2
Carbon Disulfide1
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 [ppm] or milligrams per cubic meter [mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory

1

This document was prepared by the AEGL Development Team composed of Jens-Uwe Voss (Toxicological Advisory Services, Chemical Hazard and Risk Assessment and Chemical Managers George Rodgers and George Woodall (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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2 Carbon Disulfide1 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 [ppm] or milligrams per cubic meter [mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory 1 This document was prepared by the AEGL Development Team composed of Jens- Uwe Voss (Toxicological Advisory Services, Chemical Hazard and Risk Assessment and Chemical Managers George Rodgers and George Woodall (National Advisory Commit- tee [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). 50

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51 Carbon Disulfide 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 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 levels that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsensory effects. With increasing airborne concentrations above each AEGL, there is a progres- sive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGLs represent threshold levels for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL. SUMMARY Pure carbon disulfide (CS2) is a colorless, mobile, refractive liquid with a sweetish aromatic odor similar to chloroform. Commercial and reagent grade products are yellowish with an unpleasant, repulsive odor of decaying radish or overcooked cauliflower. Due to its high volatility, low flash point, low autoigni- tion temperature, and wide range of explosive limits in air, CS2 poses an acute fire and explosion hazard. The most important industrial use of CS2 has been in the manufacture of regenerated cellulose rayon by the viscose process. A wide range of odor thresholds from 0.0243 mg/m³ to 23.1 mg/m³ (0.0078 to 7.4 ppm) for CS2 were reported. Amoore and Hautala (1983) reported a geometric mean air odor threshold of 0.11 ppm (standard error [SD], 0.058 ppm) Leonardos et al. (1969) determined an odor recognition threshold of 0.21 ppm. AIHA (1997), in a critical overview of odor thresholds for chemicals, re- ported a range of all referenced values from 0.016 to 0.42 ppm. No geometric mean and no “range of acceptable values” for CS2 were presented, and the use of the 0.21 ppm threshold was rejected because it represented a 100% recognition concentration. Few data are available with respect to concentrations of CS2 caus- ing odor annoyance. In one controlled human study (Lehmann 1894), 180-240 ppm caused “moderate odor annoyance,” and there were no complaints to expo- sures at 10-20 ppm in a toxicokinetic study (Rosier et al. 1987). The database is not sufficient to calculate a level of distinct odor aware- ness (LOA). It also must be taken into account that strong smelling decomposi-

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52 Acute Exposure Guideline Levels tion products of CS2 are rapidly formed under the influence of light and air. Therefore, the odor threshold and the hedonic tone of CS2 will markedly change with the presence and formation of such impurities. CS2 is rapidly absorbed from the respiratory tract and distributed throughout the body, the highest con- centration occurring in lipid rich tissues. Dithiocarbamates and similar products build up the so-called “acid-labile” CS2 by the reaction of CS2 with NH2, SH, and OH groups of amino acids, proteins, and amines. Although unbound CS2 is eliminated rapidly after the termination of exposure, the acid labile part shows a longer half-life and may accumulate with repeated exposure. On acute exposure, CS2 acts on the central nervous system (CNS) in hu- mans and animals. In humans, acute effects on the CNS following CS2 exposure manifest in dizziness, headaches, autonomic nervous system reactions, nausea, vertigo, vomiting, central paralysis, and narcosis. In animals (rats, mice, rabbits, cats, and dogs), acute exposure led to reduced activity but also hyperexcitability, stupor, ataxia, tremors, convulsions, deep narcosis, and finally respiratory arrest and death. Irritation of eyes and mucous membranes occur only at concentra- tions already affecting the CNS. However, low concentrations without notable effects on the CNS led to an inhibition of xenobiotic biotransformation reac- tions, inhibition of ethanol metabolism via the alcohol and aldehyde dehydro- genase pathway, and alterations of carbohydrate and energy metabolism in the liver. In several toxicokinetic studies in humans, occasional slight headaches but no other subjective symptoms were reported to occur in some individuals at ex- posure concentrations in the range of 17-51 ppm (Harashima and Masuda 1962; Teisinger and Soucek 1949). Inhibition of biotransformation was observed in humans after 6 h of exposure to CS2, at 10 ppm, the lowest concentration tested (Mack et al. 1974). In rats, 8 h of exposure to 20 ppm, the lowest concentration tested, also inhibited biotransformation of drugs and solvents and caused a de- crease of the glycogen content of the liver. All effects were rapidly reversible within about 24 h, and no increase of liver enzymes in serum was observed (Freundt and Dreher 1969; Freundt and Kuttner 1969; Kürzinger and Freundt 1969; Freundt and Schauenburg 1971; Freundt et al. 1974b, 1976a; Freundt and Kürzinger 1975). In one controlled human study, two volunteers were exposed to concentrations from about 180 ppm to more than 3,000 ppm (Lehmann 1894). In this study, CNS symptoms and irritation of eyes and throat occurred at 260- 420 ppm. CNS symptoms increased in severity with exposure concentration and time. Severe CNS effects that continued after exposure ended were seen at about 2,000 ppm. Concentrations from 2,000 ppm increasing to above 3,000 ppm led to seminarcotic state and irregular respiration. The AEGL-1 values are based on studies investigating CS2-induced inhi- bition of ethanol metabolism in humans (Freundt and Lieberwirth 1974a; Freundt et al. 1976b). In this controlled study, volunteers were exposed to CS2 at 20 ppm for 8 h by inhalation and simultaneously or afterwards took in alcoholic beverages to obtain a blood ethanol level of 0.75 grams per liter (g/L) (75 mg/deciliter [dL]). Each person served as his or her own control. CS2 exposure

