Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 7 (2009) / Chapter Skim
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2 Carbon Disulfide
2 Carbon Disulfide
Pages 50-134
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From page 50... ...
Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels.
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From page 51... ...
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 progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL.
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From page 52... ...
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)
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From page 53... ...
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 characterized the concentration time–response relationship.
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From page 54... ...
, and no supporting 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.
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mg/m3) (inhibition of escape response)
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HUMAN TOXICITY DATA 2.1. Acute Lethality According to Flury and Zernik (1931)
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. Due to the lack of exposure data and the concomitant exposure to other chemicals, no conclusions valid for the derivation of AEGL values can be derived from these data.
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From page 58... ...
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 viscose rayon plant in India (Kamat 1994)
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From page 59... ...
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)
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From page 60... ...
. 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; Henschler and Greim 1975, 1997; WHO 1979; Fielder et al.
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From page 61... ...
To determine the concentration of CS2 in air, CS2 was absorbed in ethanolic potassium hydroxide, and the xanthogenate formed was determined by titration. In the course of the whole study, the exposure concentrations varied between 0.55 mg/L (180 ppm)
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From page 62... ...
Up to 4 h 0.8-1.3 (260-420) Tension in the eyes, slight dizziness, headache, slight cough, feeling of exhaustion, at the end: slight lacrimation, burning of eyes, persistent headaches 0.7-2.55 mg/L Tickle in the throat, burning eyes, tingling; slight headaches, temporary (435-820 ppm)
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From page 63... ...
) : increase in blood acetaldehyde to twice of control values, no disulfiram effect 4 trained staff 0.21 ppm Odor recognition threshold Leonardos et al.
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The CS2 concentrations actually prevailing within the chamber were monitored before and during the entire exposure period with an automatically recording infrared analyzer (Uras 1, Hartmann & Braun) that was mounted outside and connected with the exposure chamber by a glass tube.
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From page 65... ...
after the 8-h exposure to CS2 at 20 ppm, the blood acetaldehyde concentration reached slightly more than twice the control value. A nearly identical quantitative effect was also seen after repeated exposure to CS2 at 20 ppm for 8 h/d on 5 consecutive days and simultaneous administration of ethanol only on the last day.
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From page 66... ...
Alcohol intake alone significantly lowered blood glucose by about 12%. In subjects with alcohol intake who were exposed to CS2 at 40 ppm, no significant changes of any serum parameters (cholesterol, calcium, inorganic phosphate, total bilirubin, albumin, total protein, uric acid, urea-N, glucose, lactate dehydrogenase [LDH]
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From page 67... ...
over a period of 16-24 h after the exposure to CS2, a 108% increase in the serum total bilirubin concentration to above the upper normal range and slight nonsignificant increases (18-52%) in serum albumin, total protein, uric acid, and alkaline phosphatase were observed.
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2.3. Reproductive and Developmental Toxicity Data regarding the reproductive or developmental toxicity of acute exposure of humans to CS2 were not available.
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A number of epidemiologic studies on mortality in workers exposed to CS2, especially in the viscose rayon industry, have been presented. However, these studies focus on the association between exposure and mortality from car
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From page 70... ...
A similar effect was seen when the intake of alcohol started 16 h after exposure to CS2 at 20 ppm and after 8 h/d for 5 consecutive days of exposure to CS2 at 20 ppm with alcohol intake only on the last day. Under the conditions of the study, there were no complaints about a disulfiram effect (Antabuse syndrome)
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Data regarding reproductive or develomental toxicity following acute exposure were not available. Epidemiologic studies have provided conflicting evidence of effects on reproduction, spontaneous abortions, and malformations.
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From page 72... ...
Because of instrumental difficulties, no analytic confirmation was performed at 3,000 ppm. The data indicate a very steep concentration-response curve for lethality: Whereas all six rats exposed at 3,500 ppm died during exposure or less than 2 h later, none of six rats exposed at 3,000 ppm died during exposure or within the 14-day postexposure observation period.
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From page 73... ...
