National Toxicology Program

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. ¹

Names (NTP)

• Carbon disulfide
• CARBON BISULFIDE

Human Toxicity Excerpts

• HUMAN EXPOSURE STUDIES: Effects of carbon disulfide in air: slight or none (160-230 ppm); slight symptoms after several hr (320-390 ppm); symptoms after 30 min (420-510 ppm); serious symptoms after 30 min (1150 ppm); dangerous to life after 30 min (3210-3850 ppm); fatal in 30 min (4815 ppm) /From table/ [Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984., p. V4 753 (1978)]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: In ... reports of poisoning following pulmonary exposure to 1560 to 3125 mg carbon disulfide/cu m, a range of psychiatric disturbances was reported, while concentrations of approximately 15,625 mg/cu m resulted in central nervous system depression, coma, respiratory paralysis, and death. In several case reports, ingestion of approximately 18 g caused neurological signs, cyanosis, peripheral vascular collapse, and hypothermia, followed by death due to central nervous system depression and respiratory paralysis within a few hours ... [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: ... Exposure to carbon disulfide at levels generally in excess of 31 mg/cu m was associated with significant increases in serum cholesterol and LDL-C and decreases in HDL-C and ... with increases in blood pressure. In contrast ... findings were negative ... in a study of ... male viscose rayon workers exposed to a median personal airborne concentration of 13 mg/cu m ... No association between various measures of exposure (exposure category, levels in personal air, or TTCA levels in urine) and blood pressure or blood levels of cholesterol, LDL-C, HDL-C, triglycerides, apolipoproteins, electrolytes, or glucose /was found/. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 15, 2006. ]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: A study of neuropsychological variables in carbon disulfide-exposed workers investigated 120 workers selected on the basis of age not exceeding 50 years and an absence of family or personal history of nervous disorders. The test battery consisted of three intelligence tests, three personality questionnaires, a test of memory involving measures of perception, recognition, and free recall, and two performance measures. Workers were grouped according to exposure categories (none; low, about 20 ppm; medium, between 20 and 38 ppm; and high, greater than 38 ppm). The no-exposure and low-exposure categories were combined for analysis. Differences in the groups' measurements were statistically analyzed and revealed decreased intelligence scores, performance, and memory and increased fatigue and depression in the workers with higher exposures. These changes were dose related, although the exposure variable was categorical and not quantitative. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 18, 2006. ]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Death has been reported from exposure to a vapor concentration of 4,815 ppm for 30 minutes. An exposure of 500 ppm for 30 minutes may cause a situation immediately dangerous to life and health. [DHHS/ATSDR; Medical Management Guidelines for Carbon Disulfide (CAS# 75-15-0) p5 (2006). Available from http://www.atsdr.cdc.gov/MHMI/mmg82.pdf as of September 22, 2006. ]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: /After ingestion/ victims exhibited spasmodic tremors, prostration, dyspnea, cyanosis, peripheral vascular collapse, hypothermia, mydriasis, convulsions, coma and death in few hr from respiratory paralysis. Only mild gastrointestinal irritation and visceral congestion were noted at autopsy. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-90]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Women appear to be more sensitive than men to the neurotoxic effects of carbon disulfide. ... Abnormally high serum levels of cholesterol and beta-lipoprotein ... in chronically exposed workers ... with high incidence of hypertension and atherosclerosis and ... reduction in fibrinolysis activity of blood serum. ... Chronic gastritis with dyspepsia ... . [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-92]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Industrially exposed workers have exhibited ... neuropsychiatric disorders ranging from irritability to manic-depressive psychosis ... Clinical manifestations of nerve damage are ... blindness, and signs of parkinsonism ... [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-90]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: It dissolves fatty layer of epidermis, and workmen who put their hands in liq suffer from dry, cracked skin, on which eczematous lesions and even ulcers appear. [Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968., p. 118]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: In a survey of rayon factories where carbon disulfide in air was 37 to 56 mg/cu m, female spinners showed high incidence of menstrual disturbances and pregnancy toxemia. [CAI SX, BAO YS; IND HEALTH 19 (1): 15 (1981) ]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: SYMPTOMATOLOGY: Acute: 1. Mild to moderate irritation of skin, eyes and mucous membranes from liquid or concentrated vapors. If its evaporation is prevented, the liquid acts as a skin vesicant. Percutaneous absorption occurs. 2. Headache. 3. Garlicky breath, nausea, vomiting, diarrhea (even after vapor exposures), and occasionally abdominal pain. 4. Weak pulse, palpitations. 5. Fatigue, weakness in the legs, unsteady gait, vertigo. 6. Hyperesthesia, agitation, mania, hallucinations of sight, hearing, taste, and smell in acute, massive vapor exposures and sometimes in ingestion episodes. 7. Central nervous depression with respiratory paralysis. 8. Death may occur during coma or after a convulsion. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-92]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: SYMPTOMATOLOGY: Chronic: 1. Headache, fatigue, inability to concentrate, insomnia, dyspepsia, tremor, giddiness or vertigo. 2. Peripheral polyneuritis is often encountered: formication, pain, weakness, paralysis. The absence of a corneal reflex is highly characteristic ... 3. Emotional instability of all grades ranging from mild neurasthenia and depression to frank psychosis with psychomotor excitement, delirium and hallucinations. 4. Chronic, low-grade exposures of many years duration are associated with a high incidence of hypertension, atherosclerosis, renal and other parenchymal lesions (for example, stomach and perhaps liver). 5. Recovery may occur within a few months or perhaps a few years, but paralyses may be permanent. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-92]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Type of exposure: occupational; group exposed: male workers; type of study: semen analysis, reproductive history; effects: impotence, loss of libido /From table/ [National Research Council. Drinking Water and Health, Volume 6. Washington, D.C.: National Academy Press, 1986., p. 72]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Effects on eye-sight have been observed before other symptoms became evident. Studies indicated a gradual and slow incr in the sensitivity of the eyes to light. Alterations in dark adaptation also occurred, in most cases after 4 yr of exposure. ... [Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984., p. V4 752 (1978)]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Five hundred synthetic fiber workers who had been exposed to carbon disulfide at concentrations reportedly not exceeding 0.01 mg/L (3 ppm) were studied. Workers were 18 to 60 years old and had been exposed for periods of 0.5 to 30 years. Those exposed for short periods of time (usually less than 5 years) generally had mild visual disturbances such as conjuntival inflammations, temporary corneal opacities, and disturbed color vision. Prolonged exposure to carbon disulfide was reported to have caused irreversible vascular effects and inflammatory degenerative changes in the retina. [Szymankowa G; Klin Oczna 38: 41-4 (1968) ]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Thirty workers of a viscose rayon industry had a complete eye examination in 1979 including visual acuity, perimetry, color vision testing, fluorescein angiography, ERG and EOG, for possible signs of chronic carbon disulfide poisoning. Fundus anomalies and abnormal electrooculogram's and electroretinogram's were found. Twenty-nine of these thirty workers were reexamined in 1983. A number of them were no longer exposed to carbon disulfide for a period varying between 1 and 43 months. The fundus signs (pigmentary changes and vascular lesions) increased in frequency, even if the patient was no longer exposed. [De Rouck A, et al; Int Ophthalmol 9 (1): 17-27 (1986) ]**PEER REVIEWED** PubMed Abstract
  
• SIGNS AND SYMPTOMS: Exposed workers showed very little increased morbidity, but exposure dependent increases in pathological changes such as increased frequency of angina and myocardial infarction, systolic and diastolic blood velocity, increased symptoms of muscular weakness, increased low density lipoproteins, increased fasting blood sugar, increased proportion of abnormal sperm forms, and increased incidence of retinal abnormalities. [Albright BE et al; NIOSH US Department of Health and Human Services 1-201 (1984) ]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Local contact results in erythema and pain since carbon disulfide is one of the most potent fat solvents. Prolonged contact produces vesiculation and chemical burns. Severe chemical burns of the cornea result from direct contact with the eyes. [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 819]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Acute inhalation produces rapid onset of both local irritation and CNS symptoms ranging from pharyngitis, nausea, vomiting, dizziness, fatigue, headache, mood changes, lethargy, and blurred vision to agitation, delirium, hallucinations, convulsions, coma, and death. [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 819]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Carbon disulfide is a potent nerve toxin; it also may accelerate coronary artery disease. Peripheral neuropathies, cranial nerve dysfunction, and neuropsychiatric changes are present in over 70% of chronic carbon sulfide victims. Impaired psychomotor function ... and higher cortical function ... as well as neurasthenic symptoms ... characterize the neurologic illness associated with excessive carbon disulfide exposures. These neuropsychiatric symptoms may be irreversible. Chronic long-term exposures (eg, in rayon workers) may result in elevated blood cholesterol, retinopathy ... peripheral neuropathy, decreased glucose tolerance, reduced serum thyroxine levels, and parkinsonism. Increases in atherosclerosis, coronary artery disease, deaths, suicide rates, personality changes, and hypertensive disease have been suggested, but not confirmed, by epidemiological studies. [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 819]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Adverse effects of carbon disulfide exposure on reproductive function ... have been reported in exposed workers, with significantly lower sperm counts and more abnormal spermatozoa than in unexposed control subjects. [Rom, W.N. (ed.). Environmental and Occupational Medicine. 2nd ed. Boston, MA: Little, Brown and Company, 1992., p. 995]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Of 27 patients that were acutely exposed to airborne carbon disulfide, 59% had a headache, 52% experienced nausea, 4% experienced vomiting, 40% felt a burning of the throat, lips, or skin, 59% experienced dizziness, 15% had shortness of breath or chest pain, and 7% experienced impotence. [Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992., p. 1118]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: ... /A/ study reported that women exposed to 0.5 to 4.7 ppm (1.7 to 14.8 mg/cu m) had significantly more menstrual disorders than nonexposed women; however, there was no increase in the rate of spontaneous abortion, stillbirth, premature delivery, or congenital malformation ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 18, 2006. ]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: With regard to the /nervous system/ ... CS2 is associated with the following clinical syndromes ... (1) acute and chronic encephalopathy (often with prominent psychiatric manifestations), (2) polyneuropathy (both peripheral and cranial), (3) parkinsonism, and (4) asymptomatic CNS and PNS dysfunction ... Pathologic changes occur in both the CNS and PNS ... CNS pathology consists of neuronal degeneration throughout the cerebral hemispheres, with maximal diffuse involvement in the frontal regions, Cell loss is also noted in the globus pallidus, putamen, and cerebellar cortex, with loss of Purkinje cells. Vascular abnormalities with endothelial proliferation of arterioles may be seen, sometimes associated with focal necrosis or demyelination. PNS changes consist primarily of myelin swelling and fragmentation and large focal axonal swelling, characteristic of distal axonopathy. [Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill, 2001., p. 904]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: /Carbon disulfide/ primarily affects the nervous, cardiovascular, and reproductive systems. Single exposures are characterized by /CNS depression/ and its sequelae. Symptoms of repeated exposure are nervousness, irritability, indigestion, bizarre dreams leading to insomnia, excessive fatigue, loss of appetite, and headache.[American Conference of Governmental Industrial Hygienists. Documentation of the TLV's and BEI's with Other World Wide Occupational Exposure Values. CD-ROM Cincinnati, OH 45240-1634 2005., p. 2]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: ... Significant reductions in motor nerve conduction velocity (MCV) of the peroneal nerve, after adjustment for potential confounders (age, weight, height, glucose tolerance, and cigarette and alcohol consumption), /were found/ in workers exposed to carbon disulfide (median 13 mg/cu m in personal air). There were also reductions in sensory nerve conduction velocity (SCV) of the sural nerve in workers from those departments with high exposure ... [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: ... Early clinical reports of pronounced psychological and central nervous system damage following single or long-term exposure to high, but poorly characterized, levels of carbon disulfide in the rubber and viscose rayon industries ... led to the recognition of chronic carbon disulfide intoxication, characterized by psychoses, polyneuropathy of the lower extremities, gastrointestinal disturbances, myopathy of the calf muscles, nerasthenic syndrome, optic neuritis, and atherosclerotic vasculencephalopathy ... [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Exposure to carbon disulfide at levels greater than 31 mg/cu m was associated with damage to the retinal capillaries, in the form of microaneurysms or hemorrhages, in a number of cross-sectional studies. However, there appears to be considerable variation in the susceptibility to this effect among populations, and there is no clear evidence that exposure to lower levels of carbon disulfide is associated with retinopathy ... Such effects are of uncertain clinical significance ... Effects on colour vision in viscose rayon workers with current or historical exposures to carbon disulfide at levels greater than 31 mg/cu m /were also reported/ ... while colour vision was not affected in workers exposed to lower levels ... There were no other effects on measures of vision, including visual acuity, visual field, eye motility, depth perception, and pupillary reaction. [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: EFFECTS OF SHORT-TERM EXPOSURE: ... /Carbon disulfide/ irritates the eyes, the skin and the respiratory tract. Swallowing the liquid may cause aspiration into the lungs with the risk of chemical pneumonitis. The substance may cause effects on the central nervous system. Exposure could cause lowering of consciousness. Exposure between 200 and 500 ppm could cause death. EFFECTS OF LONG-TERM OR REPEATED EXPOSURE: Repeated or prolonged contact with skin may cause dermatitis. The substance may have effects on the cardiovascular system and nervous system, resulting in coronary heart disease and severe neurobehavioral effects, polyneuritis, psychoses. Animal tests show that this substance possibly causes toxic effects upon human reproduction. [IPCS, CEC; International Chemical Safety Card on Carbon Disulfide. (Date of review: October 2000). Available from http://www.inchem.org/documents/icsc/icsc/eics0022.htm as of September 15, 2006. ]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: For workers exposed to carbon disulfide, deficits have been reported in three or more independent studies on tests of intelligence, memory, vigilance, coding, spatial relations, motor coordination, response speed, and personality. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 2:104]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: ... The prevalence of electrocardiography (ECG) abnormalities was much higher in the carbon disulfide exposure group (25.9%, n = 65) than in the reference group (2.7%, n = 6), with an odds ratio (OR) of 12.8 (95% confidence interval [CI] = 5.4-30.2). The foremen were at the highest risk of abnormal ECG (OR = 20.6, 95% CI = 6.5-65.2), followed by filament-spinning workers (OR = 14.2, 95% CI = 5.7-35.3), viscose-manufacturing workers (OR = 11.3, 95% CI = 4.3-30.1), and carbon disulfide-manufacturing workers (OR = 8.1, 95% CI = 2.7-25.6). The multivariate logistic regression analysis based on cumulative exposure index also showed a dose-response relationship with the exposure, and the risk of ECG abnormality could be initiated at the exposure history of 31 to 57 year-ppm with an OR of 7.2 (95% CI = 1.5-36.7). [Chang SJ et al; J Occup Environ Med 48 (4): 394-9 (2006) ]**PEER REVIEWED** PubMed Abstract
  
