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3
1,2-Dichloroethene1
cis-1,2-Dichloroethene
trans-1,2-Dichloroethene
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, 1 h, 4 h, 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
1
This document was prepared by the AEGL Development Team composed of Cheryl B. Bast (Oak Ridge National Laboratory) and Chemical Manager Ernest V. Falke (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guideline reports (NRC 1993, 2001).
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experience notable discomfort, irritation, or certain asymptomatic, non-sensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.
AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape.
AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening health effects or death.
Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, non-sensory 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 corresponding AEGL.
SUMMARY
1,2-Dichloroethene is a flammable, colorless liquid existing in both cis-and trans- forms and as a mixture of these two isomers. It is one of a number of two carbon chlorocarbons produced in a reaction mixture resulting from processes involved in the chlorination of ethylene to produce chlorinated monomers and solvents. The trans-isomer is commercially isolated by distillation and sold as a highly purified product that is used in precision cleaning of electronic equipment. The compound is a narcotic. Data on narcosis in humans, cats, rats, and mice, and systemic effects in cats, rats, and mice were available for development of AEGLs. The data were considered adequate for derivation of the three AEGL classifications.
The AEGL-1 was based on human exposure to 825 ppm trans-1,2-dichloroethene for 5 min (Lehmann and Schmidt-Kehl 1936). This concentration is a no-effect-level for eye irritation. This value was divided by an uncertainty factor of 3 to protect sensitive individuals and is considered sufficient because using the default value of 10 for intraspecies variability would generate AEGL-1 values which are not supported by the total data set. (Using the full uncertainty factor of 10, yields an AEGL-1 value of 83 ppm; no effects were noted in humans exposed to 275 ppm). This uncertainty factor of 3 was applied for AEGL-1 values for both the cis- and trans-isomers. Since data suggest that the cis- isomer is approximately twice as toxic as the trans-isomer with regard to narcosis and
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lethality in experimental animals, a modifying factor of 2 was applied in the derivation of the cis- isomer values only. Although the AEGL-1 point-of-departure is a NOEL for eye irritation, the use of the modifying factor is justified for the cis- isomer because slight dizziness, a possible mild narcotic effect, was noted at the concentration used as starting point for the derivation of the AEGL-1. The same value was applied across the 10- and 30-min, 1-, 4-, and 8-h exposure time points since mild irritation is a threshold effect and generally does not vary greatly over time. Thus, prolonged exposure will not result in an enhanced effect.
The AEGL-2 for the 4- and 8-h time points was based on narcosis observed in pregnant rats exposed to 6,000 ppm of the trans- isomer for 6 h (Hurtt et al. 1993). Uncertainty factors of 3 each (total UF = 10) were applied for both inter- and intraspecies differences. The interspecies UF of 3 is considered sufficient because data suggest that the critical brain concentration of a halocarbon required to produce a given level of narcosis is relatively constant across species (McCarty et al. 1991). The intraspecies UF of 3 is considered sufficient because data suggest that there is little variability between vapor concentrations of anesthetic required to produce anesthesia and age or sex of the patient (Gregory et al. 1969; de Jong and Eger 1975; Stevens et al. 1975). This total uncertainty factor of 10 was applied for AEGL-2 values for both the cis- and trans- isomers. The concentration-exposure time relationship for many irritant and systemically-acting vapors and gases may be described by Cn × t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al. 1986). To obtain conservative and protective AEGL values in the absence of an empirically derived chemical-specific scaling exponent, temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the Cn × t = k equation. The AEGL-2 for the 10- and 30- min and 1-h time points was set as a maximum exposure level for anesthetic effects in humans (Lehmann and Schmidt-Kehl 1936). Since data suggest that the cis- isomer is approximately twice as toxic as the trans- isomer with regard to narcosis and lethality in experimental animals, a modifying factor of 2 was applied in the derivation of the cis- isomer values only.
The AEGL-3 for the 4- and 8-h time points was based on a concentration (12,300 ppm) causing no mortality in rats exposed to trans-1,2-dichloroethene for 4-h (Kelly 1999). An uncertainty factor of 3 was applied for interspecies differences because rat and mouse lethality data indicate little species variability with regard to death. The interspecies UF of 3 is also considered sufficient because data suggest that the critical brain concentration of a halocarbon required to produce a given level of narcosis is relatively constant across species (McCarty et al. 1991). An intraspecies UF of 3 was also applied and is considered sufficient because data suggest that there is little variability between vapor concentrations of anesthetic required to produce anesthesia and age or sex of the patient (Gregory et al. 1969; de Jong and Eger 1975; Stevens et al. 1975). The total uncertainty factor of 10 was applied for AEGL-3 values for both the cis-and trans- isomers. The concentration-exposure time relationship for many irri-
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tant and systemically-acting vapors and gases may be described by Cn × t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al. 1986). To obtain conservative and protective AEGL values in the absence of an empirically derived chemical-specific scaling exponent, temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the Cn × t = k equation. The AEGL-3 for the 10- and 30- min and 1-h time points was set as a maximum exposure level for intracranial pressure, nausea, and severe dizziness in humans (Lehmann and Schmidt-Kehl 1936). Since data suggest that the cis- isomer is approximately twice as toxic as the trans-isomer with regard to narcosis and lethality in experimental animals, a modifying factor of 2 was applied in the derivation of the cis- isomer values only.
The calculated values are listed in Tables 3-1 and 3-2.
1.