1974 30 min/d, 3 d 3,000 ppm 21/30 animals died 6 h/d, 2-5 d 800 ppm No death after one exposure; 21/57 died in group on Lewis et al. 1999 high-fat diet; no death in group on normal diet 6 h/d, 5 d/wk, 13 wk 800 ppm 4/30 died 13th wk ToxiGenics 1983a 1h 220 ppm LC50 Gibson and Roberts 1972 Rabbit 6 h, 15 min 3,220 ppm 2½ h: lying on its side; narcosis at the end; death Flury and Zernik 1931 after 7 d (Continued)
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74 TABLE 2-4 Continued Species Exposure Concentration Effect/Remarks Reference Rabbit 6h 3,000 ppm 4/6 died and 2/6 moribund and euthanized after PAI 1991 exposure 6 h/d, 13 d 1,200 ppm Developmental toxicity study 2/24 dams died PAI 1991 Cat 48 min 112 mg/L (36,000 ppm) Lying on its side, convulsions, 1¾ h: narcosis, died Lehmann and Flury 1938 after half a day 3 h, 8 min ≥23 mg/L (≥7,400 ppm)
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From page 75... ...
Not all animals died on the same day, and none died after a single exposure to CS2 (J.G. Lewis, personal communication)
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3.1.3. Rabbits In an unpublished range finding experiment for a reproductive or developmental toxicity study, six pregnant New Zealand rabbits were exposed to CS2 at 3,000 ppm for 6 h on the 6th day of gestation (PAI 1991)
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A number of studies with repeated inhalation exposure have reported acute effects in laboratory animals after the first exposure or at the end of the daily exposure period. Nonlethal effects are summarized in Table 2-5.
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Severe narcosis, reduced cardiac and respiratory rate, Tarkowski and straightening of hind limbs, reduced body temperature; Sobczak 1971 uncoupling of oxidative phosphorylation in brain mitochondria Rat, Porton, 6, m 15 h 2.5 mg/L (800 ppm) Ataxia, tremors, occasional convulsions; 25% lowering of Tarkowski and blood glucose; alterations of brain amino acid metabolism Cremer 1972 Rat, Wistar, 7, f 12 h 2.4 mg/L (770 ppm)
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1993 after 14 h return to normal levels of alertness and activity 600 ppm, ≥9 d: circling behavior, retropulsion 800 ppm, ≥4 d: circling behavior, retropulsion Rat, Wistar, 14, m 6h 500 ppm Reduced activity level, not strongly irritating or prenarcotic Kivisto et al. 1995 Rat, Wistar, 5-15, f 8h 20 ppm Decrease of liver glycogen Freundt and 100 ppm Increased oxygen consumption Kürzinger 1975 400 ppm No change of serum ASAT, ALAT, LDH, biliary BSP clearance; increased hepatic lactate Rat, Wistar, 5 or 8h 200 ppm No hepatic damage Freundt et al.
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1974b; microsomal drug biotransformation Freundt and Kuttner 1969 Rat, S-D, 20-23 f 6 h/d, gestation day 100, 200, 400, 800 No deaths of dams ≥400 ppm: reduced weight gain Saillenfait et al. 1989 6-20 ppm Mouse 20 min 11,000 ppm Narcosis; recovery after termination of exposure Flury and Zernik 1931 Mouse, H, 8, f 2h 2,600 ppm 30% depression of response to electric seizure Frantik et al.
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From page 81... ...
No signs of acute toxic effects observed Lehmann 1894 Rabbit 6 h/d, 13 d 1,200 ppm Developmental toxicity study PAI 1991 Dams: reduced weight gain, ataxia, tremors, wheezing, labored respiration Rabbit 6 h/d, 5 d/wk, 17 wk 750 ppm No signs of acute toxicity observed Cohen et al. 1959 Dogs, mixed, 8 8 h/d, 5 d/wk, 400 ± 102 ppm During exposure: sleep Lewey et al.
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No toxic effects observed
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The data of this study indicate a very steep concentration-response curve since all of six rats exposed to 3,500 ppm for 4 h died during exposure or before 2 h post-exposure (see section 3.1.1)
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Two animals receiving this concentration died within a few days following the last exposure. Studies Mainly to Investigate Effects on Liver The acute effects on hepatic energy potential and functions were studied in female Wistar rats (Kürzinger and Freundt 1969; Freundt and Kürzinger 1975)
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Single or repeated exposure to 400 ppm produced a slight additional increase in blood acetaldehyde (up to 1.5fold of control values)
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exposed male Wistar rats to analytically monitored concentrations of CS2 at 0 or 2.5 mg/L (800 ppm) continuously for 18 h.
