate of the quantitative consequences of this multipathway exposure can be given. There is great uncertainty in these calculations. Appendix D summarizes a number of epidemiologic studies of occupational exposure to VC. There is no evidence from these studies that short-term exposure to VC results in an in- creased prevalence of tumors. For example, Ward et al. (2000) and Mundt et al. (1999) report that workplace exposures of <4 years or <6 years show no increase in the prevalence of liver or liver and biliary tract cancer. In addition, Ward et al. (2000) showed that cumulative exposures to VC of <734 ppm/year were not associated with a statistically significant increase in liver cancer. When the ex- posure was <287 ppm/year, there were no angiosarcomas reported in workers. A concentration of 40 ppm for 8 h (estimated from Calculation B to be associated with a cancer risk of 1 × 10-4) is equivalent to a cumulative exposure of 0.16 ppm/year. Thus, human experience with VC is inconsistent with the cancer risk values calculated from the laboratory animal data. TABLE C-6 Cancer Risks from Vinyl Chloride Based on Calculation B Cancer Risk 30 min 1h 4h 8h 1 ×10-4 1,180 ppm 350 ppm 80.9 ppm 40.3 ppm 3,110 mg/m3 922 mg/m3 213 mg/m3 106 mg/m3 1 × 10-5 64.6 ppm 32.1 ppm 7.98 ppm 3.99 ppm 170 mg/m3 84.4 mg/m3 21.0 mg/m3 10.5 mg/m3 1 ×10-6 6.38 ppm 3.19 ppm 0.798 ppm 0.399 ppm 16.8 mg/m3 8.40 mg/m3 2.10 mg/m3 1.05 mg/m3 TABLE C-7 Comparison of AEGL Values for Vinyl Chloride and Cancer Risks Based on Calculation B 10 min 30 min 1h 4h 8h 1 ×10-4 risk — 1,180 ppm 350 ppm 80.9 ppm 40.3 ppm 3,110 mg/m3 922 mg/m3 213 mg/m3 106 mg/m3 AEGL-1 450 ppm 310 ppm 250 ppm 140 ppm 70 ppm 1,200 mg/m3 800 mg/m3 650 mg/m3 360 mg/m3 180 mg/m3 AEGL-2 2,800 ppm 1,600 ppm 1,200 ppm 820 ppm 820 ppm 7,300 mg/m3 4,100 mg/m3 3,100 mg/m3 2,100 mg/m3 2,100 mg/m3 AEGL-3 12,000 ppm 6,800 ppm 4,800 ppm 3,400 ppm 3,400 ppm 31,000 mg/m3 18,000 mg/m3 12,000 mg/m3 8,800 mg/m3 8,800 mg/m3

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Vinyl Chloride 329 APPENDIX D OCCUPATIONAL EPIDEMIOLOGIC STUDIES OF VINYL CHLORIDE Two large studies of workers employed in industries using VC monomer and polyvinyl chloride before 1974 were evaluated. Both studies were retrospec- tive cohort mortality studies. The first study was conducted in Europe and in- cluded study populations in Italy, Norway, Sweden, and the United Kingdom. The second study included plants in the United States and Canada. Each study was updated multiple times and has been the subject of numerous publications. Only the results from the most recent updates are discussed here. The focus is to review the liver cancer incidence in workers exposed to VC for relatively short- term periods or where the cumulative dose (ppm/year) was known to have been low. Both studies have more deaths from angiosarcomas of the liver than ex- pected among workers with high or long-term exposure to VC (Mundt et al. 1999; Ward et al. 2000). A third study from Weber et al. (1981) conducted in Germany had results that conflict with the two other studies. European Study The European study included approximately 12,700 men with at least 1 year of employment in the VC or polyvinyl chloride industry from 1955 to 1974 (Ward et al. 2000). Three of the 19 plants had incomplete records, so the starting date for data from those three plants ranged from 1961 to 1974. The vital status follow-up was complete through 1997. Age- and calendar-period specific mor- tality rates for males from Italy, Norway, Sweden, and the United Kingdom were used to calculate the standardized mortality ratios (SMRs) and 95% confi- dence intervals (CIs). Typical exposure scenarios were estimated by industrial hygienists on the basis of job exposure matrices. These matrices were based primarily on job title and were reviewed by two other industrial hygienists with several years of experience in the VC industry. Information provided in the job exposure matrix was used to develop a ranked exposure index. Quantitative es- timates of exposure were obtained for 82% of the cohort. The total number of person-years at risk for the cohort was 324,701. The work force was classified by duration of employment: <3, 3-6, 7-11, 12-18, and >19 ppm-years. The SMR for liver cancer for workers with <3 years experience was 62 (95% CI: 2-345), below the expected value (see Table D-1). For workers exposed to VC for a longer duration, the incidence of liver cancer was higher than expected. In general, the incidence of liver cancer increased with years of employment in the industry.