INTRODUCTION
1,2-Dichloroethene is an extremely flammable, colorless liquid with a harsh odor, existing as both cis- and trans- forms and as a mixture (ATSDR 1996). It is one of a number of two carbon chlorocarbons produced in a reaction mixture resulting from processes involved in the chlorination of ethylene to produce chlorinated monomers and solvents. The trans- isomer is commercially isolated by distillation and sold as a highly purified product that is used in precision cleaning of electronic equipment. The compound reacts with alkalis to form chloroacetylene gas, reacts violently with potassium hydroxide and sodium hydroxide, and can be combined with dinitrogen tetraoxide to form shock-sensitive explosives. Because of volatility, inhalation is the primary route of exposure of 1,2-dichloroethene to humans. Exposure may occur as the result of releases from production or use facilities, from contaminated wastewater and waste disposal sites, and from burning of polyvinyl and vinyl polymers (ATSDR 1996). In 1977, production of the cis-/trans- mixture was reported by one company as 10 to 50 million pounds and by another company as 1 to 10 million pounds (NTP 2002). The only manufacturer of the cis- isomer reported production of 0.1 to 10 million pounds; no production estimates for the trans-isomer were reported (NTP 2002). The physicochemical data for 1,2-dichloroethene are shown in Table 3-3.
2.
HUMAN TOXICITY DATA
2.1.
Acute Lethality
2.1.1.
Case Reports
An accidental fatality from occupational exposure to 1,2-dichloroethene occurred when a male rubber factory worker entered a vat containing rubber
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TABLE 3-1 Summary of AEGL Values for trans-1,2-Dichloroethene [ppm (mg/m3)]
Classification
10-min
30-min
1-h
4-h
8-h
End Point (Reference)
AEGL-1 (Nondisabling)
280 (1,109)
280 (1,109)
280 (1,109)
280 (1,109)
280 (1,109)
Ocular irritation in humans (Lehmann and Schmidt-Kehl 1936)
AEGL-2 (Disabling)
1,000 (3,960)
1,000 (3,960)
1,000 (3,960)
690 (2,724)
450 (1,782)
Narcosis in rats: 4- and 8-h (Hurtt et al. 1993); Anesthetic effects in humans (Lehmann and Schmidt-Kehl 1936)
AEGL-3 (Lethality)
1,700 (6,732)
1,700 (6,732)
1,700 (6,732)
1,200 (4,752)
620 (2,455)
No death in rats: 4- and 8-h (Kelly 1999); Nausea, intracranial pressure, and dizziness in humans: 10-, 30-min, and 1-h (Lehmann and Schmidt-Kehl 1936)
TABLE 3-2 Summary of AEGL Values for cis-1,2-Dichloroethene [ppm (mg/m3)]
Classification
10-min
30-min
1-h
4-h
8-h
End Point (Reference)
AEGL-1 (Nondisabling)
140 (554)
140 (554)
140 (554)
140 (554)
140 (554)
Ocular irritation in humans (Lehmann and Schmidt-Kehl 1936)
AEGL-2 (Disabling)
500 (1,980)
500 (1,980)
500 (1,980)
340 (1,346)
230 (911)
Narcosis in rats: 4- and 8-h (Hurttet al. 1993); Anesthetic effects in humans (Lehmann and Schmidt-Kehl 1936)
AEGL-3 (Lethality)
850 (3,366)
850 (3,366)
850 (3,366)
620 (2,455)
310 (1,228)
No death in rats: 4- and 8-h (Kelly 1999); Nausea, intracranial pressure, and dizziness in humans: 10-, 30-min, and 1-h (Lehmann and Schmidt-Kehl 1936)
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TABLE 3-3 Chemical and Physical Data for 1,2-Dichloroethene
Parameter
Data
Reference
Chemical Name
1,2-Dichloroethene
ATSDR 1996
Synonyms
1,2-Dichloroethylene, acetylene dichloride,sym-dichloroethylene, Dioform (trade name)
O’Neil et al. 2001
CAS Registry No.
540-59-0 (mixture), 156-59-2 (cis), 156-60-5 (trans)
ATSDR 1996
Chemical formula
C2H2Cl2
O’Neil et al. 2001
Molecular weight
96.9
O’Neil et al. 2001
Physical state
Liquid
O’Neil et al. 2001
Odor threshold
17 ppm; ethereal, slightly acrid odor
O’Neil et al. 2001
Melting/boiling/flash point
−80.5°C /60.3°C /6°C (cis);
−50.0°C /48.0°C /4°C (trans)
ATSDR 1996
Density
1.2837 (cis) or 1.2565 (trans) g/cm3
ATSDR 1996
Solubility in water
3.5 (cis) or 6.3 (trans) g/L at 25°C
ATSDR 1996
Vapor pressure
180 (cis) or 265 (trans) mm Hg at 20 °C
ATSDR 1996
LogKow
1.86 (cis), 2.06 (trans)
ATSDR 1996
Bioconcentration factor (BCF)
ND
Henrys' Law constant
3.37 × 10−3 (cis) or 6.72 × 10−3 (trans) atm-m3/mol
ATSDR 1996
Conversion factors in air
1 mg/m3 = 0.25 ppm
1 ppm = 3.96 mg/m3 at 25 °C
ATSDR 1996
dissolved in 1,2-dichloroethene (Hamilton 1934). Symptoms of toxicity, exposure concentration and duration, and isomeric composition of the vapor were not reported. No other data concerning human lethality from 1,2-dichloroethene exposure were located in the available literature.