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A second experiment was carried out with rats exposed at 0, 1.2, or 2.4 mg/L (0, 385, or 770 ppm) for 7 h/d, 5 d/wk from their seventh month of life on.
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From page 88... ...
caused a moderate accumulation of fat in the liver that became severe and was accompanied by a rise of serum ASAT in animals also pretreated with phenobarbital. Neurotoxicity Studies with Repeated Inhalation Exposure Rats exposed to CS2 at 5,000 mg/m³ (1,600 ppm)
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At termination, signs of mild ataxia and moderate hindlimb paralysis were apparent. In the brain of rats exposed to CS2, an increase in the phosphorylation of endogenous MAP-2 (microtubuli associated protein)
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From page 90... ...
A concentration of 120 ppm was without effect, 580 ppm decreased responding in most mice, 2,200 ppm decreased responding in all mice, and 3,700 ppm abolished responding. Recovery from these acute effects was slow; full recovery required 6 h.
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. No differences were observed in the acute toxic effects of freshly
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No maternal toxicity or adverse effects on the developing embryo or fetus were seen at 100 and 200 ppm. Exposure to 400 or 800 ppm CS2 resulted in dose-related reduction of maternal weight gain and fetal body weight.
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Behavioral and neurotoxic effects of prenatal exposure to CS2 in rats were studied also by Lehotzky et al.
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(1984) studied the effects of CS2 on the reproductive system of male Long-Evans rats exposed to monitored concentrations of 0 or 600 ppm for 6 h/d, 5 d/wk for 10 weeks.
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From page 95... ...
New Zealand White rabbits received CS2 at 0, 25, 75, or 150 mg/kg of body weight each day on gestational days 6 to 19 and were examined on gestational day 30 for gross, visceral, and skeletal malformations. Significant maternal toxicity occurred at 75 and 150 mg/kg.
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From page 96... ...
The concentrations in this study were not measured, and the data are in contrast with other observations regarding lethal effects in this and other species in acute and in repeated exposure studies. It is likely that this value is erroneous,2 and no conclusions will be drawn from it.
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From page 97... ...
In mice, 30% of maximum possible effect was seen at 2,600 ppm, and the calculated EC10 was 100 ppm. In rats, acute exposure to CS2 at 2,000 ppm for 4 h caused an inhibition of the escape and avoidance response in a pole climbing test in 12% and 50% of the animals, respectively; no such effects were seen after one 4-h exposure to 1,000 ppm (Goldberg et al.
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From page 98... ...
These effects are described in other studies following acute exposure at similar and lower concentrations (see above)
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Human data As shown in controlled exposure studies, CS2 is rapidly and extensively absorbed through the respiratory tract. Unmetabolized CS2 is mainly excreted via the lungs.
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after 2 h and 31.7% (20-40%) after 5 h at CS2 exposure concentrations of 53-445µg/L (17142 ppm)
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The apparent total volume of distribution was 4.2 L/kg, the terminal elimination half-life was 24 min, and the total clearance was 112 mL/min/kg. Finally, in this study, experiments were conducted with rats exposed via inhalation to 50, 500, and 800 ppm, respectively, for up to 13 weeks.
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From page 102... ...
In rats exposed to CS2 at 60-350 ppm, the substance was rapidly eliminated during the first 6-8 h after exposure. Low concentrations of CS2 could still be detected in brain, liver, and kidney 20 h after exposure (Beauchamp et al.
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From page 103... ...
On the other hand, subsequent reactions of thiocarbamates may lead to long-lived protein modifications. Crosslinking of globin and spectrin in erythrocytes and of neurofilaments in spinal cord has been demonstrated in rats after repeated exposure to CS2 at 50 ppm by inhalation or repeated i.p.
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4.2. Mechanism of Toxicity The acute exposure to CS2 primarily manifests in rapidly occurring effects on the nervous system.
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Nonlethal effects on the CNS in different species are seen at similar exposure concentrations and exposure duration. In humans, such effects have also been observed in a controlled exposure study and in case of accidents.
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From page 106... ...
(1976b) , the effect of CS2 exposure on the blood acetaldehyde level in ethanol-treated humans and rats was observed not only when the alcohol was taken in during CS2 exposure but similarly when the alcohol intake only started 16 h after CS2 exposure.
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From page 107... ...
Hence, the odor would have warning properties at concentrations that are unlikely to represent any health hazard at acute exposure. This may be more important since irritation occurs only at concentrations of CS2 that already have depressant effects on the CNS, and therefore, irritation offers no warning.