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53 Carbon Disulfide caused a 50-100% increase in acetaldehyde in blood as compared with condi- tions without CS2. The effect occurred when alcohol was taken up during the CS2 exposure, and similarly when the alcohol uptake started 8 h after the end of CS2 exposure. Apparently, CS2 inhibits the metabolism of ethanol at the second step of the pathway, that is, the oxidation of acetaldehyde via aldehyde dehydro- genase (ALDH). The observed increase of acetaldehyde in the controlled studies was asymptomatic, that is, no disulfiram effect (“Antabuse syndrome” with flush, hypotension, and tachycardia) was observed. However, alcohol intoler- ance has repeatedly been mentioned in workers occupationally exposed to un- known (most probably higher) concentrations of CS2, and in its guidelines, the German Society for Occupational and Environmental Medicine includes alcohol intolerance as a further adverse effect induced by CS2 (Drexler 1998). There are different forms of ALDHthat differ in their activity. The pres- ence of the ALDH2(2) allele (which is common in Asians but rare or absent in Caucasians) results in lower ALDH activity and thus higher levels of acetalde- hyde after ingestion of alcohol as compared with persons in which the normal enzyme is present. Although individuals homozygous in ALDH2(2) are consid- ered hypersusceptible to ethanol (many avoid drinking ethanol at all), individu- als heterozygous in ALDH are considered as a sensitive subgroup within the normal population. In this group, an additional increase of the acetaldehyde con- centration due to a CS2-mediated ALDH inhibition may lead to an disulfiram effect (Antabuse syndrome) or aggravate otherwise mild symtpoms. An intraspecies factor of 3 was applied to account for the protection of the sensitive subpopulation. Extrapolation was made to the relevant AEGL time points using the relationship Cn × t = k, where C = exposure concentration, t = exposure duration, k = a constant, and n represents a chemical-specific expo- nent. The default of n = 3 was used for shorter exposure periods, due to the lack of experimental data for deriving the concentration exponent. For the AEGL-1 for 10 min, the AEGL-1 for 30 min was applied because the derivation of AEGL values was based on a study with a long experimental exposure period of 8 h, and no supporting studies using short exposure periods were available that char- acterized the concentration time–response relationship. The derived AEGL-1 values are above the odor thresholds but below the concentrations reported to cause moderate odor annoyance (see above). The derivation of the AEGL-2 is based on the no-observed-exposure level (NOEL) of 1,000 ppm for behavioral alterations in rats exposed to CS2 for 4 h (Goldberg et al. 1964). At the next higher concentration of 2,000 ppm, an inhibi- tion of the escape (and also the avoidance) response was observed. A total un- certainty factor of 10 was used. The interspecies uncertainty factor was reduced to 3 because of the similarity of acute effects produced by agents affecting the CNS seen in rodents compared with humans. Moreover, use of a default inter- species uncertainty factor of 10 would have resulted in values that are contra- dicted by experimental human studies in which no serious or escape-impairing effects were reported during or following 6-8 h of exposure to 80 ppm. An in- traspecies uncertainty factor of 3 was applied to account for sensitive individuals

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54 Acute Exposure Guideline Levels because the threshold for CNS impairment is not expected to vary much among individuals. Time scaling was performed according to the regression equation Cn × t = k, using the default of n = 3 for shorter exposure periods (30 min and 1 h) and n = 1 for longer exposure periods (8 h), because of the lack of suitable ex- perimental data for deriving the concentration exponent. For the 10-min AEGL- 2, the 30-min value was used because the derivation of AEGL-2 values was based on a long experimental exposure period (4 h), and no supporting studies using short exposure periods were available for characterizing the concentration- time-response relationship. The AEGL-3 was based on a study with rats (Du Pont 1966). In that study, all six animals exposed to 3,500 ppm for 4 h died during or within 2 h after ex- posure, whereas none of six rats exposed to 3,000 ppm died during the exposure or within the 14-day post-exposure observation period. A total uncertainty factor of 10 was used. An interspecies uncertainty factor of 3 was applied because the acute effects on the CNS are not expected to vary much between species. More- over, use of a default interspecies uncertainty factor of 10 would have resulted in values that are contradicted by experimental human studies in which no life- threatening effects were reported during or following 6-8 h exposure to 80 ppm. An intraspecies uncertainty factor of 3 was applied to account for sensitive indi- viduals because the threshold for CNS impairment is not expected to vary much among individuals. Time scaling was performed according to the regression equation Cn × t = k, using the default of n = 3 for shorter exposure periods (30 min and 1 h) and n = 1 for longer exposure periods (8 h), because of the lack of suitable experimental data for deriving the concentration exponent. For the 10- min AEGL-3, the 30-min value was used because the derivation of AEGL-3 values was based on a long experimental exposure period (4 h), and no support- ing studies using short exposure periods were available for characterizing the concentration-time-response relationship. A summary of AEGL values is shown in Table 2-1. 1. INTRODUCTION Pure CS2 is a colorless, mobile, refractive liquid with a sweetish aromatic odor similar to chloroform. Under the action of light (and air), CS2 is decom- posed with the formation of yellow decay products and a disagreeable odor. Similarly, commercial and reagent grade products are yellowish with a repulsive odor of decaying radish (WHO 1979). The odor was also described as “dis- agreeable, sweet” (Ruth 1986) or that of overcooked cauliflower. CS2 is released into the environment from natural sources such as soil, marshes, lakes, and volcanoes. The total global emission of CS2 and the anthro- pogenic share of the total emission is not well-known. However, according to more recently modelled scenarios, it is suggested that the majority of CS2 may be produced through human activity, rather than naturally (Environment- Canada/Health Canada 2000).