2.2.
Nonlethal Toxicity
2.2.1.
Case Reports
Short-term inhalation experiments were conducted with “relatively” low concentrations of trans-dichloroethene (Lehmann and Schmidt-Kehl 1936). Two doctoral candidates self-administered the chemical (as a vapor) in a well insulated 10 m3 room. Using a manual sprayer and later a vaporizer (with attached oxygen tank), the chemical was uniformly distributed through the exposure chamber by means of fan and a ventilator. The concentration of trans-dichloroethene in the exposure chamber was determined analytically by determining the chlorine content in the gas mixture employing the “lime method” from which the dichloroethene content was then calculated. Both individuals were exposed simultaneously
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in the same room. They appeared to react very similarly. Experiments lasted for 5 to 30 min. Based on concentrations of trans-dichloroethene in inspired and expired air, the authors estimated that approximately 73% of the chemical was absorbed. Exposure parameters and effects are presented in Table 3-4.
2.2.2.
Epidemiologic Studies
Epidemiologic studies regarding human exposure to 1,2-dichloroethene were not available.
2.3.
Developmental and Reproductive Toxicity
No developmental and reproductive toxicity data concerning 1,2-dichloroethene were identified in the available literature.
2.4.
Genotoxicity
No data concerning the genotoxicity of 1,2-dichloroethene in humans were identified in the available literature.
2.5.
Carcinogenicity
No data concerning the carcinogenicity of 1,2-dichloroethene in humans were identified in the available literature.
TABLE 3-4 Effects of Inhalation Exposure to trans-1,2-Dichloroethenea
Time
Concentration (ppm)
Effect
5 min
275
No effect
950
Slight burning of eyes
1700b
Dizziness after 3 min; slight burning of eyes; intracranial pressure; nausea
2200b
Severe dizziness after 5 min; intracranial pressure; nausea
10 min
825
Slight dizziness after 5 min
1200
Dizziness after 5 min; initially, slight burning of the eyes; drowsiness
30 min
1 000
Dizziness after 10 min; slight burning of eyes
aTwo human subjects were exposed.
bSymptoms persisted for 2 hours post-exposure.
Source: Adapted from: Lehmann and Schmidt-Kehl 1936.
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2.6.
Summary
Only anecdotal data regarding human lethality from exposure to 1,2-dichloroethene were available, and exposure concentration, time and isomeric composition were not reported. Nonlethal exposure-response data suggest that 1,2-dichloroethene induces reversible neurological symptoms in humans. Exposures involved two human subjects exposed to concentrations of 275 to 2,200 ppm trans-1,2-dichloroethene/m3 for 5 to 30 min.
3.
ANIMAL TOXICITY DATA
3.1.
Acute Lethality
3.1.1.
Mice
Gradiski et al. (1978) reported a 6-h LC50 of 21,723 ppm trans-1,2-dichloroethene for female OF1SPF mice; the cause of death was not reported.
Lehmann and Schmidt-Kehl (1936) exposed groups of three mice (sex and strain not specified) to cis-1,2-dichloroethene as follows: 65,000 mg/m3 (16,250 ppm) for 140 min, 70,000 mg/m3 (17,500 ppm) for 77 min, or 90,000 mg/m3 (22,500 ppm) for 66 min. All of these mice died. In the same study, groups of three mice were also exposed to the trans- isomer as follows: 75,000 mg/m3 (18,750 ppm) for 102 min, 80,000 mg/m3 (20,000 ppm) for 95 min, 105,000 mg/m3 (26,250 ppm) for 32 min, or 129,000 (32,250 ppm) mg/m3 for 30 min (see Table 3-10). All of these mice also died.
3.1.2.
Rats
Groups of 5 male and 5 female Crl:CD (SD)BR rats were exposed to 12,300, 22,500, 28,100, or 34,100 ppm trans-1,2-dichloroethene or 12,100, 13,500, 15,700, or 23,200 ppm cis-1,2-dichloroethene for 4 h in a 300-L stainless steel and glass chamber (Kelly 1999). The test atmospheres were generated by metering liquid dichloroethene into a heated glass Instatherm flask with either a Fluid Metering pump or a Hamilton Syringe Drive. Nitrogen introduced into the flask swept the dichloroethene vapor into the air supply duct to the exposure chamber. The chamber concentration of dichloroethene was controlled by varying the amount of the metered liquid delivered to the evaporation flask. The chamber concentration of test substance was determined by gas chromatography at 15-min intervals during each exposure. Chamber airflow, temperature, and relative humidity were monitored continually. Liver, kidney, lung, and heart were examined histologically. The 4-h LC50 value was 24,100 ppm for trans-1,2 dichloroethene and 13,700 ppm for cis-1,2-dichloroethene. Data are summarized in Table 3-5.