• SIGNS AND SYMPTOMS: The natural course of clinical manifestations and electrophysiological changes were studied in six patients with carbon disulfide (CS(2)) induced polyneuropathy. All of the six patients worked in the cutting-machine department of a viscose rayon plant. The environmental monitoring was also conducted in the initial stage and followed up 3 years later. In the 3-year follow-up period, the neurological symptoms and signs persisted. The highest concentration of CS(2) in the cutting machine where these patients worked was about 100-200 ppm. Three years later, the highest concentration was decreased to between 10 and 20 ppm in the cutting machine of the new production line after the engineering control had been improved.Nerve conduction velocity (NCV) studies revealed persistent abnormality in motor and sensory NCVs. Although, a tendency to improvement was noted, it did not reach a statistical significance except for conduction velocity of sural nerve in sensory NCV. Sural nerve biopsy from one patient, 2 years after diagnosis showed degeneration of both axon and myelin and a predominant loss of large myelinated fibers. A remyelination process was also noted. [Huang CC et al; Clin Neurol Neurosurg 104 (2):115-20 (2002) ]**PEER REVIEWED** PubMed Abstract
  
• SIGNS AND SYMPTOMS: ... Thiobarbituric reactive substances (TBARS) concentrations were significantly increased both in carbon disulfide (CS2)-exposed subjects and in patients with peripheral atherosclerosis. Subjects in both groups presented also with decreased levels of plasma alpha-tocopherol, a major plasma antioxidant. In addition, decreased activities of two enzymatic antioxidants, glutathion peroxidase and catalase, were noted both in CS2-exposed subjects and patients with peripheral atherosclerosis. Finally, LDL isolated from both groups showed increased susceptibility to transition metal-induced oxidation in vitro. [Wronska-Nofer T et al; Arch Toxicol 76 (3):152-7 (2002) ]**PEER REVIEWED** PubMed Abstract
  
• CASE REPORTS: Cases of carbon disulfide poisoning were reported. A 24 year old male, employed in the curing room of an India rubber factory, was exposed to carbon disulfide vapors for 8 months. He was admitted to the hospital complaining of loss of sensation in the limbs, weakness, restlessness, insomnia, memory loss, weight loss, and atrophy of arm and leg muscles. The subject had a high stepping gait, and had difficulty standing erect. He had no ability to produce dorsal flexion of the ankle, extension of the big toe, or inversion of the foot. After 2.5 months, some traces of paralysis were still seen, particularly in the dorsal flexions of the foot. Another subject, a 36 year old male, had been exposed to carbon disulfide fumes for 9 months in the curing room of an India rubber factory. He complained of weakness, visual effects, deafness in one ear, pains and cramping in the lower extremities, headache, insomnia, apathy, and memory loss. His paralysis was very similar to that described for the other subject. After 1 month in the hospital, the subject was much improved, although the muscles that produced dorsal flexion of the feet were still comparatively paralyzed. [Ross J; Medical Chronicle 5 (28): 257-69 (1987) ]**PEER REVIEWED**
  
• CASE REPORTS: ... Histopathological findings in a male viscose rayon worker exposed to a TWA concentration of 125 to 209 mg/cu m /was reported/, with clinical and neurophysiological signs of peripheral neuropathy. The results of sural nerve biopsy revealed ultrastructural changes similar to those in the peripheral nervous system of animals exposed to carbon disulfide (axonal degeneration with disorganized neurofilaments) ... [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• CASE REPORTS: ... Three cases of poisoning due to excessive exposure to carbon disulfide /was cited on 10 years of experience in the manufacture of viscose rayon/: one of mental derangement and two with impaired motor nerves that adversely affected the leg muscles. All three workmen recovered completely within a few months after exposure terminated ... /It was stated/ when the carbon disulfide in the air was kept below 30 ppm and the hydrogen sulfide below 20 ppm, no trouble whatsoever was experienced. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 3:505]**PEER REVIEWED**
  
• CASE REPORTS: ... A patient developed headache, limb tremors, gait disturbance, dysarthria, memory impairment, and emotional lability after long-term exposure to carbon disulfide (CS(2)). The brain magnetic resonance images (MRI) showed diffuse hyperintensity lesions in T(2)-weighted images in the subcortical white matter, basal ganglia, and brain stem. The brain computed tomography perfusion study revealed a diffusely decreased regional cerebral blood flow and prolonged regional mean transit time in the subcortical white matter and basal ganglion. ... The (99m)Tc-TRODAT-1 single photon emission computed tomography showed a normal uptake of the dopamine transporter. [Ku MC et al; Eur Neurol. 50 (4): 220-4 (2003) ]**PEER REVIEWED** PubMed Abstract
  