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330 Acute Exposure Guideline Levels TABLE D-1 Liver Cancer Incidence for All European Countries by Duration of Employment Duration of Incidence Employment Number of Number of (observed/ SMR Individualsa (95% CI)b (years) expected) Person (years) <3 10,961 91,970 1/1.61 62 (2-345) 3-6 8,999 79,747 3/1.44 208 (43-609) 7-11 6,919 65,789 7/1.35 517 (208-1,060) 12-18 4,610 55,149 5/1.42 352 (114-821) 1>9 2,006 32,050 13/1.46 893 (475-1,530) Total 12,700 324,706 29/7.29 398 (267-572) a The number of individuals cited for various employment intervals is greater than 12,700 because individuals can meet more than one criteria as defined by the author. b Observed/expected × 100. Abbreviations: CI, confidence interval; SMR, standardized mortality ratio. Source: Adapted from Ward et al. 2000. In addition, Ward et al. (2000) examined cumulative exposures in the co- hort (see Table D-2). The work force was subdivided into 0-734, 735-2,379, 2,380-5,188, 5,189-7,531 and >7,532 ppm/years. The SMR was 107 (95% CI: 54-192) based on 11 observed liver cancers and 10.26 expected. Assuming workers are employed in the industry for up to 30 years, to be included in this first category, the highest average concentration the worker would have been exposed to was ~25 ppm. Workers with shorter work histories may have been exposed at much higher concentrations. Under this scenario there was no in- crease in the incidence of liver cancer. As previously noted, the incidence of liver cancer increased with cumulative exposure; the SMR was 1,140 (95% CI: 571-2,050) for workers with a cumulative exposure of >7,532 ppm/years. How- ever, of the 11 liver cancers observed in the 0-734 ppm/year cumulative expo- sure group, four were angiosarcomas. These angiosarcomas occurred in indi- viduals with 287-734 ppm/years cumulative exposure (Ward et al. 2001). There were no angiosarcomas reported in workers with less than 287 ppm/years of cumulative exposure. North American Study The North American study consisted of approximately 10,100 men em- ployed for at least 1 year in the VC or polyvinyl chloride industry from 1942- 1974 (Mundt et al. 1999). This group was followed through December 31, 1995. Thus, most workers were followed for at least 21 years. Because the industries were located in 16 states and one province of Canada, mortality rates for 16

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Vinyl Chloride 331 states were used to calculate SMRs. For the Canadian province, mortality-rate data from Michigan was used because it is the state closest to the Canadian plant. As of December 31, 1995, 30% of the study group was deceased. Al- though the authors of previous studies have attempted to categorize individuals by exposures, no consistent criteria have been used and thus no attempt was made to estimate exposure levels in this study. The age at first exposure, duration of exposure, and year of first exposure appeared to be related to cancer of the liver and biliary tract. Of these, duration of exposure had the greatest significance and appeared to be independent of age at first exposure and year of first exposure (see Table D-3). Mundt et al. (2000) categorized the cohort into groups working 1-4, 5-9, 10-19, or >20 years in the VC industry. Nearly half of the cohort worked for <5 years in the industry, with fewer workers in each of the subsequent groups. These data show that working in the VC industry for 1-4 years resulted in a slightly lower liver cancer rate than expected. Working in this industry for longer periods of time resulted in higher death rates than expected for liver and biliary tract cancer. Mundt et al. also examined the incidence of angiosarcomas in relation to duration of expo- sure. Three individuals working in the VC industry for 1-4 years had angiosar- comas of the liver. No further information on exposure or job classification was provided. TABLE D-2 Liver Cancer Incidence for All European Countries by Cumulative Exposure Cumulative Incidence Exposure Number of Number of (observed/ Individualsa SMR (95% CI)b (ppm-years) Person (years) expected) Unknown 2,243 52,300 2/3.19 63 (8-227) 0-734 9,552 188,204 11/10.26 107 (54-192) 735-2,379 2,772 43,174 9/3.32 271 (124-515) 2,380-5,188 1,463 26,480 10/2.62 382 (183-703) 5,189-7,531 515 9,274 10/1.77 566 (271-1,040) >7,532 215 5,274 11/0.96 1,140 (571-2,050 Total 12,700 324,706 53/22.11 240 (1,800-3,140) a The number of individuals cited for various employment intervals is greater than 12,700 because individuals can meet more than one criteria as defined by the author.b b Observed/expected × 100. Abbreviations: CI, confidence interval; SMR, standardized mortality ratio. Source: Adapted from Ward et al. 2000.