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TABLE 3-5 Four-Hour Exposure of Rats to cis- and trans-1,2-Dichloroethene
Concentration (ppm)
Mortality
Observations
trans-1,2-Dichloroethene
During Exposurea
After Exposure
12,300
0/10
Prostrate, decreased response followed by no response to alerting stimulus, normal response 30 min after exposure
Normal weight gain
22,500
4/10
Prostrate, no response to alerting stimulus (recovery time not noted)
Lethargy, irregular respiration, slight weight loss one day followed by normal weight gain
28,100
7/10
Prostrate, no response to alerting stimulus (recovery time not noted)
Weakness, slight to severe weight loss one day followed by normal weight gain
34,100
10/10
Prostrate, no response to alerting stimulus
—
cis-1,2-Dichloroethene
12,100
0/10
Prostrate, no response to alerting stimulus (recovery in 1 h post-exposure)
Normal weight gain rate
13,500
6/10
Prostrate, no response to alerting stimulus (recovery time not noted)
Weakness, irregular respiration, immediately after exposure, slight to severe weight loss one day followed by normal weight gain; centrilobular fatty liver changes (2/10)
15,700
10/10
Prostrate, no response to alerting stimulus
Centrilobular fatty liver changes (4/10)
23,200
10/10
Prostrate, no response to alerting stimulus
—
aDeaths occurred during exposure.
Source: Kelly 1999. Reprinted with permission; copyright 1999, Dupont.
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3.1.3.
Cats
Cats (2/concentration) were exposed to cis-1,2-dichloroethene at concentrations ranging from 20,000 to 114,000 mg/m3 (5,000 to 28,500 ppm) for 9 to 360 min (Lehmann and Schmidt-Kehl 1936). “Pure” chemical was obtained from I.G. Farben and was further purified by multiple fractionated distillations followed by boiling point measurements. Ambient air was suctioned from a 360-L exposure chamber utilizing a large gas valve which was rotated by means of a bucket wheel located in a water container on the same level as the valve. The experimental aerosol was produced by one of two methods: (1) either by passing a small stream of air through a Woulfsche flask containing a measured amount of chemical for a given time period and adding chemical by opening a burette or (2) by forcing a side air stream through a bulb tube containing the liquid dichloroethene and mixing with the main air stream. The concentration of dichloroethene in the exposure chambers was determined in one of two ways: (1) by dividing the evaporated portion of the chemical by the air volume over a specific time period or (2) analytically by determining the chlorine content in the gas mixture employing the “lime method” from which the dichloroethene content was then calculated. Actual concentrations achieved ranged from 98.2% to 100.7% of the nominal concentrations, suggesting reliability and accuracy in the exposure concentrations. The mean experimental ventilation rate was 1050 L/h. The exposures resulted in death at various times, ranging from 3 min to 7 days, after exposure (see Table 3-9 for details).
3.2.
Nonlethal Toxicity
3.2.1.
Cats
Fasted cats (2/experiment) were exposed to cis- or trans-1,2-dichloroethene vapors in a series of experiments (Lehmann and Schmidt-Kehl 1936). “Pure” chemical was obtained from I.G. Farben and was further purified by multiple fractionated distillations followed by boiling point measurements. Ambient air was suctioned from a 360 L exposure chamber utilizing a large gas valve which was rotated by means of a bucket wheel located in a water container on the same level as the valve. The experimental aerosol was produced by one of two methods: 1) either by passing a small stream of air through a Woulfsche flask containing a measured amount of chemical for a given time period and adding chemical by opening a burette or 2) by forcing a side air stream through a bulb tube containing the liquid dichloroethene and mixing with the main air stream. The concentration of dichloroethene in the exposure chambers was determined in one of two ways: 1) by dividing the evaporated portion of the chemical by the air volume over a specific time period or 2) analytically by determining the chlorine content in the gas mixture employing the “lime method” from which the dichloroethene content was then calculated. Actual concentrations achieved ranged from 98.2% to 100.7% of the nominal concentrations. The
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mean experimental ventilation rate was 1050 L/h. Due to the variability in researchers, there were some inconsistencies in observations. End points measured included equilibrium effects, lethargy, light narcosis, and deep narcosis. Effects on equilibrium were defined as swaying and difficulty in getting up and moving around. Lethargy was defined as the complete inability to move and was tested by gently lifting the head with a wooden rod. If the head fell back following removal of the rod, the cat was considered lethargic. Light narcosis was defined as the absence of extremity reflexes, and deep narcosis was defined as the absence of corneal and extremity reflexes. Also observed were irritating effects on mucous membranes (eyes, nose, mouth, salivary glands) and respiratory rate. The animals were observed for at least 8 days after exposure. Respiratory rates corresponding to lethargy, light narcosis, and deep narcosis were 61, 75, and 72 breaths/min, respectively, for the trans isomer; and 85, 99, and 92 reaths/min, respectively, for the cis- isomer. Study design and observations are presented in Tables 3-6 through 3-9.
3.2.2.
Rats
Groups of six female SPF Wistar rats (180-200 g) were given single 8-h exposures to trans-1,2-dichloroethene vapors at 0, 200, 1,000, or 3,000 ppm (Freundt et al. 1977). Experimental concentrations were monitored by gas chromatography, and were within 3% of the nominal concentrations. Animals were sacrificed immediately after the exposure period. The incidence of slight to severe fatty degeneration of hepatic lobules and Kupffer cells and pulmonary capillary hyperaemia and alveolar septum distention was increased in all treatment groups when compared to controls. Pneumonic infiltration and fibrous swelling and hyperemia of cardiac muscle with poorly maintained striation were observed in animals in the 3,000 ppm group. Decreased serum albumin, urea nitrogen, and alkaline phosphatase activity were observed in the 1,000 ppm group after 8 h of exposure; however, these effects are of questionable biological significance because none were outside the normal range for rats. Leukocyte counts were decreased after exposure to 200 ppm 1,2-dichloroethene for 8 h, and a decreased erythrocyte count was observed in the 1,000 ppm group after 8 h. It should be noted that the results of this study are inconsistent with the total database for 1,2-dichloroethylene and results, especially the reported pathological changes, are of questionable toxicological significance.