• EPIDEMIOLOGY STUDIES: ... In ... 343 viscous rayon workers and 343 non-exposed men, tested for coronary heart disease the total mortality was 48 (14%) in the exposed group and 31 (9%) in the non-exposed group. [TOLONEN M ET AL; SCAND J WORK ENVIRON HEALTH 5 (2): 109 (1979) ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: 350 artificial-fiber plant workers were examined to determine if there were changes in the oral cavity associated with exposure to carbon disulfide. The workers had been exposed to carbon disulfide at concentrations of 0.02 to 0.065 mg/L (6 to 21 ppm) and to hydrogen sulfide at 0.002 to 0.006 mg/L (1 to 4 ppm) during the preceding 6 years ... . The group exposed to carbon disulfide for less than 5 years had significantly lower pH values for both the mucous membrane and the saliva than did the controls (5.28 versus 6.09 and 5.30 versus 6.29, respectively). Workers exposed for longer periods did not show this difference. Based on an index of periodontic disturbances, the frequency of pathologic changes in the periodontium of the exposed workers was significantly higher than that of the controls. The intensity of these changes increased with length of exposure, although the levels of significance did not. ... [Gondzik W et al; Med Pracy 20: 78-83 (1969) as cited in NIOSH; Criteria Document: Carbon Disulfide p.81 (1977) DHEW Pub NIOSH 77-156 ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: /A study was conducted to compare/ 118 male viscose rayon workers who had been exposed /to carbon disulfide/ for a mean of 15 years with 100 papermill workers (controls) for possible neurophysiologic differences. ... The greatest difference between exposed and control workers was found in the conduction velocities of the slower motor fibers in the ulnar nerve (39.8 versus 44.1 m/second, p< 0.0005) and the deep peroneal nerve (35.5 versus 38.2 m/second, p< 0.0005). Significant differences from normal were also found in the maximum motor conduction velocities of the posterior tibial nerve (40.5 versus 42.4 m/second, p< 0.0005) and deep peroneal nerve (45.9 versus 47.3 m/second, p< 0025). A conduction velocity was determined for each nerve tested such that 5% of the controls showed a conduction velocity below this value; each subject was then assigned a total conduction velocity score by counting one point for each nerve whose conduction velocity was below the limit for that nerve. The distribution of scores showed significantly slower conduction velocities in exposed workers. The lower conduction velocity scores /were regarded/ as an indication of increased polyneuropathy. The exposed group also had a larger number of abnormal EEG's (21 of 54) than did the controls (6 of 50); was significant at the 1% level. [Seppalainen AM, Tolonen MT; Work Environ Health 11: 145-53 (1974) as cited in NIOSH; Criteria Document: Carbon Disulfide p.66 (1977) DHEW Pub NIOSH 77-156 ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: Pregnancy data for 380 women employed in the viscose industry /were analyzed/ to determine the effects of carbon disulfide on pregnancy. The exposed group included 189 women who, before and during pregnancy, were exposed to carbon disulfide at concentrations reported to be 2.7 times the Soviet permissible limit of 10 mg/cu m (3 ppm). ... Several pregnancy complications were recorded, and comparisons were made between exposed and control women. The rate of threatened pregnancy terminations in the exposed group was 25.9/100 pregnant women versus 13.1/100 pregnant women in the controls (p< 0.05). The difference was still significant after adjustment for the differences in age and job longevity. Threatened pregnancy terminations occurred more frequently in the exposed women than in the controls, 12.5% versus 9.4% in the 20- to 24-year-old age group and 35.4% versus 13.6% in the 25- to 29-year-old age group. Spontaneous abortions occurred in 14.3% of the exposed women and 6.8% of the controls (p< 0.05). [Petrov MV; Pediatr Akush Ginekol 3: 50-2 (1969) as cited in NIOSH; Criteria Document: Carbon Disulfide p.58 (1977) DHEW Pub NIOSH 77-156 ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: An investigation was conducted to determine the effects of carbon disulfide exposure on/ female viscose rayon workers in three different departments for possible effects of /the compound/ on ovarian function and menstruation. The study included 500 workers in the spinning shop, where carbon disulfide concentrations sometimes exceeded 20 mg/cu m (6 ppm) and hydrogen sulfide concentrations reportedly never exceeded 10 mg/cu m (7 ppm); 209 workers in the trimming department, where the concentration of neither carbon disulfide nor hydrogen sulfide exceeded 10 mg/cu m (3 ppm); and 429 workers in the rewinding-sorting department (controls), not exposed to either substance. Durations of menstrual flow of more than 5 days occurred in 17.8% of the spinners, 10.5% of the trimmers, and 5.1% of the controls (p< 0.0001). Workers in the spinning shop experienced irregular menstruation significantly more frequently than the controls (7.6% and 1.6%, respectively; p< 0.0001). The frequency of irregular menses increased with longer occupational exposure. Heavy menstrual flow occurred in 12.5% of the spinners, 11% of the trimmers, and 2.3% of the controls (p< 0.001); painful menstruation was also significantly more common in exposed workers (36% and 38%) than controls (17%). [Vasilyeva IA; Gig Sanit 7: 24-7 (1973) as cited NIOSH; Criteria Document: Carbon Disulfide p.56 (1977) DHEW Pub NIOSH 77-156 ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: The spinners, the workers most heavily exposed to carbon disulfide, have a significantly higher mortality from all causes than the least exposed group. The excess mortality is largely accounted for by ischemic heart disease for which the spinners have a standard mortality ratio of 172. When mortality is related to an exposure score in the same group, both all cause (p< 0.01) and ischemic heart disease (p< 0.001) mortality increase with increasing exposure level. When this analysis is repeated covering all ages these trends become much less strong and only that for ischemic heart disease remains significant (p< 0.05). Over the age of 65 there is a tendency for mortality to decline with increasing exposure. [Sweetnam RM et al; Br J Ind Med 44 (4): 220-7 (1987) ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: A series of reports describing studies performed in Finland on viscose rayon workers revealed significant excess mortality (16 deaths from cardiovascular heart disease versus 3 expected in cohorts of 343 males) in those workers exposed to carbon disulfide for at least 5 years between 1942 and 1968 when concentrations of carbon disulfide and hydrogen sulfide varied from 20 to 40 ppm in the 1950s to 10 to 30 ppm in the 1960s. Most workers, however, had been exposed repeatedly at concentrations far higher than those measured in the general room air. This was caused by having to work with their heads inside the machine coverings during operational difficulties. Evidence of neurotoxicity in viscose rayon workers after long-term exposure to carbon disulfide was reported on a portion (118) of the same cohort examined in the cardiovascular study. About twice as many exposed workers had pathologically reduced nerve conduction velocities (48% versus 24%) as did the unexposed. This subclinical polyneuropathy (ulnar, deep peroneal, and posterior tibial nerves) was believed to be irreversible. Electroencephalograms were abnormal in 21 of 54 exposed workers, compared with 6 of 50 controls. As part of the cross-sectional study above, microcirculation of the ocular fundus and behavioral symptoms were studied. Delayed peripapillary filling occurred in 68 of 100 exposed workers versus 38 of 97 controls. It was concluded that delayed peripapillary filling was the primary effect in chronic, subclinical, carbon disulfide poisoning; the probability was 100% that carbon disulfide was the causative agent for either the reported coronary heart disease, the polyneuropathy and the eye disorder, or these three components plus behavioral symptoms. [American Conference of Governmental Industrial Hygienists. Documentation of the TLV's and BEI's with Other World Wide Occupational Exposure Values. CD-ROM Cincinnati, OH 45240-1634 2005., p. 2]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: Cardiovascular mortality was significantly greater in the most highly exposed workers in a cohort of 2939 male workers at a viscose rayon factory in the United Kingdom ... Among spinners with at least 10 years of employment in the industry, who were considered to have the highest continuous exposures, mortality was significantly in excess for all causes, ischaemic heart disease (73 deaths, standardized mortality ratio (SMR) 172, P < 0.001), and other circulatory diseases combined (33 deaths, SMR 165, P < 0.01), compared with the general population. There was also a significant excess of mortality from ischaemic heart disease in non-process fitters (nine deaths, SMR 290, P < 0.01). A significant trend between mortality from ischaemic heart disease among long-term older workers and cumulative exposure score or exposure score over the last 2 years was observed. These patterns were not evident in workers who had left employment or those with less than 10 years of exposure. Based on a report of an earlier follow-up, levels in the spinning department frequently exceeded 63 mg/cu m ... While there was concomitant exposure to hydrogen sulfide, the excess of mortality from ischaemic heart disease was similar among workers with high-level exposure to carbon disulfide alone or to both compounds. [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: In a historical cohort study of 3322 Dutch male viscose rayon workers, mortality from circulatory diseases was significantly increased among the 1434 workers exposed to carbon disulfide compared with the general population ... Among workers from the bleaching and spinning departments, who had continuous exposure to carbon disulfide, there was a significant excess of mortality from cardiovascular diseases (103 deaths, standardized mortality ratio (SMR) 126, 95% confidence interval (CI) 103-154) and a non-significant excess from ischaemic heart disease (65 deaths, SMR 125, CI 96-162). Among these workers, mortality from cardiovascular diseases and ischaemic heart disease was inversely related to cumulative exposure, although this was estimated from personal air samples collected late in the study period, and historical exposures were most likely higher. The risk for cardiovascular disease was reported to be most pronounced 20 to 30 years after the first exposure. In contrast to the results of other studies ... the risk for cardiovascular mortality did not decrease after termination of exposure. No information was available on other risk factors for heart disease, but there was no excess of cardiovascular diseases in unexposed workers, who were considered to be similar to the exposed workers in terms of lifestyle. [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: A follow-up study of 343 Finnish viscose rayon workers was performed to examine the incidence of cardiovascular mortality from 1967 to 1982 ... Exposure to carbon disulfide varied greatly (approximately 22 ppm to
• EPIDEMIOLOGY STUDIES: Compared to age-matched controls, an increase in total cholesterol (ch), HDL-Ch, and LDL-Ch was observed in women 40 to 49 years of age and 50 to 59 years of age ... The women were exposed to carbon disulfide at 5 to 7 ppm for 0.5 to greater than 20 years. Only HDL cholesterol and LDL cholesterol were increased when the values were examined by duration of carbon disulfide exposure. Rather than being a hepatic effect, the investigators suggest that the effect may be on hormone production by the ovaries resulting in altered lipid metabolism. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 15, 2006. ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: American subjects from a viscose rayon plant (156 exposed, 233 unexposed) underwent pupillary dilation (with a short-acting mydriatic), direct ophthalmoscopy, and retinal photography with monochromatic light ... Photographs were read by an ophthalmologist and rated as normal, as having definite or uncertain microaneurysms, or as having definite or uncertain hemorrhages. Subjects were categorized by job and characterized as having definitely low (DL<3 ppm), moderate (M = 3 to 7.1 ppm), or definitely high exposure (DH>7.1 ppm). Retinal microaneurysms and hemorrhages were more prevalent in the combined exposed groups than in the comparison group (p < or = 0.04). There was a concentration-related increase in the incidence of both definite and uncertain microaneurysms with exposure to carbon disulfide. No such trend was apparent for hemorrhages, nor for definite aneurysms alone. The combined exposed groups had almost 20% retinal microaneurysms (both definite and uncertain) compared to 7.5% for the comparison groups (significant, p < or = 0.01). The combined exposed groups had 10.5% retinal hemorrhages (both definite and uncertain) compared to 3% for the comparison group (significant, p < or = 0.01). [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 15, 2006. ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: In a cross-sectional study of the chronic effect of carbon disulfide exposure on the central nervous system, researchers measured the brain stem auditory evoked potential (BAEP) in Japanese spinning workers from a viscose rayon factory ... The workers were divided into three groups depending upon length of exposure: 34 current workers exposed for more than 240 months, 24 current workers exposed for 24 to 84 months, and 16 former workers exposed for more than 120 months. The 39 unexposed controls were workers in a nylon filament factory. The TWA exposures ranged from 3.3 to 8.2 ppm (mean 4.76 ppm). The latencies of the three main components of BAEP increased compared to those in the control group. The significantly higher interpeak latencies in workers exposed to carbon disulfide for more than 240 months suggest that chronic exposure to carbon disulfide involves the auditory ascending tract in the brain stem. Despite long exposure, BAEP parameters in workers exposed to more than 120 months were not significantly higher than those of the control group. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 18, 2006. ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: The effect of carbon disulfide exposure on the cardiovascular system was investigated in 162 workers with a minimum of 1 year of work in a viscose rayon factory in central Taiwan. The exposed group included 118 workers (113 men and 5 women) in the manufacturing areas such as viscose manufacturing, cellophane processing, ripening, and filament spinning. Nine percent of all subjects, exposed and control, were treated for existing cardiovascular conditions. In the exposure group, 8.5% of the subjects had hypertension and 5.8% had a previous diagnosis of renal disease. The equivalent figures for the control group were 11.4% and 5.9%, respectively. Workers in the cellophane processing area during heating were exposed to 54.60 parts per million (ppm) CS2 compared with 167 parts per billion (ppb) in the laboratory testing area for the reference group. Persons in the filament spinning section were exposed to 28.21 ppm CS2. The exposed group had a significantly higher incidence of abnormal sodium levels (12.8%) compared with the reference group (2.3%). The exposed group exhibited statistically significant abnormalities in both generalized ST-T segment changes (13.2%) and generally conducted disturbances (16.7%) compared with 3% and none for the reference group, respectively. Exposed workers had a 4.18 times greater risk of exhibiting ECG abnormalities. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 3:504]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: A cohort of male viscose rayon workers exposed to carbon disulfide (n = 145) was compared with a group of nonexposed artificial fiber plant workers (n = 233) located on the same premises ... Based on current personal monitoring, the mean carbon disulfide concentrations were estimated to be 7.3 ppm for the combined exposure group and 1.2, 5.1, and 12.6 ppm for the low-, medium-, and high-exposure categories, respectively ... The overall average for the historical area samples was 18 ppm, suggesting that the current personal samples may not be representative of exposure levels in earlier years ... Individuals were assigned to exposure categories based on current job title (n = 40, 61, and 44 in the low, medium, and high groups, respectively) ... Cumulative exposures by exposure category were 802, 1002, and 2077 ppm-months for the low, medium, and high groups, respectively (overall cumulative exposure was 1248 ppm-months) ... Workers were excluded on the basis of excess alcohol consumption, diabetes, or elevated blood lead levels. Surface electrodes were used to measure maximum motor conduction velocity (MCV) in the ulnar and peroneal nerves and sensory nerve conduction velocity (SCV) in the sural nerve. Latency and amplitude ratios were calculated. Data were presented after they were normalized for temperature and terminal distance. The numbers of measurements actually recorded varied due to time constraints on the field investigations and were 85, 130, and 137 in the combined exposed cohort and 105, 198, and 199 in the comparison cohort for the ulnar, sural, and peroneal nerves, respectively. In addition, participants' responses to a medical questionnaire with questions relevant to both central and peripheral nervous system symptoms were tabulated ... Peroneal MCV and amplitude ratio were significantly decreased in the overall exposed group, and the decrease was statistically significant in the high-concentration exposure group vs the comparison group. A concentration-response trend is evident across exposure categories. When MCV was stratified according to the cumulative exposure index (ppm-months), a significant association was made between this index and decreased MCV. Sural nerve SCV was decreased in the combined exposed groups vs the comparison groups, however there was no concentration-response relationship in the three exposure groups. No differences in the number of self-reported symptoms related to the peripheral nervous system were found. The decrease in MCV constitutes a LOAEL. When evaluated using the three exposure categories, the only significant effect is shown in the high exposure category. Splitting the exposed group into three exposure levels raises the concern that the resulting smaller numbers of subjects would reduce the power to observe an effect. A power analysis was conducted, and the results indicate that the power was 84% in the mid-exposure group, which is considered to be adequate power to observe an effect. Using the arithmetic mean exposures, this study identifies a LOAEL of 12.6 ppm (39.2 mg/cu m) and a NOAEL of 5.1 ppm (15.9 mg/cu m). The duration-adjusted LOAEL and NOAEL are 14.0 and 5.7 mg/cu m, respectively. [U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Carbon disulfide (CAS# 75-15-0). Available from: http://www.epa.gov/iris/index.html on the Substance File List as of September 22, 2006. ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: ... The ... exposed (n = 146) and nonexposed workers (n = 233) /were used in cross-section studies/ ... Historical exposures sampled from 1957 to 1978 averaged below 20 ppm (62 mg/cu m), however brief periods of high excursions in carbon disulfide levels occurred occasionally ... A number of parameters /were examined/ ... including cardiovascular status (clinical chemistries, ECG, and blood pressure), retinal abnormalities, CNS symptoms, psychological tests, endocrine and metabolic status (blood hormone levels and serum trace metals), and reproductive status (semen analysis and reproductive history). Results of these studies included significant increases in retinal microaneurysms and hemorrhages in exposed individuals compared with controls, but a concentration-related increase in response is not evident when analyzed by exposure category. In addition, an increased prevalence of blurred vision, memory difficulty, dizziness, insomnia, and fatigue was reported among carbon disulfide-exposed individuals. However, results of objective psychological and psychomotor tests do not corroborate the symptomatology. No effects were found in reaction time, visual acuity, visual search ability, or psychological or memory tests. No exposure-related effects on other parameters were reported. [U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Carbon disulfide (CAS# 75-15-0). Available from: http://www.epa.gov/iris/index.html on the Substance File List as of September 22, 2006. ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: ... Psychoorganic syndrome was diagnosed significantly more often in workers with heavy carbon disulfide (CS2) exposure, with adjusted OR of 17.9 (95% CI 2.18-146.73), and insignificantly in workers with intermediate exposure. Prevalence of workers with more than 6 positive answers on the Q16 was higher in the heavily exposed workers (OR=4.76; 95% CI 1.80-12.60). A similar result was found for almost all the questions in the Q16, and the most pronounced psychological symptom was of less interest in sex (adjusted OR=8.14; 95% CI 2.19-30.22). High correlation was found between symptoms recorded on neuropsychiatric examination and on Q16. Both neuropsychiatric exams and Q16 indicated disturbances in the central nervous system due to the long-term heavy exposure to CS2. Disorders of the central nervous system were found more often in workers with heavy exposure to CS2. [Krstev S et al; J Occup Health 45 (2): 81-7 (2003) ]**PEER REVIEWED** PubMed Abstract
  