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332 Acute Exposure Guideline Levels TABLE D-3 Liver and Biliary-Tract Cancer Incidence in the United States by Duration of Employment Duration of Incidence Employment Number of Number of (observed/ SMR (95% CI)a (years) expected) Individuals Person (years) 1-4 4,774 136,200 7/8.43 83 (33-171) 5-9 2,383 71,806 10/4.65 215 (103-396) 10-19 1,992 69,015 39/5.74 679 (483-929) >20 960 39,524 24/3.49 688 (440-1,023) Total 10,109 a Observed/expected × 100. Abbreviations: CI, confidence interval; SMR, standardized mortality ratio. Source: Adapted from Mundt et al. 1999. Both studies have shown that people working in the VC industry for <3 years or exposed to low concentration of VC have liver-cancer rates very close to expected values. A low incidence of angiosarcomas of the liver was reported by both Ward et al. (2000) and Mundt et al. (2000), but the Ward study sug- gested this was related to higher cumulative exposure. Weber et al. (1981) Three German cohorts were investigated in a study by Weber et al. (1981): Group 1 (1,021 VC and polyvinyl-chloride production workers; 73,734 person years), Group 2 (4,910 reference persons; 76,029 person years), and Group 3 (4,007 polyvinyl-chloride processing workers; 52,896 person years). Reference mortality rates from West Germany were used for comparison. Twelve cases of malignant tumors of the liver were found in production workers (SMR = 1,523), four cases in the reference group (SMR = 401), and three cases in processing workers (SMR = 434). No confidence intervals were provided, and the VC con- centrations were unknown. Subclassification according to duration of employ- ment demonstrates increased mortality after little more than 1 year of exposure (see Table D-4). Results from this study and the ones cited above were included in a meta-analysis by Boffetta et al. (2003), which illustrated the conflicting information about the minimum exposure duration and increased tumor risk in workers (see Figure 1 in Boffetta et al. 2003).

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Vinyl Chloride 333 TABLE D-4 Standardized Mortality Ratios for Malignant Tumors of the Liver by Duration of Exposure Employment Duration (months) Cases SMR Confidence Interval <12 0 — — Beyond 95th confidence interval 13-60 2 874 Beyond 99th confidence interval 61-120 3 1,525 Beyond 99th confidence interval >121 7 2,528 Total 12 Source: Adapted from Weber et al. 1981.

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334 Acute Exposure Guideline Levels APPENDIX E ACUTE EXPOSURE GUIDELINE LEVELS FOR VINYL CHLORIDE Derivation Summary for Vinyl Chloride AEGL-1 VALUES 10 min 30 min 1h 4h 8h 450 ppm 310 ppm 250 ppm 140 ppm 70 ppm Reference: Baretta, E.D., R.D. Stewart, and J.E. Mutchler. 1969. Monitoring exposures to vinyl chloride vapor: Breath analysis and continuous air sampling. Am. Ind. Hyg. Assoc. J. 30(6):537-544. Test species/Strain/Sex/Number: Human volunteers, male, 4-7 individuals. Exposure route/Concentrations/Durations: Inhalation, 459-491 ppm, 3.5 h Effects: Mild headache and dryness of eyes and nose in 2/7 subjects. End point/Concentration/Rationale: End points relevant for the derivation of AEGL- 1 values for VC are headache, odor recognition or detection, and irritation. Mild headache was reported in two subjects after acute exposure; mild headache can be regarded as no-effect level for notable discomfort. No appropriate studies of odor recognition or detection were available for VC. Irritation in humans and animals is reported only at very high concentrations that are lethal or cause unconsciousness. The mechanism by which headaches develop is not understood. Uncertainty factors/Rationale: Total uncertainty factor: 3 Interspecies: 1 was applied because the study involved humans. Intraspecies: 3 is used to account for toxicodynamic differences among individuals. The effects are probably from VC in the blood and not a metabolite. Only small interindividual differences in pharmacokinetics of VC are expected, as the concentration of VC required to elicit the effect is greater than that required for saturation of the metabolic pathways. Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applicable Time scaling: The duration-specific values were derived by time scaling according to the dose-response regression equation Cn × t = k, using the default of n = 3 for shorter exposure periods and n = 1 for longer exposure periods, because there were no suitable experimental data for deriving the value of n. Extrapolation from a 3.5-h exposure to a 10-min exposure is justified because humans exposed to VC at 4,000 ppm for 5 min did not experience headaches (Lester et al. 1963). Data adequacy: The study of Baretta et al. (1969) qualified for the derivation of AEGL-1 values and the end point is supported by several findings from occupational studies (Lilis et al. 1975; Suciu et al. 1975; EPA 1987). Confirmation of the observed effects in other studies with controlled exposure would be helpful, but may not be performed for ethical reasons.