In another study, Freundt and Macholz (1978) exposed groups of 10 female Wistar rats to cis- or trans-1,2-dichloroethene at 0, 200, 600, 1,000, or 3,000 ppm for 8 h. A statistically significant (p < 0.05), dose-dependent increase in hexobarbital sleeping time and zoxazolamine paralysis time was observed in all treated groups, indicating decreased activity of the P-450 enzymes that normally metabolize these compounds. The effect was observed in animals exposed to both isomers; however, the effect was more severe in rats exposed to the cis-isomer.
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is likely that analytical measurements were not as precise as those used today. Data from animal studies are more abundant and encompass a wider range of exposure periods. More recent animal studies include greater numbers of experimental animals and almost certainly improved methodology.
9.
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de Jong, R.H., and E.I. Eger. 1975. MAC expanded: AD50 and AD95 values of common inhalation anesthetics in man. Anesthesiology 42(4):384-389.
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Eger, E.I., M.J. Halsey, D.D. Koblin, M.J. Laster, P. Ionescu, K. Konigsberger, R. Fan, B.V. Nguyen, and T. Hudlicky. 2001. The convulsant and anesthetic properties of cis- trans isomers of 1,2-dichlorohexafluorocyclobutane and 1,2-dichloroethy-lene. Anesth. Analg. 93(4):922-927.
Filser, J.G., and H.M. Bolt. 1979. Pharmacokinetics of halogenated ethylenes in rats. Arch. Toxicol. 42(2): 123-136.
Freundt, K.J., and J. Macholz. 1978. Inhibition of mixed function oxidases in rat liver by trans- and cis-1,2-dichloroethylene. Toxicology 10(2):131-139.
Freundt, K.J., G.P. Liebaldt, and E. Lieberwirth. 1977. Toxicity studies on trans-1,2-dichloroethylene. Toxicology 7(2):141-153.
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Gargas, M.L., P.G. Seybold, and M.E. Andersen. 1988. Modeling the tissue solubilities and metabolic rate constant (Vmax) of halogenated methanes, ethanes, and ethylenes. Toxicol. Lett. 43(1-3):235-256.
Gargas, M.L., R.J. Burgess, D.E. Voisard, G.H. Cason, and M.E. Andersen. 1989. Partition coefficients of low-molecular-weight volatile chemicals in various liquids and tissues. Toxicol. Appl. Pharmacol. 98(1):87-99.
Gargas, M.L., H.J. Clewell III, and M.E. Andersen. 1990. Gas uptake inhalation techniques and the rates of metabolism of chloromethanes, chloroethanes, and chloroethylenes in the rat. Inhal. Toxicol. 2(3):295-319.
Gradiski, D., P. Bonnet, G. Raoult, and J.L. Magadur. 1978. Comparative acute inhalation toxicity of the principal chlorinated aliphatic solvents [in French]. Arch. Mal. Prof. Med. Trav. Secur. Soc. 39(4-5):249-257.
Gregory, G.A., E.I. Eger, and E.S. Munson. 1969. The relationship between age and halothane requirement in man. Anesthesiology 30(5):488-491.
Hamilton, A. 1934. Dichlorethylene. Pp. 217-218 in Industrial Toxicology. New York, NY:Harper and Brothers Publishers.
Hanioka, N., H. Jinno, T. Nishimura, and M. Ando. 1998. Changes in hepatic cytochrome P450 enzymes by cis- and trans-1,2-dichloroethylenes in rat. Xenobiotica 28(1):41-51.
Hurtt, M.E., R. Valentine, and L. Alvarez. 1993. Developmental toxicity of inhaled trans-1,2-dichloroethylene in the rat. Fundam. Appl. Toxicol. 20(2):225-230.
Kelly, D.P. 1998. trans-1,2- Dichloroethylene: 90-Day Inhalation Toxicity Study in Rats. E.I. Du Pont de Nemours and Company, Haskell Laboratory for Toxicology and Industrial Medicine. DuPont HL-1998-00952.
Kelly, D.P. 1999. trans-1,2-Dichloroethylene and cis-1,2-dichloroethylene: Inhalation Median Lethal Concentration (LC50) Study in Rats. E.I. du Pont de Nemours and Company, Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE. Laboratory Project ID: DuPont-2806.
Lehmann, K.B., and L. Schmidt-Kehl. 1936. The thirteen most important chlorinated aliphatic hydrocarbons from the standpoint of industrial hygiene [in German]. Arch. Hyg. 116:131-268.
Lilly, P.D., J.R. Thorton-Manning, M.L. Gargas, H.J. Clewell, and M.E. Andersen. 1998. Kinetic characterization of CYP2E1 inhibition in vivo and in vitro by the chloroethylenes. Arch. Toxicol. 72(10):609-621.
McCarty, L.S., D. Mackay, A.D. Smith, G.W. Ozburn, and D.G. Dixon. 1991. Interpreting aquatic toxicity QSARs: The significance of toxicant body residues at the pharmacologic endpoint. Sci. Total Environ. 109-110:515-525.
McCauley, P.T., M. Robinson, F.B. Daniel, and G.R. Olson. 1995. The effects of subacute and subchronic oral exposure to cis-1,2-dichloroethylene in Sprague-Dawley rats. Drug Chem. Toxicol. 18(2-3):171-184.