• EPIDEMIOLOGY STUDIES:The aims of this study were to examine the dose-response relationship of CS2 exposure and elevated lipid profile tests among CS2-exposed workers in Taiwan. A total of 132 workers were recruited from two viscose rayon plants. ... There were 21 out of 33 (63.7%) elevated triglyceride levels among high-carbon disulfide (CS2)-exposure workers, 27 out of 64 (42.2%) among the middle-CS2-exposure, and 14 out of 35 (40%) among low-CS2-exposure workers, respectively. Compared to the low-CS2-exposure workers, the age- and weight-adjusted odds ratios (and 95% confidence intervals) of the prevalence of elevated triglyceride value were 1.12 (0.5, 2.7) for middle-CS2-exposure workers, and 2.81 (1.02, 7.8) for high-CS2-exposure workers. There was a significant linear trend between CS2 exposure and the prevalence of elevated triglyceride value (P = 0.046) after adjusting for other factors. There was a lower prevalence of elevated HDL level in high-CS2-exposure workers than low-CS2-exposure workers (15.2% versus 31.4%). Compared to the low-CS2-exposure workers, the age- and weight-adjusted odds ratio (and 95% confidence intervals) of elevated HDL level were 0.34 (0.1, 1.18) for high-CS2-exposure workers, which was borderline significant. [Luo JC et al; J Occup Environ Med 45 (1): 73-8 (2003) ]**PEER REVIEWED** PubMed Abstract
  
• EPIDEMIOLOGY STUDIES: This article presents cross-sectional investigation results of ophthalmological effects for the occupational exposure to carbon disulfide of workers at a large viscose fibre factory in the middle part of China. The total of 271 exposed subjects (191 males, 80 females) and 133 workers (93 males, 40 females) not exposed to any toxic agent in the working environment underwent ophthalmological examination. The self-administered questionnaire collected data on the medical history and ophthalmological complaints during the past three months. The ophthalmologic examination included routine examination for retinal capillary anomalies and and color vision with the FM 100-Hue test method. Nearly all subjects did not use respirators, smocks or aprons, gloves or other personal protective devices during work time. The average personal CS2 exposure level in the present study was 13.7 - 20.05 mg/cu m. The FM 100-Hue test results showed that the total error scores of the exposed group, whether male or female, were higher than that of the control, the discrimination of the green and blue zones was also impaired significantly. A fundus examination showed no retinal capillary anomalies or other serious ophthalmological symptoms that may be related to effects of CS2. In conclusion, color vision was disturbed in workers exposed to CS2, at levels below the present threshold value. Reduced color discrimination may be attributed to long-term carbon disulfide exposure and suggests that health surveillance of workers exposed to carbon disulfide should include the FM 100-Hue Test as a sensitive and easy method. [Wang C et al; Int J Hyg Environ Health 205 (5): 367-72 (2002) ]**PEER REVIEWED** PubMed Abstract
  
• EPIDEMIOLOGY STUDIES: ... Study subjects were 85 male workers /exposed to carbon disulfide (CS2) at 2.34 to 32.4 mg/cu m/ in the viscose industry and 35 men without such exposure. ... From the common carotid artery diameter, the change in diameter (echography) during the heart cycle and the pulse pressure, local arterial distensibility and compliance were calculated. Global large and small artery elasticity were calculated from registrations of radial artery waveforms. Simultaneously, heart rate and blood pressure were recorded and blood samples were collected for lipid measurements. ... No significant effect of carbon disulfide (CS2) on blood pressure, total cholesterol, HDL and LDL cholesterol or triglycerides was found. Among the vascular parameters under study, common carotid artery distensibility was significantly lower, and heart rate significantly higher in exposed workers compared to controls. The differences remained significant after adjustment for age, body mass index, smoking habits, alcohol consumption, heart rate and systolic blood pressure. Common carotid artery intima media thickness and global arterial indices did not differ significantly between the two groups. [Braeckman L et al; Ann Acad Med Singapore 30 (5): 475-80 (2001) ]**PEER REVIEWED** PubMed Abstract
  
• SURVEILLANCE: Male viscose rayon workers, diagnosed as chronically poisoned by carbon disulfide were studied. ... Concentrations at which the viscose rayon workers were exposed were 10-30 ppm (31-93 mg/cu m) in the 1960's, 20-40 ppm (62-124 mg/cu m) in the 1950's, and higher than 40 ppm (124 mg/cu m) prior to 1950. The most significant differences between the poisoned and control groups were the prevalence of general fatigue, insomnia, paresthesia, and headaches in the exposed workers (p< 0.001 for all four symptoms). Psychologic testing revealed mild intellectual impairment, reduction of sensorimotor speed, and impaired psychomotor ability. The psychologic disturbances were said to correlate well with duration of exposure, ie, patients with shorter carbon disulfide histories generally had milder disturbances. [Seppalainen AM et al; Work Environ Health 9: 71-5 (1972) as cited in NIOSH; Criteria Document: Carbon Disulfide p.64 (1977) DHEW Pub NIOSH 77-156 ]**PEER REVIEWED**
  
• SURVEILLANCE: 138 artificial silk workers whose exposure to carbon disulfide, averaging more than 10 years, had been at concentrations averaging between 20 and 42 mg/cu m (6-13 ppm) during the past 8 years, with peaks of 120-180 mg/cu m (39-58 ppm) /were examined/; earlier levels, believed to have been higher, were not documented. Atherosclerotic changes, as indicated by clinical, electrocardiographic, oscillometric, and optic fundi examination and by estimation of cholesterolemia, triglyceridemia, were found in 30.4% of the subjects and arterial hypertension in 23.2%; 14.5% of the workers showed both conditions. ... [Gavrilescu N, Lilus R; Amsterdam, Excerpta Medic Foundation p.240 (1967) as cited in NIOSH; Criteria Document: Carbon Disulfide p.51 (1977) DHEW Pub NIOSH 77-156 ]**PEER REVIEWED**
  
• SURVEILLANCE: ... Employees were often exposed to carbon disulfide 10-12 hours/day at concentrations of up to 2.50 mg/L (800 ppm), although the mean concentrations ranged from 0.45 to 1.0 mg/L (144-321 ppm). In the 100 workers examined, polyneuritic symptoms were observed in 88% of the patients. ... [Vigliani EC; Br J Ind Med 11: 235-44 (1954) as cited in NIOSH; Criteria Document: Carbon Disulfide p.28 (1977) DHEW Pub NIOSH 77-156 ]**PEER REVIEWED**
  
• SURVEILLANCE: Cardiovascular effects, as assessed by blood pressure, blood coagulation, and measurement of serum creatine kinase activity, were not observed in 247 workers exposed to carbon disulfide at a median concentration of 4 ppm for a median duration of 4 years ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 15, 2006. ]**PEER REVIEWED**
  
• SURVEILLANCE: In a study that was designed to examine the effects of carbon disulfide on the sympathetic/adrenal system, decreased diurnal urinary excretion of adrenaline, decreased plasma dopamine, and increased serum beta-hydroxylase activity were observed in women occupationally exposed at 5 to 7 ppm for periods ranging from 6 months to greater than 20 years ... Blood pressure was not significantly affected in this study, although among exposed women, a negative correlation was observed between daily urinary excretion of adrenaline and systolic blood pressure. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 15, 2006. ]**PEER REVIEWED**
  
• SURVEILLANCE: The neurotoxic effects after 10 years or more of long-term, low-level occupational exposure to carbon disulfide in workers at a viscose rayon plant were examined by assessing markers of the peripheral and autonomic nervous system ... Reinvestigation of 44 of 45 exposed and 31 of 37 matched control workers revealed changes in the motor nerve conduction velocity ... The exposure concentration in the two studies varied from 1 to 30 ppm. For peripheral nerves, a decrease in the conduction velocity in both fast and slow motor nerve fibers (peroneal nerve) was observed in exposed workers. Sensory conduction velocities were reduced and the refractory period of the sural nerve was increased. The effects on the sural nerve were pronounced. A small decrease in conduction velocities in the absence of symptoms of neuropathy and decreased response amplitudes suggest a mild presymptomatic nerve impairment. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 18, 2006. ]**PEER REVIEWED**
  
• SURVEILLANCE: In studies of Finnish workers, 100 males with the longest and most marked history of exposure and 97 unexposed males were chosen for a neuro-ophthalmological investigation ... The 100 men had been exposed for between 1 and 27 years to 10 to 40 ppm ... Corrected visual acuity, visual field, eye motility, pupillary reactions, and biomicroscopy were normal in all eyes examined. No retinopathy was detected in either group of individuals. However, delayed peripapillary filling of the choroid (both circumferential and segmental) occurred in 68 exposed and 38 unexposed eyes, a significant difference (p < ot = 0.01). This was attributed to possible hemodynamic effects of carbon disulfide exposure ... The mean widths of eight retinal vessels and the smallest vein were significantly greater in the exposed group ... A follow-up study validated the hypothesis that the delayed peripapillary filling of the choroid was related to the cardiovascular effects of carbon disulfide ... 38 male viscose rayon workers exposed to carbon disulfide were compared to 40 unexposed workers (previously examined neuro-ophthalmologically). Measurements were taken by oculosphygmography and were combined with individual electrocardiograms to statistically analyze the characteristics of the ocular pulse wave. Results showed that the exposed group of workers had a significantly lower pulse wave than that of the unexposed group, suggesting an increased rigidity of the ocular vascular bed in the viscose rayon workers. This study provided further evidence that carbon disulfide was not retinopathic in this Finnish cohort and in addition suggested a possible mechanism for the ocular effects of carbon disulfide. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 15, 2006. ]**PEER REVIEWED**
  
• SURVEILLANCE: Peripheral nerve conduction velocity was measured in carbon disulfide workers suspected to have polyneuritis (n = 60) ... The concentration of carbon disulfide was approximately 5 ppm (15 mg/cu.m), but high excursion levels of 225 ppm (700 mg/cu.m) sometimes were reached ... Conduction velocity was measured in the median, ulnar, and peroneal nerves and was found decreased in exposed individuals, even in those with no clinical signs. When exposed individuals were divided into two groups on the basis of the severity of their symptoms, it was found that the more severe polyneuropathy (decreased nerve conduction velocity, muscle pain, paresthesia, fatigue, and dizziness) was not reversed 1 year after termination of carbon disulfide exposure, whereas members of the second group (lower-limb paresthesia and decreased muscular power of limbs) recovered from their symptoms. The authors concluded that decreased nerve conduction velocity may be one of the early warning signs for carbon disulfide poisoning and could be used as an index of early carbon disulfide neuropathy. [U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Carbon disulfide (CAS# 75-15-0). Available from: http://www.epa.gov/iris/index.html on the Substance File List as of September 22, 2006. ]**PEER REVIEWED**
  
• SURVEILLANCE: Ninety-one patients who had suffered carbon disulfide poisoning [male:female=87:4; age, 32-74 (mean 53.3) years] were included in this study. To determine the extent of white matter hyperintensity (Grade 0-V) and lacunar infarction, T2-weighted MR imaging of the brain was performed. RESULTS: T2-weighted images depicted white matter hyperintensity in 70 patients (76.9%) and lacunar infarcts in 27 (29.7%).T2-weighted images depicted white matter hyperintensity in 70 patients (76.9%) and lacunar infarcts in 27 (29.7%). [Cha JH et al; Korean J Radiol 3 (3): 158-62 (2002) ]**PEER REVIEWED** PubMed Abstract
  
• BIOMONITORING: The concentration of crosslinked red blood cell spectrin has been suggested as a marker of nerve protein crosslinking damage that leads to slower conduction velocities and abnormal nerves due to protein adduct formation initially with dithiocarbamates which decompose to form isothiocyanate adducts ... These latter adducts can then cause the actual crosslinking of both spectrin and nerve protein. As new red blood cells must be made to replace the damaged spectrin, the crosslinking of this protein may serve as a longer term biomarker of carbon disulfide exposure. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p89 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 20, 2006. ]**PEER REVIEWED**
  
• BIOMONITORING: Carbon disulfide levels eliminated by exhalation may yield some information about recent, short-term exposure; however, the breath test has not been widely used for monitoring occupational exposure because of several confounding factors. The first phase of carbon disulfide elimination by breath is very fast. Pollutant concentrations in the breath, therefore, may reflect variable uptake during the day but may not be a good reflection of the longer term uptake and exposure values for an entire working day ... Absorption and elimination rates of carbon disulfide by the lungs are variable among different individuals and within the same individual because of differences in activity and metabolic rates. Chronically exposed persons, for example, have a lower retention rate than those exposed for the first time ... However, one might be able to detect carbon disulfide exposure more reliably if measurements of carbon disulfide were made during a second slower elimination phase and if a more sensitive detection technique were used. A quadrupole mass spectrometer makes the measurement of carbon disulfide in exhaled breath much more sensitive, detecting exposure levels as low as 1 ppm. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p88 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 20, 2006. ]**PEER REVIEWED**
  
• BIOMONITORING: Blood carbon disulfide levels may ... serve as a biomarker of exposure. Data from blood tests, however, have not shown consistent correlation with carbon disulfide exposure levels ... because of rapid clearance ... /and/ two different species of carbon disulfide exist in the blood. “Free” carbon disulfide is unbound carbon disulfide that is still dissolved in blood plasma; “bound” or “acid-labile” carbon disulfide refers to an appreciable amount of carbon disulfide dissolved in plasma lipids or bound to proteins in the blood. The equilibrium between free and acid-labile carbon disulfide in blood varies inter- and intraindividually ... /and/ bound carbon disulfide's rate of release into other body systems may vary also ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p89 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 20, 2006. ]**PEER REVIEWED**
  