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55 Carbon Disulfide TABLE 2-1 Summary of AEGL Values for Carbon Disulfidea Classification 10 min 30 min 1h 4h 8h End Point (Reference) AEGL-1 17 ppm 17 ppm 13 ppm 8.4 ppm 6.7 ppm Increase in blood (Nondisabling) (52 (52 (42 (26 (21 acetaldehyde in mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) humans with moderate intake of alcohol (Freundt et al. 1976b) AEGL-2 200 ppm 200 ppm 160 ppm 100 ppm 50 ppm NOEL for behavioral (Disabling) (620 (620 (490 (310 (160 changes in rats mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (inhibition of escape response) (Goldberg et al. 1964) AEGL-3 600 ppm 600 ppm 480 ppm 300 ppm 150 ppm No lethality in rats (Lethality) (1,480 (1,480 (990 (930 (470 (Du Pont 1966) mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) a Cutaneous absorption may occur. Liquid CS2 is a severe skin irritant and direct skin contact with the liquid must be avoided. CS2 was discovered by Lampadius in 1796 by heating a mixture of pyrite (FeS2) and charcoal. Commercially, CS2 has been prepared by directing sulfur vapor over glowing coals. In the Western industrial countries, this process has been replaced by the reaction of methane and sulfur at temperatures between 500 and 700°C and a pressure between 4 and 9 bar (“methane process”). The CS2 is separated from H2S and by-products by liquefaction, distillation, and treatment with sodium hydroxide. The product thus purified contains a maxi- mum of 0.02% impurities (BUA 1993). About 1 million tons of CS2 was produced commercially worldwide in 1984. Since that time, production has been decreasing and was estimated at about 900,000 tons in 1990 (BUA 1993). The most important industrial use of CS2 has been in the manufacture of regenerated cellulose rayon by the viscose process and of cellophane. CS2 has also been used for the production of carbon tetrachloride which served as a starting chemical for the synthesis of fluorocar- bon propellants and refrigerants (ATSDR 1996). This application has been of declining importance in recent years. Smaller amounts of CS2 are needed as a solvent, for example, in the purification of sulfur, and for the manufacture of dithiurams, dithiocarbamates, and trithiocarbamates used as fungicides and vul- canization accelerators; for the manufacture of xanthates used as flotation agents in mineral refining processes; and for the synthesis of some other sulfur com- pounds. CS2 has also been used for soil fumigation, for example, in viniculture for fighting vine lice, and in veterinary medicine (BUA 1993; Environment Canada/Health Canada 2000). Chemical and physical properties of CS2 are presented in Table 2-2. Be- cause of its high volatility, low flash point, low autoignition temperature, and the wide range of explosive limits in air, CS2 poses an acute fire and explosion hazard.

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56 Acute Exposure Guideline Levels TABLE 2-2 Chemical and Physical Data for Carbon Disulfide Parameter Data Reference Synonyms Carbon bisulphide, carbon disulphide, HSDB 2007 carbon sulfide, dithiocarbonic anhydride, sulphocarbonic anhydride Chemical formula CS2 76.14 g mol-1 Molecular weight ATSDR 1996 CAS Reg. No. 75-15-0 ATSDR 1996 Physical state Liquid at room temperature ATSDR 1996 Solubility 2.94 g/L in water (20°C); soluble in ATSDR 1996; ethanol, benzene, ether Beauchamp et al. 1983 Vapor pressure 400 mm at 28°C Henschler and Greim 300 mm at 20°C 1975; Weast 1973 100 mm at −5.1°C 40 mm at −22.5°C Vapor density 2.62 Beauchamp et al. 1983 (air = 1) Liquid density 1.2632 (20°C) Weast 1973 (water = 1) Melting point −111.53°C Weast 1973 Boiling point 46.25°C Weast 1973 Explosive limits in air 1-50% Beauchamp et al. 1983 Flash point −29.62°C Beauchamp et al. 1983 Autoignition 100°C Beauchamp et al. 1983 temperature Conversion factors 1 ppm = 3.114 mg/m³ Calculated according (at 25°C) 1 mg/m³ = 0.321 ppm to NRC 2001 2. HUMAN TOXICITY DATA 2.1. Acute Lethality According to Flury and Zernik (1931), exposure to very high concentra- tions of CS2 is followed by acute disturbance of consciousness; delirium; loss of reflexes, including loss of pupil reaction; total paralysis; and respiratory arrest. The authors stated that exposure to CS2 at 4,800 ppm for 30 min to 1 h will im- mediately or later result in death, and 3,200-3,850 ppm over the same period of time will be life-threatening. The same statement is made by Bittersohl et al.(1972). Furthermore, they stated that “hyperacute intoxication” with very high concentrations exceeding 10 mg/L (3,200 ppm) will immediately lead to loss of reflexes, coma, and death. No details or references are presented.