Mortelmans, K., S. Haworth, T. Lawlor, W. Speck, B. Tainer, and E. Zeiger. 1986. Salmonella mutagenicity tests: II. Results from the testing of 270 chemicals. Environ. Mutagen. 8(Suppl. 7):1-119.
MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: 1,2 Dichloorethyleen. Den Haag: SDU Uitgevers [online]. Available: http://www.lasrook.net/lasrookNL/maclijst2004.ht [accessed Oct. 24, 2008].
NIOSH (National Institute of Occupational Safety and Health). 1996. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLH): NIOSH Chemical Listing and Documentation of Revised IDLH Values (as of 3/1/95)-1,2 Dichloroethylene. U.S. Department of Health and Human Services, Centers for
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Disease Control and Prevention, National Institute of Occupational Safety and Health. August 1996 [online]. Available: http://www.cdc.gov/niosh/idlh/107028.html [accessed Oct. 16, 2008].
NIOSH (National Institute of Occupational Safety and Health). 2005. NIOSH Pocket Guide to Chemical Hazards: 1,2 Dichloroethylene. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute of Occupational Safety and Health, Cincinnati, OH. September 2005 [online]. Available: http://www.cdc.gov/niosh/npg/npgd0195.html [accessed Oct. 16, 2008].
NRC (National Resource Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press.
NRC (National Research Council). 1993. Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press.
NTP (National Toxicology Program). 2002. NTP Technical Report on the Toxicity Studies of trans-1,2-Dichloroethylene (CAS No. 156-60-5) Administered in Microcapsules in Feed to F344/N Rats and B6C3F1 Mice. Toxicity Report No. 55. NIH Publication No. 02-4410. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health. April 2002 [online]. Available: http://ntp.niehs.nih.gov/ntp/htdocs/ST_rpts/tox055.pdf [accessed Oct. 24, 2008].
O’Neil, M.J., A. Smith, P.E. Heckelman, J.R. Obenchain, Jr., J. Gallipeau, and M.A. D’Arecca. 2001. Acetylene dichloride. Pp. 17-18 in The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 13th Ed. Whitehouse Station, NJ: Merck and Co.
Stevens, W.C., W.M. Dolan, R.T. Gibbons, A. White, E.I. Eger, R.D. Miller, R.H. DeJong, and R.M. Elashoff. 1975. Minimum alveolar concentrations (MAC) of isoflurane with and without nitrous oxide in patients of various ages. Anesthesiology 42(2):197-200.
ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Hazard. Mater. 13(3):301-309.
Zeiger, E., B. Anderson, S. Haworth, T. Lawlor, and K. Mortelmans. 1988. Salmonella mutagenicity tests IV. Results from the testing of 300 chemicals. Environ. Mol. Mutagen. 11(Suppl. 12):1-158.
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APPENDIX A
Time-Scaling Calculations for 1,2-Dichloroethene
Derivation of AEGL-1
Key study:
Lehmann and Schmidt-Kehl 1936
Toxicity end point:
825 ppm, 5 min: NOEL for ocular irritation in humans
Scaling:
None: values were held constant across time points
Uncertainty factors:
3 for intraspecies variability (trans- and cis-1,2-dichloroethene)
Modifying factor:
2 for differential isomer toxicity (cis-1,2-dichloroethene only)
10-, and 30-min and 1-, 4-, and 8-h AEGL-1
825 ppm ÷ 3 = 275 ppm
trans-1,2-dichloroethene AEGL-1 = 280 ppm
cis-1,2-dichloroethene AEGL-1 = 280 ppm ÷ 2 = 140 ppm
Derivation of AEGL-2
Key Studies:
Lehmann and Schmidt-Kehl 1936 (10-, 30-, and 60-min)
Hurtt et al. 1993 (4- and 8-h)
Toxicity end points:
Anesthetic effects in humans (10-, 30-, and 60-min)
Narcosis in rats (4- and 8-h)
Scaling
Maximum exposure level at 10-, 30-, and 60-min
(6,000 ppm)3 × 6 h = 1.3 × 1012 ppm.h (4-h)
(6,000 ppm)1 × 6 h = 36,000 ppm.h (8-h)
Uncertainty factors:
3 for intraspecies variability (trans- and cis- 1,2 dichloroethene; 4- and 8-h)
3 for interspecies variability (trans- and cis- 1,2-dichloroethene; 4- and 8-h)
Modifying factor:
2 for differential isomer toxicity (cis-1,2-dichloroethene only)
10- and 30-min and 1-h AEGL-2
trans-1,2-dichloroethene AEGL-2 = 1,000 ppm
cis-1,2-dichloroethene AEGL-1 = 1,000 ppm ÷ 2 = 500 ppm
4-h AEGL-2
C3 × 4 h = 1.3 × 1012 ppm.h
C3 = 3.25 × 1011 ppm
C = 6,875 ppm
4 h trans-1,2-dichloroethene AEGL-2= 6,868 ppm/10 = 690 ppm
4 h cis-1,2-dichloroethene AEGL-2 = 6,868 ppm/20 = 340 ppm
8-h AEGL-2
C1 × 8 h = 36,000 ppm.h
C1 = 4,500 ppm
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C = 4,500 ppm
8 h trans-1,2-dichloroethene AEGL-2 = 4,500 ppm/10 = 450 ppm
8 h cis-1,2- dichloroethene AEGL-2 = 4,500 ppm/20 = 230 ppm
Derivation of AEGL-3
Key Studies:
Lehmann and Schmidt-Kehl 1936 (10-, 30-, and 60-min)
Kelly 1999 (4- and 8-h)
Toxicity end point:
Nausea, intracranial pressure, dizziness in humans (10-, 30-, and 60-min)
No-effect-level for death in rats (4- and 8-h)