• BIOMONITORING: ... /To/ measured levels of carbon disulfide in urine as a biomarker of exposure ... is probably optimal only for measuring high exposure levels ... Good correlation between urinary carbon disulfide levels and work exposure was not found in any studies. The measurements of excreted or “free” carbon disulfide may have been confounded by the presence of various thiometabolites or “bound” species ... The volatility of carbon disulfide and individual variations in urinary flow rate and metabolism may have confounded results in these studies ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p89 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 20, 2006. ]**PEER REVIEWED**
  
• BIOMONITORING: The iodine-azide test measures possible carbon disulfide exposure, based on the decolorization of iodine in the presence of urinary carbon disulfide thiometabolites. The iodine-azide test is a means for determining longer term carbon disulfide exposure at air concentrations of 50 mg/cu m (around 16 to 20 ppm) and above ... It is not a very sensitive test for exposure at lower concentrations of concern ... The iodine-azide test measures the catalysis of the reaction between iodine and sodium azide by the following metabolites of carbon disulfide acting as biomarkers of exposure: thiourea, which is the main urinary thiometabolite involved in this test, 2-thio-5-thiazolidinone, and a third unidentified metabolite. The latter two chemicals are present in very small quantities and are not as important in catalyzing the iodine-azide reaction ... Exposure can be detected ... /but/ is limited by the ... /fact taht/ level or duration of exposure cannot be quantified. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p90 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 20, 2006. ]**PEER REVIEWED**
  
• BIOMONITORING: Measuring the total concentration of urinary thio compounds (including glutathione conjugates, mercapturic acids, and other sulfur-containing carbon disulfide metabolites) can serve as a good marker of exposure. The level of total thio compounds correlates with carbon disulfide exposure levels and is a more sensitive biomarker of exposure than the iodine-azide test ... This biomarker detects an exposure to 6 ppm carbon disulfide for 8 hours ... These compounds are not absolutely specific for carbon disulfide exposure. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p90 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 20, 2006. ]**PEER REVIEWED**
  
• BIOMONITORING: Thiozolidine-2-thione-4-carboxylic acid (TTCA), which is a product of glutathione conjugation, is quantitatively related to carbon disulfide uptake ... Carbon disulfide exposure levels of 2.5 ppm and above are detected by this analytical method. Carbon disulfide exposure correlates well with urinary TTCA concentrations, especially once the metabolite levels are normalized to urinary creatinine content. It appears that TTCA levels may be used as a sensitive monitor of longer term exposure in workers ... One limitation of urinary TTCA levels is that this compound has been detected at low concentrations (range, 0.005 to 0.15 mg/g creatinine) in persons not exposed to carbon disulfide ... The source of this TTCA is thought to be from dietary intake, especially the consumption of brassica vegetables (e.g., cabbage) ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p91 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 20, 2006. ]**PEER REVIEWED**
  
• BIOMONITORING: Exposure to as low as 0.5 to 1.0 ppm (1.6 to 3.2 mg/cu m) of carbon disulfide (8-hr time-weighted average) was associated with detectable amt of 2-thiothiazolidine-4-carboxylic acid (TTCA) in end-of-shift urine ... The excretion of TTCA, relative to estimated carbon disulfide uptake, appeared reasonably constant in a dose range which varied by 20-fold; on an average, 3% was excreted as TTCA. TTCA elimination exhibited both a fast (half-time of 6 hr) and a slow (half-time of 68 hr) phase. The slow elimination is compatible with a high lipid solubility and protein binding of carbon disulfide ... [Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994, p. 145]**PEER REVIEWED**
  
• GENOTOXICITY: /DNA damage in human buccal cells of workers occupationally long-term exposed to carbon disulfide (CS(2)) was monitored with comet assay. ... Ninety workers exposed to CS(2) were randomly selected as exposure group from a large-scale chemical fiber manufacturer in Hubei and 81 workers not exposed to CS(2) as control group. DNA damage in their buccal cells was detected with comet assay. ... Rate of DNA tail was 0.51% in exposure group, significantly higher than that in control group (0.23%), with very statistical significance. Rate of DNA tail was 0.50% in male exposure group and 0.56% in exposure group with short length of employment, significantly higher than that in control group (0.08% and 0.25%, respectively). Multivariate unconditional logistic regression analysis showed that possibility of DNA damage was significantly higher in exposure group than that in control group (P < 0.05). [Chen XQ, Tan XD; Zhonghua Yu Fang Yi Xue Za Zhi 38 (1): 36-8 (2004) ]**PEER REVIEWED** PubMed Abstract
  