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Vinyl Chloride 335 AEGL-2 VALUES 10 min 30 min 1h 4h 8h 2,800 ppm 1,600 ppm 1,200 ppm 820 ppm 820 ppm References: Lester, D., L.A. Greenberg, and W.R. Adams. 1963. Effects of single and repeated exposures of humans and rats to vinyl chloride. Am. Ind. Hyg. Assoc. J. 24(3):265-275. Clark, D.G., and D.J. Tinston. 1973. Correlation of the cardiac sensitizing potential of halogenated hydrocarbons with their physicochemical properties. Br. J. Pharmacol. 49(2):355-357. Mastromatteo, E., A.M. Fisher, H. Christie, and H. Danziger. 1960. Acute inhalation toxicity of vinyl chloride to laboratory animals. Am. Ind. Hyg. Assoc. J. 21:394-398. Test species/Strain/Sex/Number: Human, male and female, 3 per sex Exposure route/Concentrations/Durations: Inhalation, single exposure, VC at 0, 4,000, 8,000, 12,000, 16,000, or 20,000 ppm for 5 min. Effects: After a 5-min exposure at 16,000 ppm, five of six persons had dizziness, lightheadedness, nausea, and visual and auditory dulling. At concentrations of 12,000 ppm, one of six persons reported “swimming head, reeling,” and another was unsure of an effect and felt somewhat dizzy. A single person reported slight effects (“slightly heady”) of questionable meaning at 8,000 ppm (this person also felt slightly heady at sham exposure and reported no response at 12,000 ppm). No effects were observed at 4,000 ppm. A concentration of 12,000 ppm was regarded as a no- effect level for impaired ability to escape. End point/Concentration/Rationale: Severe dizziness may influence ability to escape, so is relevant as an end point for AEGL-2. No such effects were seen with VC at 12,000 ppm. AEGL-2 values are supported by the estimated no-effect level for cardiac sensitization of 17,000 ppm in dogs after epinephrine challenge (calculated by dividing the EC50 from the study by Clark and Tinston [1973] of 50,000 by 3). Uncertainty factors/Rationale: Total uncertainty factor: 3 Interspecies: 1 was applied because the study involved humans Intraspecies: 3 is used to account for toxicodynamic differences among individuals. The effects are probably from VC in the blood and not a metabolite. Only small interindividual differences in pharmacokinetics of VC are expected, as the concentration of VC required to elicit the effect is greater than that required for saturation of the metabolic pathways. Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applicable Time scaling: By analogy to other anesthetics, the effects are assumed to be solely concentration dependent. Thus, after reaching steady state after about 2 h, no increase in effect by duration is expected at 4 and 8 h. The other exposure duration- specific values were derived by time scaling according to the dose-response regression equation Cn × t = k, using a factor of n = 2 based on data from (Continued)