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57 Carbon Disulfide 2.1.1. Reports Death has been reported in a community in India following an accidental release of large amounts of CS2, hydrogen sulfide, and sulfuric acid from a vis- cose rayon plant (Kamat 1994). Due to the lack of exposure data and the con- comitant exposure to other chemicals, no conclusions valid for the derivation of AEGL values can be derived from these data. There are few reports of acute poisonings following oral ingestion. In a fa- tal case in which the patient had swallowed “a glass” of CS2, the victim soon became unconscious and died about 2 h after drinking the liquid (Davidson and Feinleib 1972). Generally, 30-60 mL is reported to be fatal (WHO 1993). How- ever, ingestion of about 18 g of CS2 (about 15 mL) was reported to be lethal in three occasions. Prior to death, spasmodic tremors, prostration, dyspnoea, cya- nosis, peripheral vascular collapse, hypothermia, mydriasis, convulsions, and coma developed. Death occurred within a few hours (Fielder et al. 1981). 2.2. Nonlethal Toxicity Without giving any references, Bittersohl et al. (1972) stated that at about 300 ppm, slight symptoms in humans will occur after several hours of exposure, marked symptoms of intoxication at 400 ppm, severe symptoms at 1,150 ppm after 30 min, and life-threatening effects at 3,200-3,800 ppm. Furthermore, they stated that acute intoxications at concentrations higher than 1 mg/L (320 ppm) will lead to narcosis lasting for minutes followed by severe headaches and nau- sea. No details or any references are presented in this textbook, but some of the data agree with those presented in the summarizing table in Lehmann (1894). This table is also presented by Flury and Zernik (1931) and Lehmann and Flury (1938), and the same values are repeatedly presented by other reports (NRC 1984; AIHA 1992; OSHA 1999). 2.2.1. Reports In an accident, about 30,000 L of CS2 spilled from a broken railroad tank car. As a result of this spill, about 500 people were temporarily evacuated from the adjacent area. Five people were seen at a local hospital, and one of them was admitted. During inspection of the contaminated area, a flash fire occurred in which four people were trapped for a short period of time, but no injuries re- sulted. No further details were reported (NTSB 1998). Spyker et al. (1982) reported an accident in which CS2 leaking from a rail- road tank car caught fire and was extinguished. An airborne concentration of 20 ppm CS2 was measured at a site outside the town later during transfer of CS2 from the leaking tanker, but no measurement data were reported from the town or from the area during emergency operations. About 600 residents of an adja-

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58 Acute Exposure Guideline Levels cent area were evacuated; 27 subjects, mostly police and firefighters, who were exposed to unknown concentrations of CS2 were examined at a hospital. Most of the victims complained of headaches (16 of 27), nausea (14 of 27), and dizziness (16 of 27). Burning of throat, lips, and skin (11 of 27) and shortness of breath or chest pain (4 of 27) also occurred; two victims complained of impotence, and vomiting was seen in one. Spirometry, single breath CO-diffusing capacity, and arterial blood gas measurements were made in all four victims having shortness of breath or chest pain and in seven others who appeared clinically to be the most severely ill. Vital capacity and the partial pressure of arterial O2 were lower on the day of exposure than 9 days later. No significant changes were ob- served in forced vital capacity, forced expiratory volume, or diffusing capacity. None of the patients evaluated appeared to have sustained injury lasting beyond the first few post-exposure days (Spyker et al. 1982). It is not reported but likely that these victims were exposed not only to CS2 but also to the toxic and irritant products of CS2 burning, especially sulfur dioxide and acid mists. Following acute exposure to high concentrations of CS2, fainting and loss of consciousness was observed in about one third of 123 victims in an accidental release of large amounts of CS2, hydrogen sulfide, and sulfuric acid from a vis- cose rayon plant in India (Kamat 1994). A 42-year-old woman who had used CS2 for a few years to control insects in warehouses accidentally ingested about 5 mL of CS2 from a used soft drink bottle (Yamada 1977). After 5 h of induced vomiting, numbness in the lips and nausea and noninduced vomiting occurred. Within 12 h, abdominal pain, py- rexia, and wave-form agitation appeared, and she was hospitalized with con- spicuous agitation, hyperesthesia, accentuated tendon reflex of extremities and positive Babinski reaction in lower extremities. Transient ECG abnormalities were seen (sinus tachykardia and sharp P wave) 16 h after ingestion. Repeated illusion and delusions appeared after discharge. Abnormal EEG, such as sudden group of theta waves of higher potential and light-induced theta waves, was ob- served 2 days after the accident for about a week. The patient appeared healthy 2 months later. 2.2.2. Occupational Exposures Acute effects of exposure to CS2 are described in occupational medicine and toxicology handbooks and reports. Many serious cases of intoxication have occurred among workers exposed to CS2 in the cold vulcanization of rubber dur- ing the 19th century and later in the viscose rayon production (Davidson and Feinleib 1972). In these reports, exposure concentrations, based on estimates but not on measurements, are either lacking or are stated without any reference. Also, these reports describe cases in which acute symptoms occurred in workers who previously had been exposed for weeks to years to unknown concentrations of CS2. In view of the chronic effects of CS2 on the nervous system, it seems