Scaling
Maximum exposure level at 10-, 30-, and 60-min
(12,300 ppm)3 × 4 h = 7.44 × 1012 ppm.h (4-h)
(12,300 ppm)1 × 4 h = 49,200 ppm.h (8-h)
Uncertainty factors:
3 for intraspecies variability (trans- and cis- 1,2- dichloroethene; 4- and 8-h)
3 for interspecies variability (trans- and cis- 1,2-dichloroethene; 4- and 8-h)
Modifying factor:
2- for differential isomer toxicity (cis-1,2-dichloroethene only)
10, and 30-min and 1-h AEGL-3
trans-1,2-dichloroethene AEGL-3 = 1,700 ppm
cis-1,2-dichloroethene AEGL-3 = 1,700 ÷ 2 = 850 ppm
4 h AEGL-3
C3 × 4 h = 7.44 × 1012 ppm-h
C3 = 1.86 × 1012 ppm
C = 12,298 ppm
4 h trans-1,2-dichloroethene AEGL-3= 12,298 ppm/10 = 1,200 ppm
4 h cis-1,2-dichloroethene AEGL-3 = 12,298 ppm/20 = 620 ppm
8 h AEGL-3
C1 × 8 h = 49,200 ppm-h
C1 = 6,150 ppm
C = 6,150 ppm
8 h trans-1,2-dichloroethene AEGL-3 = 6,150 ppm/10 = 620 ppm
8 h cis-1,2-dichloroethene AEGL-3 = 6,150 ppm/20 = 310 ppm
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APPENDIX B
Derivation Summary of AEGL Values for 1,2-Dichloroethene (trans- and cis- isomers)
AEGL-1 VALUES
10 min
30 min
1 h
4 h
8 h
280 ppm
280 ppm
280 ppm
280 ppm
280 ppm
Key Reference: Lehmann, K.B., and L. Schmidt-Kehl. 1936. The thirteen most important chlorinated aliphatic hydrocarbons from the standpoint of industrial hygiene [in German]. Arch. Hyg. 116:131-268.
Test Species/Strain/Number: Human subjects/2
Exposure Route/Concentrations/Durations: Inhalation: 275, 825, 950, 1000, 1200, 1700, or 2200 ppm for 5-30 min
Effects: 275 ppm: No effects (5 min Total exposure)
825 ppm: Slight dizziness after 5 min (10 min exposure); determinant for AEGL-1
950 ppm: Slight burning of eyes (5 min)
1,000 ppm: Dizziness after 10 min; slight burning of eyes (30 min exposure)
1,200 ppm: Dizziness after 5 min; drowsiness; slight burning of eyes (10 min exposure)
1,700 ppm: Dizziness after 3 min; slight burning of eyes; intracranial pressure; nausea (5 min exposure)
2,200 ppm: Severe dizziness; intracranial pressure; nausea (5 min exposure)
End Point/Concentration/Rationale: 825 ppm for 5 min; no effect level for eye irritation; odor present.
Uncertainty Factors/Rationale:
Total uncertainty factor: 3
Interspecies: Not applicable, human data used.
Intraspecies: 3 - Considered sufficient because using the default value of 10 for intraspecies variability would generate AEGL-1 values which are not supported by the total data set. (Utilizing the full uncertainty factor of 10, yields an AEGL-1 value of 83 ppm; no effects were noted in humans exposed to 275 ppm).
Modifying Factor: Not applicable.
Animal to Human Dosimetric Adjustment: Not applicable; human data used
Time Scaling: Values were held constant across time since minor irritation is a threshold effect and is not likely to increase over time.
Data Quality and Research Needs: Although the values developed are considered to be protective, data are sparse due to the exposure of only two subjects.
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AEGL-2 VALUES
10 min
30 min
1 h
4 h
8 h
1,000 ppm
1,000 ppm
1,000 ppm
690 ppm
450 ppm
Key Reference: Lehmann, K.B., and L. Schmidt-Kehl. 1936. The thirteen most important chlorinated aliphatic hydrocarbons from the standpoint of industrial hygiene [in German]. Arch. Hyg. 116:131-268. (10-, and 30-min and 1-h)
Key Reference: Hurtt, M.E., R. Valentine, and L. Alvarez. 1993. Developmental toxicity of inhaled trans-1,2-dichloroethylene in the rat. Fundam. Appl. Toxicol. 20(2):225-230. (4- and 8-h)
Test Species/Strain/Number: Human subjects/2
Test Species/Strain/Number: rat/Crl:CD BR pregnant females/24/group
Exposure Route/Concentrations/Durations: Inhalation: 275, 825, 950, 1000, 1200, 1700, or 2200 ppm for 5-30 min
Exposure Route/Concentrations/Durations: 0, 2000, 6000, or 12,000 ppm, 6 h/d, d 7-16 of gestation
Effects:
275 ppm No effects (5 min)
825 ppm Slight dizziness after 5 min
950 ppm Slight burning of eyes (5 min)
1,000 ppm Dizziness after 10 min; slight burning of eyes (30 min exposure)
1,200 ppm Dizziness after 5 min; drowsiness; slight burning of eyes (10 min exposure)
1,700 ppm Dizziness after 3 min; slight burning of eyes; intracranial pressure; nausea
2,200 ppm Severe dizziness; intracranial pressure; nausea (5 min exposure)
Effects:
2,000 ppm Clear ocular discharge (after single 6-h exposure)
6,000 ppm Narcosis, ocular irritation (after single 6-h exposure)
1,200 ppm Ocular irritation, narcosis, lethargy, decreased body weight gain
End Point/Concentration/Rationale: 1,000 ppm for 10 min; threshold for anesthetic effects
End point/Concentration/Rationale: 6,000 ppm, 6 h/narcosis
Uncertainty Factors/Rationale:
Total uncertainty factor: 1
Interspecies: Not applicable - human data used.