• GENOTOXICITY: In studies of mammalian cells exposed to carbon disulfide in the presence of metabolic activation, there were small and/or equivocal increases in chromatid gaps in human lymphocytes, in unscheduled DNA synthesis in diploid WI-38 cells derived from human embryonic lung tissue, and in sister chromatid exchanges in human lymphocytes. In one study ... in human sperm exposed to carbon disulfide in vitro, there was a significant increase in the frequency of chromosomal aberrations and in the frequency of chromosomal breaks. [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: Women employed in rayon textile jobs and paper products jobs had increased rate (p< 0.10) of spontaneous abortions; the wives of men employed in transport and communication, in rayon textile jobs and in chemical process jobs also had increased rate of spontaneous abortions. No evidence was found that level of carbon disulfide could be assoc with risk of spontaneous abortions. [HEMMINKI K, NIEMI ML; INT ARCH OCCUP ENVIRON HEALTH 51 (1): 55 (1982) ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: Severe intoxications have resulted from prolonged vapor exposures to concn as low as 30 ppm. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-90]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: /Investigators/ observed significant vascular, nervous, and biochemical changes in workers exposed to an average carbon disulfide concentration of 9 ppm for periods up to 2 years. ... The incidence and degree of these changes were proportional to the exposure. [American Conference of Governmental Industrial Hygienists. Documentation of the TLV's and BEI's with Other World Wide Occupational Exposure Values. CD-ROM Cincinnati, OH 45240-1634 2005., p. 2]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: In a study of Japanese viscose rayon workers, no effects were noted on blood pressure or on the incidence of angina. The exposed group comprised 420 rayon filament workers; 390 controls were obtained from a local cuprammonium rayon factory ... Mean carbon disulfide air levels were below 20 ppm at the time of the study (about 1975); these levels had been higher (15 to 30 ppm) during the 1950s. These observations suggest that ethnic variation or other demographic factors (eg, dietary habits) may affect the response to carbon disulfide. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 15, 2006. ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: The mechanism of action through which inhalation of high concn of CS2 vapors leads to psychotic mania is not currently established but may result from alterations in catecholamine synthesis or neuronal degeneration in several brain areas. [Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill, 2001., p. 585]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: With the exception of several reports of reduced libido and/or impotence in male workers exposed to (mostly) high concentrations of carbon disulfide in the viscose rayon industry ... there is no clear evidence of effects on human reproduction and development. Semen quality, fertility, and pregnancy outcomes were not associated with exposure of male viscose rayon workers to carbon disulfide in the better documented of the available studies ... The potential effects of carbon disulfide on female reproduction have not been adequately investigated, and there are conflicting reports of the frequency of abnormal menstrual duration or pain/bleeding in populations of female Chinese viscose rayon workers ... [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: There are ... epidemiological investigations of the association between exposure to carbon disulfide and a variety of other effects, most often alterations in circulating levels of thyroid hormones, gonadotropins, or adrenal and/or testicular hormones and increases in the prevalence of diabetes or decreased glucose tolerance ... However, the findings in the available studies ... were inconsistent and ... have often not been confirmed ... [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: It appears that there may be a group of individuals, both Eastern and Western, who are genetically predisposed to respond with retinopathy to low levels of carbon disulfide exposure ... Conflicting evidence shows no retinopathy with exposure to slightly higher levels of carbon disulfide in the Finnish population ... The differences in response by various populations have not been resolved. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 15, 2006. ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: The primary target organ for carbon disulfide toxicity is the nervous system. In humans, behavioral changes, neurophysiological changes, and neuropathology have been demonstrated ... Some studies have noted that these changes were reversed following removal from exposure; other studies have indicated no improvement. One of the major problems has been in establishing levels of exposure associated with the onset of symptoms. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p83 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 20, 2006. ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: Acute exposure to high concentrations of carbon disulfide result in immediate adverse effects. However, some of the common manifestations of acute high-level exposure may be delayed. [DHHS/ATSDR; Medical Management Guidelines for Carbon Disulfide (CAS# 75-15-0) p16 (2006). Available from http://www.atsdr.cdc.gov/MHMI/mmg82.pdf as of September 22, 2006. ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: ... Epidemiological studies of female workers in China suggested that there were increased teratogenic effects. Congenital heart defects in offspring were most frequently observed. When the workers were divided on the basis of exposure above or below 10 mg/cu m, there was no difference between the groups, suggesting that the threshold for these effects was below the exposures encountered or was unrelated to dose. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 3:505]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: Ocular and central visual system sites of action of carbon disulfide following systemic exposure are rods and cones of the outer retina, retinal ganglion cells and optic nerve /and/ tract, and lateral geniculate nucleus and visual cortex. /From table/ [Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill, 2001., p. 566]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• LABORATORY ANIMALS: Acute Exposure: In Wistar rats, a single dose of carbon disulfide administered by gavage at doses up to 632 mg/kg did not cause death ... Anesthetized male Wistar rats acutely exposed to 632 mg carbon disulfide/kg (0.5 mL/kg) had a significantly reduced occurrence of some cardiac arrhythmias after coronary occlusion by surgical ligation when compared to controls ... The heart rate measured before the procedure was significantly lower in exposed rats than in the controls ... The effects of a single gavage administration of carbon disulfide on electrocardiograph (ECG) parameters in anesthetized rats /was also observed/. Changes in ECG were noted at 373 and 506 mg/kg; dose response was noted in QTc. Heart rate was decreased at 632 mg/kg. No significant changes in contractile force of the left ventricle were noted. In conscious male Wistar rats administered 506 mg/kg carbon disulfide once by gavage, blood pressure was decreased (p < or = 0.001) 5 hours after treatment, but this change was reversible in another 5 hours ... The NOAEL was 253 mg/kg. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p53 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: ... No mortality occurred in rats exposed to as much as 2470 mg/cu m for 15 hr, although neurological effects were observed ... [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Rats exposed to ... 642 ppm of carbon disulfide for 4 hours exhibited no histological evidence of liver damage ... However, hepatotoxicity characterized by hydropic degeneration in parenchymal cells of the centrilobular zone was observed in rats pretreated with phenobarbitone to induce the liver mixed-function oxidase system and subsequently exposed to 642 ppm for 4 hours ... Starvation further potentiated the phenobarbitone induced liver lesions in rats subsequently treated with carbon disulfide. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 15, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Acute inhalation toxicity LC100 /for cats was/ 23 mg/L/3 hr and 122 mg/L/1 hr. [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Acute toxicity LD100 /for rabbits was/ 300 mg/kg sc and 315 mg/kg iv. [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Rabbits /administered carbon disulfide 1.25 to 15.6 mg sc or im, or 0.19 to 0.63 iv showed/ ... no change in size and shape of erythrocytes, no hemolysis, no methemoglobin, /and/ no distinct change in differential leukocyte. CS2 /was/ not a blood poison. [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: /Carbon disulfide was/ highly irritating to rabbit skin with/ daily application of 2.58 mg for 3 to 5 days. [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Female Wistar rats were exposed to 100 or 600 ppm of carbon disulfide for 6 hr/day, 5 days/wk, for 12 wk to determine the effects on tissue Vitamin B6 concentrations. Liver, kidney, and brain tissue were assayed at the end of 12 wk (12 rats/group and 12 controls exposed to fresh air) for five forms of B6: pyridoxine, pyroxidal, pyridoxamine, pyridoxal phosphate, and pyridoxamine phosphate. During the experiment, urine was assayed for 4-pyridoxic acid on day 5 of wk 2, 4, 6, 10, and 12. By wk eight there were significant differences (p< 0.01) in the body weights of the 3 groups; 600 ppm, 208 + or - 7.5 g; 100 ppm, 216 + or - 9.2 g; and control, 221 + or - 5.2 g. Excretion of 4-pyridoxic acid throughout the experiment after exposure to 100 ppm was essentially the same as the control, but excretion of 4-pyridoxic acid after exposure to 600 ppm was significantly decreased (p< 0.01) during the first 4 wk of exposure and was continuous (p< 0.05) for the 12 wk. Pyridoxine was not detected in liver, kidney, or brain tissue and pyridoxamine was detected only in liver tissue. Even exposure to 600 ppm, carbon disulfide had no significant effect on the content of the forms of vitamin B6 in any of the tissues examined. [Okayama A et al; Arch Toxicol 60 (6): 450-3 (1987) ]**PEER REVIEWED** PubMed Abstract
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: ... Eight dogs were exposed to 400 ppm carbon disulfide in air 8 hr per day, 5 days per week, for 10 to 15 weeks. When removed from the chamber, the dogs were drowsy and staggered and stumbled as if drunk. They were very thirsty but did not eat for hours after leaving the chamber. Although they slept most of the time they were in the chamber, they were excited and noisy at night in their kennels. The dogs also developed many clinical and pathological signs analogous to those in workers: marked behavioral changes and toxic disease of nerve cells of the cortex of the brain were observed in all of them. Rigidity and tremor (parkinsonism) and choreatic movements were seen frequently, as was disease of the nerve cells of the basal ganglia. Motor weakness, flaccid paralysis, and nerve tenderness were the most frequent signs observed; the peripheral nerves showed axonal degeneration while the myelin sheath was well preserved. Cardiovascular changes included electrocardiographic abnormalities, especially inversion of the T wave, retinal angiospasms, and arthrosclerosis of the veins of the cortex of the brain. [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 653]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Rabbits /were exposed to carbon disulfide by inhalation at/ 0.2 and 2 mg/cu m, 24 hr/day /for/ 1, 2, and 6 wk. ... Low dose intensified while high dose inhibited cortical processes as determined by EEG analysis. [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Rabbits /were exposed to carbon disulfide by inhalation at/ 300 ppm, 6 hr/day /for/ 48 days. No significant changes in EKG, no pathologic changes except minimal fibrosis, and hyaline changes. Same result /was obtained with cats exposed by/ inhalation, dose 1100 ppm, exposed 6 hr/day for 12 days. [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Wistar rats /were exposed to carbon disulfide by/ inhalation at/ 0.5 mg/L, 5 hr/day for 5 mo. Increased soluble fiber in monomer complexes in blood and decreased fibrinolytic activity /were observed/. [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Four of 22 mice died following inhalation exposure to 800 ppm for 6 hours a day, 5 days a week, for 90 days. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 15, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: In mice ... /carbon disulfide/ exposures at a concentration of 482 ppm for up to 23 days (4 hr a day, 5 days a wk) have resulted in a marked reduction in cytochrome P-450 and cytochrome c-reductase content after 2 to 3 days. The level returned to normal by the 23rd day of treatment. A significant decrease in uridine diphosphate-glucuronyl (UDP-glucuronyl) transferase was also noted, as well as a significant increase in lipid peroxidation ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 15, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Female Wistar rats exposed to 800 ppm for 15 weeks (5 days a week, 6 hours a day) showed a 10% decrease in body weight gain ... Male Long-Evans rats showed a 6 to 8% decrease at lower concentrations (350 to 600 ppm) following inhalation exposure for 10 weeks ... During a 14-day exposure (10 hours/day) to carbon disulfide at 600 ppm, male rats lost 14% of their body weight ... This concentration also resulted in a narcotic-like stupor in the exposed rats. Contrary to these findings, male Long-Evans rats that were exposed to 500 ppm for 5 or 12 weeks (5 days a week, 6 hours a day) showed no significant changes in body weight gain ... Female Long-Evans rats exposed to 800 ppm for 11 weeks (7 days a week, 7 hours a day) had a 15% decrease in body weight gain; this effect was not seen at 400 ppm ... Inhalation exposure of Fischer 344 and Sprague-Dawley rats at 800 ppm for 90 days (5 days a week, 6 hours a day) caused a 16 to 30% decrease in body weight gain in both sexes ... The percent of decrease in body weight gain depended on the strain of rat used ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 15, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: No deaths were noted after a 4-week (5 days a week) administration of 253 mg/kg/day carbon disulfide by gavage to Wistar rats ... Exposure of anesthetized male rats at ... 253 mg/kg/day daily for 4 weeks produced a decrease in left ventricular systolic pressure and changes in an electrocardiograph ... In conscious male Wistar rats ... no effects on blood pressure or heart rate were observed in rats after receiving carbon disulfide at 126 or 253 mg/kg/day for 4 weeks ... 253 mg/kg/day carbon disulfide for 4 weeks by gavage showed a 10% decrease in body weight compared to the controls. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p53 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: ... Rats /orally/ administered 25 mg carbon disulfide/kg/day for 60 days developed normochromic and normocytic anemia, eosinopenia, and an increase in reticulocyte cell numbers. No changes in leukocyte or platelet numbers were observed ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p59 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Male mice orally exposed to 3 to 300 mg/kg/day (1 to 14 days) have shown rapid, reversible, dose-related suppression of hepatic microsomal enzymes ... An acute-duration MRL of 0.01 mg/kg/day was derived based on dose-dependent decreases in the activities of liver microsomal drug-metabolizing enzymes in mice ... The LOAEL for this effect was 3 mg/kg/day. The following enzyme activities were decreased: hydroxylation of aniline, O-dealkylation of p-nitroanisole, 7-ethoxycoumarin and 7-ethoxyresorufin, N-demethylation of N,N-dimethylaniline, NADPH-cytochrome p-450 reductase activity, and p-450-associated peroxidase activity. In addition, a decrease in cytochrome p-450 content and total heme content was observed. The inhibition of enzyme activities was reversible. There were no effects on the activities of NADH-ferricyanide reductase, NADPH-cytochrome c reductase, flavin-containing monoxygenase, UDP-glucuronyltransferase, glucose-6-phosphatase, heme oxygenase, and glutathione S-transferase. Also, the content of cytochrome b5 was not altered. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p59 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Rabbits /were exposed to carbon disulfide by/ inhalation at/ 200 ppm, 3 hr/day /for/ 6 mo. Vacuolation of hepatocytic cytoplasm /was found/. [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Guinea pigs /were exposed to carbon disulfide by inhalation at/ 9630 ppm, 15 min/day for 20 days. Enhanced platelet aggregation /was observed/. [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Rats /were sacrificed after exposure to carbon disulfide by inhalation/at/ 0.1 mg/L, 3 hr/day for 1.5 mo. Thyroid activity increased. Decreases in estrus cycles /and/ adrenal function /were also observed/. Changes appeared earlier in younger animals than in older rats. [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Rats /were exposed to carbon disulfide by inhalation at 10, 50, 100, and/ 200 mg/cu m, 4 hr/day /for/ 6 mo. Disrupted glucose absorption and inhibited intestinal enzymes /were observed/. [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: ... Exposure of mice on the control diet to 500 and 800 ppm CS2 induced a small but significant increase in the rate of fatty deposit formation over non-exposed controls. ... There was marked enhancement of the rate of fatty deposit formation in mice exposed to 500 and 800 ppm over the animals on the high fat diet alone. In addition, there was a small but significant enhancement in mice exposed to 50 ppm over the rate of fatty deposit formation induced by the high fat diet alone. Analysis of erythrocyte spectrin for protein cross-linking revealed a dose-dependent formation of alpha- and beta-heterodimers in animals on both diets. [Lewis JG et al; Toxicol Sci. 49 (1): 124-32 (1999) ]**PEER REVIEWED** PubMed Abstract
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: /A study was conducted to determine the/ biochemical changes due to carbon disulfide in 11 male New Zealand white rabbits. The rabbits were exposed to carbon disulfide by inhalation for 6 hr/day, 5 days/wk, for up to 38 weeks. Concentrations of carbon disulfide were 250 ppm (775 mg/cu m) during the first 16 weeks, 500 ppm (1,555 mg/cu m) for the next 5 weeks, and 750 ppm (2,330 mg/cu m) for the final 17 weeks. ... Total serum cholesterol increased in exposed rabbits when the carbon disulfide concentration was increased to 750 ppm (2,330 mg/cu m) and returned to normal after cessation of exposure. ... Increased urinary and fecal excretion of zinc by the exposed rabbits and a gradual decrease in the mean concentration of zinc in the blood serum /was noted/ during the study. [Cohen AE, et al; Am Ind Hyg Assoc J 20: 303-23 (1959) as cited in NIOSH; Criteria Document: Carbon Disulfide p.92-4 (1977) DHEW Pub NIOSH 77-156 ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Inhalation exposure of mice to 800 ppm for 6 hours a day, 5 days a week, for 90 days produced nephropathy ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 15, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Inhalation exposure of Wistar rats to 546 ppm for 8 months or to 482 ppm for up to 14 months produced decreases in body weight. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 15, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Animal studies include a necropsy report on 10 male rabbits exposed to graded concentrations of 250 to 750 ppm carbon disulfide intermittently for 38 weeks that revealed increased adrenal weight, hyperplasia of adrenal cortex, and mild hemosiderosis of the spleen ... No information was given as to whether the controls underwent a sham exposure process, thereby controlling for the stress of the exposure procedure. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 15, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Rabbits /were exposed to carbon disulfide by inhalation at/ 250, 500 and 750 ppm, 6 hr/day /for/ 1 to 4, 5, and 6 to 9 mo. CS2 exposure increases urinary and fecal zinc excretion. Serum zinc decreases. [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Rats /were exposed to carbon disulfide by inhalation at/ 2 mg/L, 44 hr/wk /for up/ to 1 yr. Thickened glomerular basement membranes with hyalinosis, fatty degeneration and calcification /and/ Bowmans capsule lined by cuboidal epithelium /were observed/. [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Female albino rats were exposed to carbon disulfide vapor to study its effects on the course and duration of pregnancy. The animals, in groups of 12 to 20, were exposed to carbon disulfide at a concentration of 2,000 mg/cu m (642 ppm) for 2 hours/day during the entire pregnancy. Two identical series of tests were performed on rats. In the first experiment, 16.8% pre-implantation embryonic mortality occurred in the 12 exposed animals and 3.3% in the 12 controls (P< 0.05). In the second experiment, the pre-implantation mortality rate was 22.6% in 12 exposed rats and 6.5% in 14 controls (p< 0.05). The reproductive success of each exposed group was lower than that of its control group in both experiments (6.8 versus 9.7 fetuses per rat, p< 0.05, and 8.0 versus 9.3 fetuses per rat). There were seven post-implantation deaths in the fetuses of exposed rats and none in those of the controls. There were no significant differences between experimental and control rats in the mean corpus luteum counts or in mean fetal weights. [Yaroslavskiy VK; Bull Eksp Biol Med 68: 88-91 (1969) as cited in NIOSH; Criteria Document: Carbon Disulfide p.89 (1977) DHEW Pub NIOSH 77-156 ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Effects of carbon disulfide on testicular tissues of rats were studied. Three experiments were conducted using 85 mongrel rats, 2 to 5 months old and weighing 200 to 260 g. In the first experiment, 12 rats were injected ip every second day for 60 days with 12.5 mg/kg of distilled carbon disulfide dissolved in peanut oil; 5 were given pure peanut oil; and 5 were untreated. In the second experiment, 15 animals were given ip doses of 25.0 mg/kg every other day for 60 days; 10 rats were given pure peanut oil; and 9 were untreated. In the third experiment, 10 were given 25.0 mg/kg ip every other day for 120 days; 10 were injected with peanut oil; and 9 were untreated. ... The testicles of rats from exposed and control groups had similar histologic and histochemical patterns. However, exposed rats had thickened vascular walls, blood-cell-engorged vessels, disorganized seminiferous epithelium, and decreased numbers of spermatozoa. Rats injected with carbon disulfide for a 120-day period, however, showed marked testicular damage. Advanced regressive lesions involving all parts of the testicles of the usually round and smooth tubular basement membrane. Spermatogonia were few and sometimes nonexistent in the seminiferous tubules, and spermatogenesis was absent. Leydig cells showed degeneration and atrophy. [Gondzik M; Pol Med J 10: 133-9 (1971) as cited in NIOSH; Criteria Document: Carbon Disulfide p.88 (1977) DHEW Pub NIOSH 77-156 ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: In rats, carbon disulfide causes progressive testicular atrophy after repeated parenteral administration. The testes from these animals exhibit vasodilation, hemorrhage, and fluid exudation into the testicular parenchyma, suggesting a possible vascular origin for the atrophy. Testicular damage is not observed after inhalation exposure. [Thomas, J.A., K.S. Korach, J.A. McLachlan. Endocrine Toxicology. New York, NY: Raven Press, Ltd., 1985., p. 291]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: In a developmental study of albino rats, 30 to 32 animals/group were exposed to carbon disulfide at concentrations of 0, 0.01, 3.20, 32.00, or 64.00 ppm (0, 0.03, 10.00, 100, or 200 mg/cu m, respectively) for 8 hours/day throughout gestation (21 days) ... F1 animals were reared until maturity and mated within experimental groups to produce the F2 generation. The pregnant F1 females were exposed throughout gestation to the concentration of carbon disulfide to which they were exposed prenatally, including air-exposed controls ... Maternal toxicity (reduced weight gain during gestation) was observed in the parental and F1 generations exposed to 100 mg/cu m (F1 generation; 59% decrease was not reported as statistically significant) or 200 mg/cu m carbon disulfide (27% in the parental generation and 74% in the F1 generation) ... Average fetal weight is significantly decreased in this study at 100 and 200 mg/cu m (5 and 7%, respectively) ... Significantly increased preimplantation lethality at 200 mg/cu m and a slight increase at 100 mg/cu m indicate adverse developmental effects at these levels ... Malformations ... include a significant increase in clubbed foot and hydrocephaly in the 100 and 200 mg/cu m animals and increased hypognathia and tail malformations at 200 mg/cu m ... No reported evidence of prenatal developmental effects in the F1 generation exposed to 0.03 or 10.00 mg/cu m. When pregnant F1 females were exposed during gestation, evidence of more severe maternal and developmental effects were observed. These effects included greater maternal weight loss during gestation in the 200 mg/cu m-group (a larger reduction in weight than parental generation at the same exposure level) and increased incidence and severity of malformations compared with the previous generation. Increased malformations also occurred at lower concentrations (0.03 and 10.00 mg/cu m), which did not affect the F1 generation. This effect was explained ... as intrauterine sensitization, a mechanism by which exposure of the parental generation resulted in an F1 generation that was more sensitive to the developmental effects of carbon disulfide during pregnancy. A variety of observations and measurements were made to evaluate postnatal development in F1 and F2 pups. Decreased postnatal survival at 200 mg/cu m and decreased postnatal weight gain on days 4 and 7 was observed in animals exposed to 100 or 200 mg/cu m carbon disulfide ... A decrease in viability at postnatal day 21 was significant, but this effect is not seen in animals exposed to 50 or 100 mg/cu m ... Postnatal observations show significant effects on eye opening (day 18), auditory startle reflex (day 14), visual placing response (day 18), and righting behavior at 10 mg/cu m ... Narrow-path crossing is a measure of motor coordination. No effect is seen in F1 animals exposed to 0.03 or 10.00 mg/cu m. In exposed F2 animals, a significant decrement in this behavior was observed as a decrease in mean distance covered in groups exposed to 0.03 or 10.00 mg/cu m. This response shows no concentration-response relationship because the exposures differ by 300-fold, and the responses are identical, and the parameter is not reported for other exposure concentrations. Narrow-path crossing also is reported as number of slips and falls, both of which increase at 10 mg/cu m, but are not reported at higher concentrations. Open-field motor activity is reported as the number of squares crossed, the number of rearings, and gait defects. The number of squares crossed was increased at day 14 and decreased at day 21 in F1 groups at 0.03 and 10.00 mg/cu m; it was unchanged at day 14 and decreased at day 21 in F2 animals at 0.03 and 10.00 mg/cu m. The number of rearings is unchanged in F1 animals and decreased in F2 animals at 0.03 and 10.00 mg/cu m (response at 0.03 mg/cu m was slightly greater than at 10). The percent with gait defects is increased in F1 animals at 10.00 mg/cu m and in F2 animals at 0.03 and 10.00 mg/cu m and shows a reasonable concentration response ... Fifty and 75% increases in open-field motor activity were reported for the 0.03- and 10.00-mg/cu m groups, respectively ... The effects on preimplantation losses at 100 and 200 mg/cu m are the strongest data in these studies ... The increase in malformations in the F1 and F2 generations seems compelling due to the increase in incidence and severity with concentration and between the F1 and F2 generations ... The dramatic increase in response in the F2 generation indicates clearly adverse effects at concentrations as low as 0.03 mg/cu m ... A LOAEL for developmental effects at 10 mg/cu m, including malformations in the F2 generation and postnatal morphological development and postnatal behavior in F1 and F2 generations is identified ... The effects reported at 0.03 mg/cu m are not considered to be useful because the effects are of questionable significance and do not show reasonable dose-response behavior, and because of questions regarding the ability to measure such low levels. [U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Carbon disulfide (CAS# 75-15-0). Available from: http://www.epa.gov/iris/index.html on the Substance File List as of September 22, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: A developmental study was conducted using New Zealand White rabbits, which are more sensitive than rats to the effects of carbon disulfide ...Rabbits (24/group) were exposed by inhalation to 0, 60, 100, 300, 600, or 1,200 ppm, 6 hours a day, on gestation days 6 to 18. Animals were evaluated on day 29. Maternal toxicity was observed as reduced body weight gain and adverse clinical signs (ataxia, lowered food consumption, wheezing) in the 1,200-ppm group, with some sporadic hematologic alterations at 600 ppm (for example, decreased hematocrit on gestation day 19). These effects were not seen in an initial range-finding study in which rabbits were exposed to 1,000 ppm carbon disulfide. Embryotoxic effects (reduced mean fetal body weight) and post-implantation loss were seen in the 600- and 1,200-ppm exposure groups. Teratogenic effects (increased cumulative skeletal and visceral malformations) were also seen at 1,200 ppm carbon disulfide. In this study the NOAEL for developmental effects was 300 ppm and the NOAEL for maternal toxicity was 600 ppm because of the lack of biological significance in the hematologic findings at this exposure concentration. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 18, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Administration of carbon disulfide by oral gavage at doses up to 150 mg/kg/day to New Zealand white rabbits (gestational days 9 to 19) ... resulted in signs of maternal toxicity, such as transient hind-limb paralysis and loss of body weight over the period of gestation ... There were statistically significant, dose-related increases in the number of resorptions: mean values of 12, 43, 42, and 61 resorption at 0, 25, 75, and 150 mg/kg/day, respectively. Also, dead fetuses were found: 13%, 33%, 43%, and 62% dead/litter for each respective dose group (p<0.00l). Average fetal body weight was decreased significantly in each dose group: 45.5, 45.2, 41.6, 39.5 g/litter for each dose group, respectively ... There was a significant increase in the number of malformed fetuses in 150-mg/kg/day (highdose) animals; however, there was no characteristic pattern of carbon disulfide-related malformations. Males were affected to a greater extent than females. The teratogenic effect of carbon disulfide appears to be more severe in males at the 150-mg/kg/day dose than in females (when separated by dose, p<0.036 for males and p<0.481 for females), whereas the percentage of live fetuses and the average fetal body weight are not sex-dependent. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p61 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ... There were no effects on estrous cycling, mating index, or fertility index in rats exposed to up to 1560 mg carbon disulfide/cu m, 6 hr/day, before and during mating and throughout gestation. This dose adversely affected maternal weight and weight gain and increased pup mortality, decreased pup viability, and decreased live litter size, but development of the pups was otherwise unaffected. There were no effects at 780 mg/cu m, except for a small increase in the length of gestation (also at 1560 mg/cu m) ... [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ... In utero exposure of rats to levels of 1250 or 2500 mg/cu m did not induce a significant increase in the incidence of club foot, although it did cause maternal and fetal toxicity and minor skeletal anomalies ... There was no effect at 625 mg/cu m ... [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Male Long-Evans rats exposed to 600 ppm carbon disulfide 5 or 6 hours a day, 5 days a week, for 10 weeks showed significant alterations in copulatory behavior and a decrease in ejaculated sperm counts by the 4th and 7th weeks of exposure, respectively. Caudal epididymal sperm counts were not depressed and testes appeared histologically normal. The plasma testosterone levels were significantly reduced. Exposed rats had significantly reduced weight gains during the experiment ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 18, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ... B6C3Fl mice and Fischer and Sprague-Dawley rats were exposed to 0, 49, 297, or 798 ppm carbon disulfide 6 hours a day, 5 days a week, for 90 days ... Examination of the mice and rats that received the highest dose revealed maternal toxicity but no developmental toxicity. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 18, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Maternal reproduction and fetal parameters were evaluated for groups of 20 to 23 pregnant Sprague-Dawley rats exposed to 0, 100, 200, 400, and 800 ppm carbon disulfide, 6 hours a day, during days 6 to 20 of gestation ... Maternal toxicity for the animals exposed to 400 or 800 ppm was evidenced by the significant decrease in maternal body weight gain (19% and 31% decrease) of the exposed rats compared to the controls (p < or = 0.01). When gravid uterine weight was subtracted from the dam's body weight gain, the maternal weight was significantly reduced ... Exposure to 400 or 800 ppm carbon disulfide resulted in a significant reduction of fetal body weights for both sexes; the respective weight reduction from control for males was 7% and 14% (p < or = 0.01), and for females was 6% and 20% (p < or = 0.01). Clubfoot was the only external malformation occurring at higher frequency than in the controls; however, the one fetus affected in one litter at 400 ppm and the seven fetuses affected in five litters at 800 ppm were not sufficient for statistical significance. Incidence of unossified stemebrae was significantly increased in groups exposed to 800 ppm (p < or = 0.01), but no other soft tissue anomalies or major skeletal anomalies were present in any treated groups. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 18, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Rats and rabbits were exposed to 20 ppm or 62.3 mg/cu m (recommended occupational exposure limit) and 40 ppm or 124.6 mg/cu m of carbon disulfide during the entire length of the pregnancy period and also 34 weeks before breeding to simulate occupational exposure ... No effects on fetal development in rats or rabbits /was observed/ following inhalation exposure to 62.3 or 124.6 mg/cu m, which corresponds to estimated equivalent oral dosages of 5 and 10 mg/kg for rats and 11 and 22 mg/kg for rabbits ... [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 3:503]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Neurological effects such as hind-limb motor difficulties, reduced nerve conduction velocity, and degeneration of nerve fibers were seen in rats exposed to 700 ppm of carbon disulfide for 5 hours a day, 5 days a week, for 12 weeks ... These pathologies continued to 3 weeks postexposure but were slightly improved 6 weeks after carbon disulfide exposure. The improvement continued up to the 18th week of recovery, suggesting that the process may be reversible ... Paralysis of hind limbs was observed in Wistar rats exposed to 546 ppm for 8 months (5 hours a day, 6 days a week); this effect was not seen at 321 ppm ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 18, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Morphological changes in the peripheral nerve and the spinal cord were studied in rats and mice exposed to 50, 300, or 800 ppm carbon disulfide, 6 hours a day, 5 days a week, for 90 days ... Rats exposed to 50 ppm showed no changes in any parameters; rats exposed to 300 ppm showed only occasional swelling of axons in dorsal corticospinal fibers of the lumbar spinal cord; and rats exposed to 800 ppm showed extensive neurofilamentous axonal swelling in the spinal cord. Neurofilamentous axonal swelling was particularly seen in the distal portion of long fiber tracts, including prominent swellings in the dorsal ascending sensory fibers, whereas it was only intermittently seen in the dorsal corticospinal fibers. In addition, extensive peripheral nerve changes were seen at the level of the posterior tibial nerve. The sciatic nerve showed no appreciable loss and only occasional axonal swelling. Ultrastructurally, the axonal swellings contained abundant disorganized neurofilaments, decreased microtubules, and thin or absent myelin. Brain and body weight were decreased in proportion to the concentration, with the decrease in brain weight statistically significant in the 800-ppm group. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 18, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: ... Reductions in nerve conduction velocity have ... been observed in the central nervous system and in the optic pathway, as indicated by increased latencies and decreased amplitudes of somatosensory-, visual-, or brainstem auditory-evoked potentials in rats exposed to 2500 mg carbon disulfide/cu m for periods of 11 to 15 weeks ... There was also a transient increase in the latency of some components of the brainstem auditory-evoked potential at 630 mg/cu m ... [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: ... Rats exposed to between 800 and 2500 mg carbon disulfide/cu m for between 3 and 15 months developed an axonopathy in the peripheral nerves and/or spinal cord ... The distal portions of the largest and longest myelinated axons (which are the most rapidly conducting axons) are affected first. Structural changes proceed through the development of large axonal swellings composed of disorganized masses of neurofilaments proximal to the nodes of Ranvier, followed by axonal atrophy and Wallerian-like degeneration proximal and distal to the swellings, respectively. These features are characteristic of giant neurofilament axonopathies induced by other compounds, such as 2,5-hexanedione, the neurotoxic metabolite of hexane ... [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Neurobehavioural effects have been observed in a number of studies in rats. Neuromuscular effects, most notably reductions in grip strength and gait alterations, were observed following 2 to 4 weeks of exposure to 1600 and 2500 mg/cu m. [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: ... Rats were exposed to 160, 1600, or 2500 mg/cu m, 6 hr/day, 5 days/week, for up to 13 weeks, neurofilament protein cross-linking in the spinal cord was observed as early as 2 to 4 weeks at all exposure levels ... Other early indicators were increased expression of nerve growth factor receptor mRNA in the sciatic nerve (an indicator of alterations in the axon-Schwann cell relationship) ... and gait abnormalities ... By 4 weeks, the neuromotor alterations progressed to reductions in grip strength of the hind limbs and forelimbs ... Axonal swelling and degeneration ... and electrophysiological alterations ... in the peripheral nerves and/or spinal cord occurred only in the later stages of the study and at the two highest dose levels. [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Four female monkeys exposed to 256 ppm for 6 hours a day, 5 days a week, for 5 to 13 weeks suffered permanent visual impairment with degeneration of retinal ganglion cells compared to one control ... Visual acuity thresholds in two macaque female monkeys were severely disrupted after 5 weeks of intermittent exposure (6 hours a day, 5 days a week) to 256 ppm carbon disulfide. One monkey showed some recovery at 16 weeks postexposure; the other showed no improvement ... The observed effects were secondary to the effects on the optic nerve. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 15, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: In a study that examined effects in rats (Wistar) and mice (H strain) exposed to carbon disulfide for 4 hours, rats appeared to be more sensitive than mice ... The concentration that resulted in a 30% inhibition of electrically evoked seizure discharge was 1,370 ppm in male rats and 2,600 ppm in female mice. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 18, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Short-term exposures to inhaled carbon disulfide in rats have shown consistent results with respect to brain chemistry changes and sensory and motor nerve conduction alterations. Rats exposed for 4 hours a day for 10 days at 642 ppm showed decreased noradrenaline, increased dopamine, and elevated tyrosine in the brain ... The authors proposed that changes in tyrosine, dopamine, and noradrenalin may be caused by a feedback mechanism in which the increase in dopamine prevents a conversion of tyrosine to dopamine. No relationship to clinical signs or behavioral effects was noted. Further work at the same exposure level indicates that the noradrenaline concentration remains significantly decreased for at least 20 hours after a 1-hour exposure, but the dopamine levels return to normal ... Female rats exposed to 777.1 ppm for 12 hours showed swollen brain mitochondria and elevated brain adenosine triphosphate (ATP) levels compared to controls ... No histopathological changes were noted in brain tissue ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 18, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Male Wistar rats were exposed to 578 ppm carbon disulfide for 10 months /and/ ... to 803 ppm /for 18 hr/ ... The l0-month exposure caused loss of motor equilibrium, muscular weakness, and hind-limb paresis, and the acute dosing caused severe /CNS depression/, reduced cardiac and respiratory rate, straightening of hind limbs, and lower body temperature. However, brain mitochondria in both groups of animals exhibited the same types of disturbances in oxidative phosphorylation-uncoupling of oxidative phosphorylation, decreased phosphorus-oxygen (P:O) ratio, and a lower ATP-inorganic phosphorus (ATP-Pi) exchange rate ...[DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 18, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: The chronic effect of carbon disulfide exposure on the central nervous system was examined by auditory brainstem responses (ABR) in female JCl Wistar rats ... Rats were exposed by inhalation to 200 or 800 ppm, 6 hours a day, 5 days a week, for 15 weeks. Auditory responses were measured before exposure, every 3 weeks during exposure, and in weeks 2 and 6 after exposure. The delayed latencies of ABR were observed at 800 ppm suggesting a conduction dysfunction. The transient delay of ABR responses at 200 ppm indicated only slight conduction dysfunction. Rats recovered 2 to 6 weeks after carbon disulfide exposure. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 18, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Neuromuscular and sensory effects were evaluated in Long Evans rats exposed to 500 ppm (6 hours a day for 5 or 12 weeks) using an acoustic startle test ... Neuromuscular integrity was shown to be compromised based on auditory startle reflex amplitude; animals showed a 70% recovery 4 weeks postexposure. No clinical signs of neurotoxicity or changes in hearing function or acoustic tone thresholds were noted. Use of a single exposure concentration precluded assessment of dose response. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) (August 1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 18, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Compared to untreated rats, significant decreases in noradrenaline in the midbrain, hypothalamus, and medulla oblongata were observed in rats 2 hours after they received a single gavage dose of 300 mg carbon disulfide/kg body weight ... 3,4-Dihydroxyphenylalanine was significantly increased in the midbrain, as was dopamine in the medulla oblongata. In the hippocampus, no change in acetylcholine was observed ... Hind-limb paralysis was noted in New Zealand rabbits and outbred rats administered 25 and 400 mg/kg/day, respectively, for l0 to 14 days during gestation ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p61 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Cats /were exposed to carbon disulfide by inhalation at/ 2560 to 3210 ppm, 0.5 to 3 hr/day, 19 to 74 hr over a period of 24 to 92 days. Neurocellular changes were observed ranging from chromatolysis to severe degeneration throughout the brain. Proliferation of capillaries and hypertrophy of blood vessel with swollen endothelial cells /were also seen/. Lesions /were/ prominent in cerebellar nuclei. [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Acute intraperitoneal injections of 504 mg/kg carbon disulfide for 3 consecutive days in male rats caused a significant decrease in aminopeptidase activity in the thalamus and cerebellum of the brain ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p77 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 20, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Wistar rats /exposed to carbon disulfide by inhalation at/ 2 mg/L, 4 hr/day /for 2 days were/ sacrified after exposure. Dopamine concn decr by 16% after the second exposure and nonadrenaline by 13% ... Inhibition of dopamine-B-hydroxylase /was suggested/. [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Sprague-Dawley rats /exposed to carbon disulfide by inhalation at/ 750 ppm, 6 hr/day, 5 days/wk for 5 wk to 5 mo /showed/ appearance of nonspecific cholinesterase in intramuscular nerve tracts in adult rats with polyneuropathy. [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Rats /were exposed to carbon disulfide by inhalation at/ 2.4 or 3.6 mg/L, 6 hr/day, 5 days/wk for 3 and 6 mo. Electromyography demonstrated reduced conduction. Copper levels were elevated in affected nerves. [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Inhalation studies were conducted on ... carbon disulfide, which targets the central nervous system (spinal cord) and peripheral nervous system (distal portions of long myelinated axons) . ... Carbon disulfide produced intra- and intermolecular protein cross-linking in vivo. The observation of dose-dependent covalent cross-linking in neurofilament proteins prior to the onset of lesions is consistent with this process contributing to the development of the neurofilamentous axonal swellings characteristic of carbon disulfide neurotoxicity. Of significance is that valine-lysine thiourea cross-linking on rat globin and lysine-lysine thiourea cross-linking on erythrocyte spectrin reflect cross-linking events occurring within the axon. [Sills RC et al; Toxicol Appl Pharmacol 207 (2 Suppl): 245-50 (2005) ]**PEER REVIEWED** PubMed Abstract
  