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59 Carbon Disulfide likely that such “acute” poisonings were actually acute exposure and acute out- break of symptoms superimposed on chronic inhalation exposure. Therefore, it is unknown to what extent the effects described were due to acute exposure to CS2. Eye irritation in workers in the viscose-producing industry has also been described. However, this effect is considered to be mainly caused by hydrogen sulfide, which always is present together with CS2 in the viscose production process (BUA 1993; Greim 1999). Acid mists may also contribute to the effects. Gordy and Trumper (1938) described six cases of intoxication in workers who had been employed for at least 11 months. Especially in one case, the early effects are probably due to acute poisoning: A 27-year-old woman described to be in generally good health had been working in the rayon industry for 6 years as a reeler of artificial silk. On a day when she handled incompletely dried vis- cose, symptoms began with violent headache, faintness, restlessness, weeping, screaming, laughing, and loss of consciousness. After recovering consciousness, the victim felt as “though she had been beaten all over.” She spit blood and had “bloody bowel movements” and was semiconscious and stuporous most of the rest of the day. No data regarding the possible concentration of CS2 were pre- sented. The victim also complained of long-lasting effects after this episode. Repeated spells occurred from that day on, lasting about 15 min and consisting of headaches and numbness in various parts of the body. Her hands and feet felt as though they were asleep. She developed psychotic episodes characterized by auditory hallucinations, vasomotor instability, and disturbance of vision. In a short notice, Münchinger (1958) briefly summarized medical and neu- rologic findings in 100 workers in a Swiss viscose factory. The workers were 24-66 years old. Exposure duration varied between 1 and 39 years, and the mean CS2 concentration at the workplace was reported to fluctuate between 5 and 35 mg/m³ (1.6-11.2 ppm). Peak or maximum exposures were not reported. About two-thirds of the workers complained about subjective symptoms, especially alcohol intolerance, sleep disorders, noticeable tiredness at work, and irritability. About one third each complained of gastrointestinal problems and had patho- logic cardiovascular findings or respiratory tract disease. Medical and psychiat- ric examination revealed in about two-thirds of the workers alterations of the functions of the autonomic, peripheral, and CNS compatible with a mild-to- moderate psychoorganic syndrome. No detailed evaluation was presented. Alcohol intolerance in subjects exposed to CS2 has been mentioned in several other reports, and in its guidelines, the German Society for Occupational and Environmental Medicine points to alcohol intolerance as a further adverse effect induced by CS2 (Drexler 1998). Freundt et al. (1976b) cite several early reports regarding the development of alcohol intolerance in workers manufactur- ing rubber or viscose rayon. Reports date back to as early as 1856 and 1910 (Williams 1937), when exposure was probably very high. However, precise data regarding the concentration of CS2, the amount of alcohol intake, and the tempo- ral relationship were not available. Djuric (1971) noticed that in a group of vis-

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60 Acute Exposure Guideline Levels cose factory workers exposed to “pretty high concentrations” of CS2, slight in- tolerance to alcohol may occur. Vigliani (1954) described findings in Italian viscose rayon factories. From 1940 to 1941, he observed 100 cases of CS2 poisoning. Outbreaks of poisonings occurred in two plants after war-time measures led to bad ventilation, length- ened work shifts up to 12 h/d, and improper handling. The concentrations in the two plants ranged from a minimum of 0.11 mg/L (35 ppm) in the churn to a maximum of 2.5 mg/L (800 ppm) in the staple bleaching. In the staple rooms, the workers were exposed 4-5 h/d to CS2 concentrations between 1 and 2 mg/L (320-640 ppm). Concentrations higher than 0.5 mg/L (160 ppm) with a maxi- mum of 2 mg/L (640 ppm) were reported to poison workers in 2 to 6 months. In the 100 cases described, symptoms (in decreasing frequency) included polyneu- ritis, gastric disturbances, headaches, vertigo, sexual weakness, tremors, myopa- thy, psychoses, extrapyramidal symptoms, opticoneuritis, hemiparesis, and pseudobulbar paralysis. Concentrations of 0.40 to 0.50 mg/L (130-160 ppm) caused toxicity after 1 or more years of work. Some cases of mild poisoning were also seen in workers exposed to 0.2-0.3 mg/L (64-96 ppm). A great number of epidemiologic studies on the chronic effects of CS2 in occupationally exposed workers have been carried out, and these studies have been repeatedly reviewed and summarized (Davidson and Feinleib 1972; Hen- schler and Greim 1975, 1997; WHO 1979; Fielder et al. 1981; Beauchamp et al. 1983; BUA 1993; ATSDR 1996; Griem 1999 EnvironmentCanada/Health Can- ada 2000; WHO 2000). A detailed description of the findings from the epidemi- ologic studies is beyond the scope of this document, because these studies do not provide data that could be used for the derivation of AEGLs. Briefly, in chronic intoxication with CS2, almost every organ of the body may be affected. Generalized, subjective symptoms, such as tiredness, sleep- lessness, headaches, irritability, excitability, nausea, digestive disorders, reduc- tion of libido, neurasthenia, and dizziness, have been reported. Further effects include gastritis, ulcers, liver disfunction, paresis, paralysis, myopathy, and car- diac arrhythmia. Exposure to very high concentrations might result in psychoses, hallucinations, delirium, and dementia. In chronic exposure, the most common effects are polyneuritis with paresthesia, ataxia, reflex disorders, and atonia. In the vascular system, hypertonia and arteriosclerosis-like lesions in the vessels of the brain, coronary heart disease, lesions of the kidney, pancreas, and eye might develop. Increased levels of blood lipids have also been reported (Greim 1999). Neurotoxic effects were described to occur in workers exposed for dec- ades to concentrations lower than 30 mg/m³ (10 ppm). Increased mortality from cardiac infarction, neurotoxicity, and changes in blood lipids have been de- scribed at concentrations of about 20 mg/m³ (6 ppm) (Greim 1999). An expo- sure-response analysis concluded that the lowest levels associated with reduc- tions in peripheral nerve conduction velocity in CS2-exposed humans range from 13 to <31 mg/m³ (4 to <10 ppm) (EnvironmentCanada/Health Canada 2000).