Intraspecies:1 -threshold for anesthetic effect
Uncertainty Factors/Rationale:
Total uncertainty factor: 10
Interspecies: 3
Intraspecies: 3
The interspecies UF of 3 is considered sufficient because data suggest that the critical brain concentration of a halocarbon required to produce a given level of narcosis is relatively constant across species (McCarty et al. 1991). The intraspecies UF of 3 is considered
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10 min
30 min
1 h
4 h
8 h
1,000 ppm
1,000 ppm
1,000 ppm
690 ppm
450 ppm
sufficient because data suggest that there is little variability between vapor concentrations of anesthetic required to produce anesthesia and age or sex of the patient (Gregory et al. 1969; Stevens et al. 1975; de Jong and Eger 1975)
Time Scaling: Held constant at threshold for anesthetic effects
Time Scaling: Cn × t = k, where the exponent, n, is the conservative default of 1 (8-h) or 3 (4-h)
Data Quality and Research Needs: Although recent studies are well conducted, human and animal data are in apparent conflict.
AEGL-3 VALUES
10 min
30 min
1 h
4 h
8 h
1,700 ppm
1,700 ppm
1,700 ppm
1,200 ppm
620 ppm
Key Reference: Lehmann, K.B., and L. Schmidt-Kehl. 1936. The thirteen most important chlorinated aliphatic hydrocarbons from the standpoint of industrial hygiene [in German]. Arch. Hyg. 116:131-268. (10-, and 30- min and 1-h)
Key Reference: Kelly, D.P. 1999. trans-1,2-dichloroethylene and cis-1,2-dichloroethylene: Inhalation Median Lethal Concentration (LC50) Study in Rats. E.I. du Pont de Nemours and Company, Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE. Laboratory Project ID: DuPont-2806. (4- and 8-h)
Test Species/Strain/Number: Human subjects/2
Test Species/Strain/Number: Rat/Crl:CD (SD)/5/sex/group
Exposure Route/Concentrations/Durations: Inhalation: 275, 825, 950, 1,000, 1,200, 1,700, or 2,200 ppm for 5-30 min
Exposure Route/Concentrations/Durations: Inhalation/ 0, 12,300, 22,500, 28,100, or 34,100 ppm/4 h
Effects:
275 ppm No effects (5 min)
825 ppm Slight dizziness after 5 min
950 ppm Slight burning of eyes (5 min)
1,000 ppm Dizziness after 10 min; slight burning of eyes (30 min exposure)
1,200 ppm Dizziness after 5 min; drowsiness; slight burning of eyes (10 min exposure)
Mortality:
12,300 ppm 0/10
22,500 ppm 4/10
28,100 ppm 7/10
34,100 ppm 10/10
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10 min
30 min
1 h
4 h
8 h
1,700 ppm
1,700 ppm
1,700 ppm
1,200 ppm
620 ppm
1,700 ppm Dizziness after 3 min; slight burning of eyes; intracranial pressure; nausea
2,200 ppm Severe dizziness; intracranial pressure; nausea (5 min exposure)
End Point/Concentration/Rationale: 1,700 ppm for 3 min; dizziness, intracranial pressure, nausea
End Point/Concentration/Rationale: 12,300 ppm, 4 h/NOEL for death
Uncertainty Factors/Rationale:
Total Uncertainty Factor: 1
Interspecies: Not applicable - human data used.
Intraspecies 1 - conservative AEGL-3 end point
Uncertainty Factors/Rationale:
Total Uncertainty Factor: 10
Interspecies: 3
Intraspecies: 3
An uncertainty factor of 3 was applied for interspecies differences because rat and mouse lethality data indicate little species variability with regard to death. The interspecies UF of 3 is also considered sufficient because data suggest that the critical brain concentration of a halocarbon required to produce a given level of narcosis is relatively constant across species (McCarty et al. 1991). The intraspecies UF of 3 is considered sufficient because data suggest that there is little variability between vapor concentrations of anesthetic required to produce anesthesia and age or sex of the patient (Gregory et al. 1969; Stevens et al. 1975; de Jong and Eger 1975).
Time Scaling: Held constant across time points; conservative AEGL-3 end point
Time Scaling: Cn × t = k, where the exponent n is the conservative default of 1 (8-h) or 3 (4-h)
Data Quality and Research Needs: Although recent studies are well conducted, human and animal data are in apparent conflict.
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APPENDIX C
Category Plots for trans-1,2-Dichloroethene and cis-1,2-Dichloroethene
FIGURE C-1 Category plots for trans-1,2-dichloroethene.
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FIGURE C-2 Category plots for cis-1,2-dichloroethene.