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From page 108... ...
An increase in blood acetaldehyde levels occurred in ethanol-treated rats following CS2 exposure at 20 or 400 ppm (Freundt and Netz 1973; Freundt et al.
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From page 109... ...
. For the 10-min AEGL-1, the 30-min value was applied because the derivation was based on a long experimental exposure period of 8 h, and no supporting studies using short periods were available for characterizing the concentrationtime relationship.
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From page 110... ...
is rapidly eliminated from the body after ceasing exposure, the so-called "acid-labile" pool of bound CS2 containing thiocarbamates has a long half-life and increases with daily repeated exposures. Therefore, it is unclear whether developmental effects observed after repeated exposure to CS2 are of relevance for single acute exposures.
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From page 111... ...
was applied owing to the lack of suitable experimental 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, and no supporting studies using short exposure periods were available for characterizing the concentration-time-response relationship.
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From page 112... ...
was applied owing to the lack of suitable experimental data for deriving the concentration exponent. For the 10min AEGL-3, the 30-min value was used because the derivation of AEGL-3 values was based on a long experimental exposure period, and no supporting studies using short exposure periods were available for characterizing the concentration-time-response relationship.
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From page 113... ...
The data from this study were used to derive AEGL-2 and AEGL-3. In view of the severe acute effects of CS2 observed in this study and of the chronic effects TABLE 2-9 Summary of AEGL Values for Carbon Disulfidea Classification 10 min 30 min 1h 4h 8h AEGL-1 17 ppm 17 ppm 13 ppm 8.4 ppm 6.7 ppm (Nondisabling)
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114 FIGURE 2-4 Categorical representation of all carbon disulfide inhalation data. Note: 1, severity category could not be established.
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Carbon Disulfide 115 TABLE 2-10 Extant Standards and Guidelines for Carbon Disulfide Exposure duration Guideline 10 min 30 min 1h 4h 6h 8h 24 h AEGL-1 17 17 13 8.4 6.7 ppm ppm ppm ppm ppm AEGL-2 200 200 160 100 50 ppm ppm ppm ppm ppm AEGL-3 600 600 480 300 150 ppm ppm ppm ppm ppm ERPG-1 (AIHA)
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From page 116... ...
The ERPG-3 for carbon disulfide is based upon reports of severe poisoning at 1,150 ppm for 30 min and reports of psychosis and paralysis following acute exposure at 500 ppm. b IDLH (immediately dangerous to life and health, National Institute of Occupational Safety and Health)
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From page 117... ...
. The REL for a 6-h exposure protective against severe adverse effects of carbon disulfide is based on a developmental toxicity study in rats (Saillenfait et al.
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From page 118... ...
These data are in agreement with the limited data from controlled human studies, and support the AEGL values derived from human studies. Epidemiologic studies on occupational cohorts chronically exposed to CS2 cause suspicion of developmental or reproductive effects.
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From page 119... ...
1987. The potentiation of the non-behavioural effects of amphetamine by carbon disulphide.
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From page 120... ...
1992. Regional distribution of neuropeptide-degrading enzyme activity in the rat brain: Effects of subacute exposure to carbon disulfide.
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From page 121... ...
1975. Energy potential and hepatic function in rats under acute exposure to carbon disulphide.
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1962. Quantitative determination of absorption and elimination of carbon disulphide through different channels in the human body.
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From page 123... ...
1978. Activation of brain tyrosine hydroxylase in rats exposed to carbon disulfide and sodium diethyldithiocarbamate.
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1974. Inhibition of oxidative N-demethylation in man by low doses of inhaled carbon disulphide.
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2001. Standing Operating Procedure for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
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From page 126... ...
1971. Oxidation and phosphorylation processes in brain mitochondria of rats exposed to carbon disulphide.
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From page 127... ...
1980. The content of high energy phosphates and ultrastructure of mitochondria in the brain of rats exposed to carbon disulphide.
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From page 128... ...
1992. An Assessment of Reproduction in Female Rats Exposed to CS2 via Inhalation.
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From page 129... ...
. The increase of blood acetaldehyde in the key study was asymptomatic, that is, no disulfiram effect ("Antabuse syndrome")
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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.
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From page 131... ...
Carbon Disulfide 131 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)
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From page 132... ...
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.
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From page 133... ...
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.
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From page 134... ...
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.
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