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124 Acute Exposure Guideline Levels Lam, C.W., and V. DiStefano. 1982. Behavior and characterization of blood carbon di- sulfide in rats after inhalation. Toxicol. Appl. Pharmacol. 64(2):327-334. Lam, C.W., and V. DiStefano. 1983. Blood-bound carbon disulfide: An indicator of car- bon disulfide exposure, and its accumulation in repeatedly exposed rats. Toxicol. Appl. Pharmacol. 70(3):402-410. Lam, C.W., and V. DiStefano. 1986. Characterization of carbon disulfide binding in blood and to other biological substances. Toxicol. Appl. Pharmacol. 86(2):235- 242. Le, J.Y., and X.M. Fu. 1996. Human sperm chromosome analysis-study on human sperm chromosome mutagenesis induced by carbon disulfide. Biomed. Environ. Sci. 9(1):37-40. Lefaux, R. 1968. Carbon disulphide. Pp. 117-119 in Practical Toxicology of Plastics. Cleveland, OH: Chemical Rubber Company. Lehmann, K.B. 1894. Experimental studies on the effect of technically and hygienically important gases and vapours on the organism. Part VII: Carbon disulphide and sulphur chloride [in German]. Arch. Hyg. 20:26-79. Lehmann, K.B., and F. Flury. 1938. Toxikologie und Hygiene der technischen Lösung- smittel: Im Auftrage des Ärztlichen Ausschusses der Deutschen Gesellschaft für Arbeitsschutz. Berlin: Springer. Lehotzky, K., J.M. Szeberenyi, G. Ungvary, and A. Kiss. 1985. Behavioural effects of prenatal exposure to carbon disulphide and to aromatol in rats. Arch. Toxicol. Suppl. 8:442-446. Leonardos, G., D. Kendall, and N. Barnard. 1969. Odor threshold determinations of 53 odorant chemicals. J. Air Pollut. Control Assoc. 19(2):91-95. Lewey, F.H., B.J. Alpers, S. Bellet, A.J. Creskoff, D.L. Drabkin, W.E. Ehrich, J.H. Frank, L. Jonas, R. McDonald, E. Montgomery, and J.G. Reinhold. 1941. Experi- mental chronic carbon disulfide poisoning in dogs. J. Ind. Hyg. Toxicol. 23(9):415-436. Lewis, J.G., D.G. Graham, W.M. Valentine, R.W. Morris, D.L. Morgan, and R.C. Sills. 1999. Exposure of C57BL/6 mice to carbon disulfide induces early lesions of atherosclerosis and enhances arterial fatty deposits induced by a high fat diet. Toxicol. Sci. 49(1):124-132. Liang, Y.X., J.R. Glowa, and P.B. Dews. 1983. Behavioral toxicology of volatile organic solvents. III. Acute and subacute effects of carbon disulfide exposure on the be- havior of mice. J. Am. Coll. Toxicol. 2(6):379-389. Mack, T., K.J. Freundt, and D. Henschler. 1974. Inhibition of oxidative N-demethylation in man by low doses of inhaled carbon disulphide. Biochem. Pharmacol. 23(3):607-614. Magos, L., R.C. Emery, R.D. Lock, and B.G. Firmager. 1970. A vertical-type constant flow inhalation chamber for rats. Lab Pract. 19(7):725-727. Magos, L., A. Green, and J.A. Jarvis. 1974. Half life of CS2 in rats in relation to its effect on brain catecholamines. Int. Arch. Arbeitsmed. 32(4):289-296. Manuel, J. 1998. Carbon disulfide neurotoxicity defined. Environ. Health Perspect. 106(9):A428-A430. Mapleson, W.W. 1996. Effect of age on MAC in humans: A meta-analysis. Br. J. An- aesth. 76(2):179-185. McKee, R.W., C. Kiper, J.H. Fountain, A.M. Riskin, and P. Drinker. 1943. A solvent vapor, carbon disulfide: Absorption, elimination, metabolism and mode of action. JAMA 122:217-222.

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129 Carbon Disulfide APPENDIX A DERIVATION OF AEGL VALUES FOR CARBON DISULFIDE Derivation of AEGL-1 Values Key study: Freundt et al. 1976b Toxicity end point: Exposure to 20 ppm for 8 h in volunteers with a blood ethanol concentration of 0.75 g/L (75 mg/dL) caused a 50% increase in blood acetaldehyde level. This effect is explained by an inhibition of acetaldehyde dehydrogenase (ALDH) by CS2 which is similarly caused by dithiocarbamates and disulfiram (“Antabuse”). The increase of blood acetaldehyde in the key study was asymptomatic, that is, no disulfiram effect (“Antabuse syndrome”) was observed. However, ALDH is a polymorphic enzyme and individuals with low ALDH-activity (as frequently observed in Asians) may experience discomfort under conditions as in the experiment described. Individuals heterozygous in ALDH are considered a sensitive subgroup within the normal population. Scaling: C³ × t = k for extrapolation to 8 h, 4 h, 1 h, and 30 min. The 10-min AEGL-1 was set at the same concentration as the 30-min AEGL-1. k = 20³ ppm³ × 8 h = 64,000 ppm³-h Uncertainty/ 3 for intraspecies variability. modifying factors Calculations: 10-min AEGL-1 10-min AEGL-1 = 30-min AEGL-1 = 17 ppm (52 mg/m³) 30-min AEGL-1 C³ × 0.5 h = 64,000 ppm³-h C = 50 ppm 30-min AEGL-1 = 50 ppm/3 = 17 ppm (52 mg/m³) 1-h AEGL-1 C³ × 1 h = 64,000 ppm³-h C = 40 ppm 1-h AEGL-1 = 40 ppm/3 = 13 ppm (42 mg/m³) 4-h AEGL-1 C³ × 4 h = 64,000 ppm³-h C = 25 ppm 4-h AEGL-1 = 25 ppm/3 = 8.4 ppm (26 mg/m³) 8-h AEGL-1 C³ × 8 h = 64,000 ppm³-h C = 20 ppm 8-h AEGL-1 = 20 ppm/3 = 6.7 ppm (21 mg/m³)