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336 Acute Exposure Guideline Levels AEGL-2 VALUES Continued 10 min 30 min 1h 4h 8h 2,800 ppm 1,600 ppm 1,200 ppm 820 ppm 820 ppm (continued) Mastromatteo et al. (1960). Mastromatteo et al. observed various time-dependent prenarcotic effects in mice and guinea pigs after less than steady-state exposure conditions. Time extrapolation was performed from 5 min to 10 min, 30 min, 60 min, and 2 h. Data adequacy: The overall quality of the key study (Lester et al. 1963) is medium. A dose-response relationship was observed that supported the quantitative estimates. Subjective reporting of effects leads to limited precision. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 12,000 ppm 6,800 ppm 4,800 ppm 3,400 ppm 3,400 ppm References: Clark, D.G., and D.J. Tinston. 1973. Correlation of the cardiac sensitizing potential of halogenated hydrocarbons with their physicochemical properties. Br. J. Pharmacol. 49(2):355-357. Clark, D.G., and D.J. Tinston. 1982. Acute inhalation toxicity of some halogenated and non-halogenated hydrocarbons. Hum. Toxicol. 1(3):239-247. Aviado, D.M., and M.A. Belej. 1974. Toxicity of aerosol propellants in the respiratory and circulatory systems. I. Cardiac arrhythmia in the mouse. Toxicology 2(1):31-42. Belej, M.A., D.G. Smith, and D.M. Aviado. 1974. Toxicity of aerosol propellants in the respiratory and circulatory systems. IV. Cardiotoxicity in the monkey. Toxicology 2(4):381-395. Prodan, L., I. Suciu, V. Pislaru, E. Ilea, and L. Pascu. 1975. Experimental acute toxicity of vinyl chloride (monochloroethene). Ann. NY Acad. Sci. 246:154-158. Mastromatteo, E., A.M. Fisher, H. Christie, and H. Danziger. 1960. Acute inhalation toxicity of vinyl chloride to laboratory animals. Am. Ind. Hyg. Assoc. J. 21:394-398. Test species/Strain/Sex/Number: Dog, beagle, sex not reported, 4-7 dogs/dose (Clark and Tinston 1973) Exposure route/Concentrations/Durations: Inhalation, several doses, 5 min (Clark and Tinston 1973) Effects: Short-term exposure (5 min) of dogs to VC induced cardiac sensitization towards epinephrine (EC50: 50,000 and 71,000 ppm in two independent experiments; Clark and Tinston 1973, 1982). The lower EC50 of 50,000 ppm was taken as the no- effect level for life-threatening effects. These effects also were seen in mice at higher concentrations (Aviado and Belej 1974). In monkeys, only myocardial depression after inhalation of VC at 2.5-10% was observed. It was unclear whether an additional challenge with epinephrine was applied (Belej et al. 1974). Severe cardiac sensitization is a life-threatening effect, but at 50,000 ppm no animals died. (Continued)

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Vinyl Chloride 337 AEGL-3 VALUES Continued 10 min 30 min 1h 4h 8h 12,000 ppm 6,800 ppm 4,800 ppm 3,400 ppm 3,400 ppm End point/Concentration/Rationale: Considering possible sensitive subpopulations and increased excitement in case of emergency reaction, epinephrine-induced cardiac reactions might occur and could be enhanced by exposure to high concentrations of VC. The respective effects are well known for certain unsubstituted and halogenated hydrocarbons. The test method using beagle dogs is well established. Cardiac sensitization data are supported by lethality data at slightly higher concentrations (Prodan et al. 1975). Uncertainty factors/Rationale: Total uncertainty factor: 3 Interspecies: 1 was used because the cardiac sensitization model with the dog is considered an appropriate model for humans and is highly sensitive as the response is optimized by the exogenous administration of epinephrine (Brock et al. 2003; ECETOC 2009). This protocol is designed conservatively with built in safety factors and thus no additional safety factor is needed (ECETOC 2009). Intraspecies: 3 was used to account for toxicodynamic differences among individuals. Only small interindividual differences in pharmacokinetics of VC are expected, as the concentration of VC required to elicit the effect is greater than that required for saturation of the metabolic pathways. Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Insufficient data Time scaling: By analogy with other halocarbons (e.g., Halon 1211, HFC 134a) that induce cardiac sensitization, the effects are assumed to be solely concentration dependent. Thus, after reaching steady state after about 2 h, no increase of effect by duration is expected at 4 and 8 h. The other exposure duration-specific values were derived by time scaling according to the dose-response regression equation Cn × t = k, using a factor of n = 2 based on data from Mastromatteo et al. (1960). Mastromatteo et al. observed various time-dependent prenarcotic effects (muscular incoordination, side position, and unconsciousness, effects which occur immediately before lethality) in mice and guinea pigs after less than steady-state exposure conditions. Time extrapolation was performed from 5 min to 10 min, 30 min, 60 min, and 2 h. Data adequacy: Because of discrepancies between the two studies by Clark and Tinston (1973, 1982), the data quality is judged to be medium. Adequate data from human experience is lacking.

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