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130 Acute Exposure Guideline Levels Derivation of AEGL-2 Values Key study: Goldberg et al. 1964 Toxicity end point: Behavioral alterations (Inhibition of escape response) in rats exposed to 2,000 ppm for 4 h; NOEL: 1,000 ppm, 4 h. Scaling: C³ × t = k for extrapolation to 30 min, 1 h. The 10-min AEGL-2 was set at the same concentration as the 30-min AEGL-2. k = 1,000³ ppm³ × 4 h = 4 × 109 ppm³-h C1 × t = k for extrapolation to 4 h and 8 h k = 1,000 ppm × 4 h = 4,000 ppm-h Uncertainty/ 3 for interspecies variability. modifying factors 3 for intraspecies variability. Combined uncertainty factor of 10. Calculations: 10-min AEGL-2 10-min AEGL-2 = 30-min AEGL-2 = 200 ppm (620 mg/m³) C³ × 0.5 h = 4 × 109 ppm³-h 30-min AEGL-2 C = 2,000 ppm 30-min AEGL-2 = 2,000 ppm/10 = 200 ppm (620 mg/m³) C³ × 1 h = 4 × 109 ppm³-h 1-h AEGL-2 C = 1,587 ppm 1-h AEGL-2 = 1587 ppm/10 = 160 ppm (490 mg/m³) 4-h AEGL-2 C × 4 h = 4000 ppm-h C = 1,000 ppm 4-h AEGL-2 = 1,000 ppm/10 = 100 ppm (310 mg/m³) 8-h AEGL-2 C × 8 h = 4,000 ppm-h C = 500 ppm 8-h AEGL-2 = 500 ppm/10 = 50 ppm (160 mg/m³) Derivation of AEGL-3 Values Key study: Du Pont 1966 Toxicity end point: Acute lethality in rats following 4-h exposure: 6/6 rats died at 3,500 ppm, 0/6 rats died at 3,000 ppm. Scaling: C³ × t = k for extrapolation to 30 min, 1 h. The 10-min AEGL-1 was set at the same concentration as the 30-min AEGL-1. k = 3,000³ ppm³ × 4 h = 1.08 × 1011 ppm³-h

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131 Carbon Disulfide C1 × t = k for extrapolation to 4 h and 8 h k = 3,000 ppm × 4 h = 12,000 ppm-h Uncertainty/ 3 for interspecies variability modifying factors 3 for intraspecies variability Combined uncertainty factor of 10 Calculations: 10-min AEGL-3 10-min AEGL-3 = 30-min AEGL-3 = 600 ppm (1,870 mg/m³) C³ × 0.5 h = 1.08 × 1011 ppm³-h 30-min AEGL-3 C = 6,000 ppm 30-min AEGL-3 = 6000 ppm/10 = 600 ppm (1,870 mg/m³) C³ × 1 h = 1.08 × 1011 ppm³-h 1-h AEGL-3 C = 4,762 ppm 1-h AEGL-3 = 4,762 ppm/10 = 480 ppm (1500 mg/m³) 4-h AEGL-3 C × 4 h = 12,000 ppm-h C = 3,000 ppm 4-h AEGL-3 = 3,000 ppm/10 = 300 ppm (930 mg/m³) 8-h AEGL-3 C × 8 h = 12,000 ppm-h C = 1,500 ppm 8-h AEGL-3 = 1,500 ppm/10 = 150 ppm (470 mg/m³)

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132 Acute Exposure Guideline Levels APPENDIX B ACUTE EXPOSURE GUIDELINES FOR CARBON DISULFIDE Derivation Summary for Carbon Disulfide AEGL-1 VALUES 10 min 30 min 1h 4h 8h 17 ppm 17 ppm 13 ppm 8.4 ppm 6.7 ppm (52 mg/m³) (52 mg/m³) (42 mg/m³) (26 mg/m³) (21 mg/m³) Key Reference: Freundt, K.J., K. Lieberwirth, H. Netz, and E. Pöhlmann. 1976b. Blood acetaldehyde in alcoholized rats and humans during inhalation of carbon disulphide vapor. Int. Arch. Occup. Environ. Health 37, 35-46. Test Species/Strain/Number: Human/ Healthy young males/12. Exposure Route/Concentrations/Durations: Inhalation/0, 20, 40, 80 ppm, 8 h. Effects: At 20 ppm, increase in blood acetaldehyde concentration (ca. 50% above control level) in healthy human subjects with moderate intake of alcohol (blood ethanol ca. 0.7 g/L [70 mg/dL]). The effect can be explained by an inhibition of the ALDH. The rise in acetaldehyde was not accompanied by signs of a “disulfiram effect.” However, alcohol intolerance has been reported in workers occupationally exposed to unknown concentrations of CS2. In further controlled human studies, exposure to 10-80 ppm CS2 caused a temporary reversible inhibition of xenobiotic biotransformation, but no signs of liver damage were observed. End Point/Concentration/Rationale: Increase in blood acetaldehyde concentration at 20 ppm, 8 h. Uncertainty Factors/Rationale: Interspecies: 1, test subjects were humans. Intraspecies: 3, subjects were healthy male volunteers. An uncertainty factor of 3 was applied to account for the protection of sensitive population subgroups with an acetaldehyde dehydrogenase (ALDH2[2]) less active than the typical form ALDH2. The presence of the ALDH2(2) allele (which is especially common in Asians but rare or absent in Caucasians) results in low enzyme activity and higher levels of acetaldehyde after ingestion of alcohol compared with persons in which the normal enzyme is present. Individuals heterozygous in ALDH are considered as a sensitive subgroup within the normal population. An additional increase of the acetaldehyde concentration due to exposure to CS2 may lead to a disulfiram effect or aggravate otherwise mild symptoms. Modifying factor: NA Animal to Human Dosimetric Adjustment: NA Time Scaling: Extrapolation was made to the relevant AEGL time points using the relationship Cn × t = k with the default of n = 3 (ten Berge et al. 1986) for shorter exposure periods, due to the lack of experimental data for deriving the concentration (Continued)

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133 Carbon Disulfide AEGL-1 VALUES Continued 10 min 30 min 1h 4h 8h 17 ppm 17 ppm 13 ppm 8.4 ppm 6.7 ppm (52 mg/m³) (52 mg/m³) (42 mg/m³) (26 mg/m³) (21 mg/m³) exponent. For the AEGL-1 for 10 min, the AEGL-1 for 30 min was adopted because the derivation of AEGL values was based on a study with a long experimental exposure period of 8 h, no supporting studies using short exposure periods were available characterizing the concentration time-response relationship, and it is considered inappropriate to extrapolate back to 10 min.The derived AEGL-1 values are above the reported odor thresholds but below concentrations reported to cause moderate odor annoyance. Confidence and Support for AEGLs: A well-conducted study with a sufficient number of human volunteers and an appropriate end point for AEGL-1 was available. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 200 ppm 200 ppm 160 ppm 100 ppm 50 ppm Key Reference: Goldberg, M.E., H.E. Johnson, D.C. Pozzani, and H.F.Jr. Smyth. 1964. Effect of repeated inhalation of vapors of industrial solvents on animal behavior. I. Evaluation of nine solvents vapors on pole-climb performance in rats. Am. Ind. Hyg. Assoc. J. 25: 369-375. Test Species/Strain/Number: Rats/ Carworth Farms Elias/ Groups of 8-10 females. Exposure Route/Concentrations/Durations: Inhalation, 0, 250, 500, 1,000, 2,500 ppm, 4 h. Effects: At 2,000 ppm, inhibition of escape reponse in 12% (and of avoidance response in 50%) of the animals was observed. No inhibition of escape (and avoidance) response was observed at 1,000 ppm. End Point/Concentration/Rationale: Exposure to 1,000 ppm for 4 h was a NOAEL for inhibition of escape response. Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3, based on the similarity of acute effects seen in rodents compared with humans produced by agents affecting the CNS. Intraspecies: 3, human data suggest that acute effects of volatile anesthetics and gases on the CNS show little intraspecies variability (about 2-3 fold). Modifying factor: Not applicable. Animal to Human Dosimetric Adjustment: Not applicable. Time Scaling: Extrapolation was made to the relevant AEGL time points using the relationship Cn × t = k with the default of n = 3 for shorter exposure periods of 1 h and of 30 min and of n = 1 for longer exposure periods of 4 and 8 h (ten Berge et al. 1986; NRC 2001). The 10-min AEGL-2 was assigned the same value as that for the 30-min AEGL-2 as it was considered inapproprate to extrapolate from an experimental period of 4 h to 10 min. (Continued)

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134 Acute Exposure Guideline Levels AEGL-2 VALUES Continued 10 min 30 min 1h 4h 8h 200 ppm 200 ppm 160 ppm 100 ppm 50 ppm Confidence and Support for AEGLs: AEGL-2 values are protective of human health. The level is based on a NOEL for inhibition of escape response in a behavioral study with rats in which concentrations in the exposure chamber were monitored. The AEGL values are supported by data from human studies in which no effects meeting the AEGL-2 definition were observed at similar concentrations. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 600 ppm 600 ppm 480 ppm 300 ppm 150 ppm Key Reference: Du Pont. 1966. Acute inhalation toxicity–progress report. Haskell Laboratory Report No. 161-66. EI Du Pont De Nemours and Company. Haskell Laboratory, Newark, DE. Test Species/Strain/Number: Rats/CD/6 males. Exposure Route/Concentrations/Durations: Inhalation, 3,500 ppm, 3,000 ppm/4 h. Effects: 6/6 rats died at 3,500 ppm, none of 6 rats died at 3,000 ppm. End Point/Concentration/Rationale: No lethality following 4 h of exposure to 3,000 ppm. Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3, based on the similarity of acute effects seen in rodents compared with humans produced by agents affecting the CNS. Intraspecies: 3, human data suggest that acute effects of volatile anesthetics and gases on the CNS show little intraspecies variability (about 2-3 fold). Modifying factor: Not applicable. Animal to Human Dosimetric Adjustment: Not applicable. Time Scaling: Extrapolation was made to the relevant AEGL time points using the relationship Cn × t = k with the default of n = 3 for shorter exposure periods of 1 h and of 30 min and of n = 1 for longer exposure periods of 4 and 8 h (ten Berge et al. 1986; NRC 2001). The 10-min AEGL-2 was assigned the same value as that for the 30-min AEGL-2 as it was considered inapproprate to extrapolate from an experimental period of 4 h to 10 min. Confidence and Support for AEGLs: AEGL-3 values are protective of human health. The available indicate a very steep concentration-lethality response curve and the values are based on a no-observed lethality concentration in rats. Additionally, the AEGL-3 values are supported by data from a human study in which the effects noted were milder than those defined by the AEGL-3 definition.