• LABORATORY ANIMALS: Neurotoxicity: ... At the phases of follicle developing, implanting and post-implantation of blastocyst, female mice were injected intraperitoneally with carbon disulphide 631.4 mg/kg per day for three days while controls with plant oil. All indexes were detected at the fourteenth day of pregnancy. ... (1) In follicle developing CS(2) exposed group, the weight of embryos fossa [(1.23 +/- 0.36) g] was 41% less than that in controls [(2.08 +/- 0.48) g] ... and in implanting CS(2) exposed group the weight of embryo fossa, and embryos [(1.27 +/- 0.97) g, and (0.12 +/- 0.09) g respectively] were 39% and 37% less than those in controls [(2.08 +/- 0.48), (0.19 +/- 0.06) g, P = 0.068, P = 0.045]; (2) In both follicle developing and implanting CS(2) exposed group, the weights of uterus and placenta were also less than those in controls (P < 0.01). (3) In post-implantation CS(2) exposed group, the above parameters were not significantly different from those in controls. [Wang ZP et al; Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 23 (2): 139-41 (2005) ]**PEER REVIEWED** PubMed Abstract
  
• LABORATORY ANIMALS: Neurotoxicity: ... Behavioral changes in rats were measured using a functional observational battery (FOB), which is a series of observations and manipulations designed to assess the neuronal integrity of autonomic, motor, sensory, and integrative functions. Young adult male and female Fischer-344 rats were exposed to one of four CS2 concentrations (0, 50, 500, or 800 ppm, six hours/day, five days/week) and tested at the end of one of several exposure durations (two, four, eight, or 13 weeks). All rats were also tested before exposure began to obtain baseline values. Neuromuscular deficits which were more pronounced in the hindlimbs, e.g., decreased strength and gait alterations, were detected in rats of both sexes. These changes were closely related to CS2 concentration and exposure duration, with mild gait changes evident after only two weeks of exposure. Other effects, mostly observed at 13 weeks, included decreased responsiveness to a visual stimulus and mild tremors. Reactivity in response to handling was generally increased, and excitability in the open field was decreased, in rats tested after the shorter exposures (two and four weeks). [Moser VC et al; Neurotoxicology 19 (1): 147-57 (1998) ]**PEER REVIEWED** PubMed Abstract
  
• LABORATORY ANIMALS: Neurotoxicity: ... The effects of subchronic exposure to carbon disulfide (CS2) on ventral caudal tail nerve compound nerve action potential (CNAP) amplitudes and latencies, and nerve conduction velocity (NCV) in rats were examined. Male and female Fischer 344 rats were exposed to 0, 50, 500, or 800 ppm CS2 for 6 hrs/day, 5 days/week. Using separate groups, exposure duration was 2, 4, 8, or 13 weeks. Exposure to 500 or 800 ppm CS2 for 13 weeks decreased NCV /nerve conduction velocity/ compared to the 50 ppm CS2 group. CNAP /compound nerve action potential/ amplitudes were increased, and peak P1P2 interpeak latency decreased, after exposure to 500 or 800 ppm CS2 for 13 weeks. Most of the changes in NCV and CNAPs were not attributable to differences in tail or colonic temperature. ... Assessment of tail nerve morphology after 13 weeks exposure to 800 ppm CS2 revealed only minor changes compared to the extent of axonal swelling and degeneration observed in the muscular branch of the tibial nerve and axonal swelling in the spinal cord. In older animals the NCV increased, the CNAP amplitudes increased, and the CNAP latencies decreased. [Herr DW et al; Neurotoxicology 19 (1): 129-46 (1998) ]**PEER REVIEWED** PubMed Abstract
  
• LABORATORY ANIMALS: Neurotoxicity: The study objectives were to examine the morphological progression and dose response of carbon disulfide (CS2) distal axonopathy in the muscular branch of the posterior tibial nerve (MBPTN) and spinal cord. Male and female F344 rats were exposed to 0, 50, 500 or 800 ppm CS2 by inhalation, 6 hours/day, 5 days per week, for 2, 4, 8 or 13 weeks. At 8 weeks, in the MBPTN, single fascicles contained individual swollen axons. By 13 weeks, multiple fascicles had giant swollen axons with thin myelin sheaths and occasional degenerated and regenerated axons. At 8 weeks, in the spinal cord, white matter changes in cervical segments 1 and 2 consisted of prominent multifocal axonal swelling in the fasciculus gracilis nerve tracts. In lumbar segments 1 and 2, multifocal axonal swelling was first present at 8 weeks in the lateral and ventro-medial funiculus. By 13 weeks, axonal swelling was diffuse in the fasciculus gracilis nerve tracts of the cervical spinal cord and the lateral and ventral funiculus nerve tracts in the lumbar spinal cord. Compared to the spinal cord, where axonal swelling was present in rats exposed to 800 and 500 ppm, in the muscular branch of the posterior tibial nerve, axonal swelling was only present at 800 ppm at both 8 and 13 weeks. Electron microscopic examination demonstrated marked accumulations of neurofilaments in swollen axons in the spinal cord and MBPTN /muscular branch of the posterior tibial nerve/ . Axonal swelling was not present in the spinal cord at 50 ppm, or in the MBPT at 50 and 500 ppm. Axonal swelling was not present at earlier time points of 2 and 4 weeks in either the spinal cord or MBPTN. [Sills RC et al; Neurotoxicology 19 (1): 117-27 (1998) ]**PEER REVIEWED** PubMed Abstract
  
• LABORATORY ANIMALS: Neurotoxicity: ... Changes in monoamine transmitter, amino acid transmitter and their metabolites in brain tissues were observed in rats exposed to CS2 at levels of 0, 1,200 and 2,400 mg/m3 respectively, for two months. Results indicated that exposure to CS2 could cause decrease in 3-methoxy-4-hydroxy mandelic acid (VMA), increase in 3,4-dioxybenzoic acid, a metabolite of dopamine, and high vanillic acid in rat straitum, decrease in excitatory amino acids and their metabolites (glutamine, aspartic acid and asparagine), with a certain relationship between contents of VMA, aspartic acid and asparagine and changes in neurobehavior. [Gao Y et al; Zhonghua Yu Fang Yi Xue Za Zhi 32 (1): 28-30 (1998) ]**PEER REVIEWED** PubMed Abstract
  
• LABORATORY ANIMALS: Neurotoxicity: ... NGF-R /nerve growth receptor factor/ mRNA expression increased in a dose- and time-dependent manner. Message levels were already increased after 2 wks of exposure to 800 ppm CS2, and increased further with continued exposure. Morphological alterations were not apparent in the sciatic nerve, even at the highest dosage levels with the longest exposure times. [Toews AD et al; Neurotoxicology 19 (1): 109-16 (1998) ]**PEER REVIEWED** PubMed Abstract
  
• ALTERNATIVE and IN VITRO TESTS: In rats treated by gavage with carbon disulfide in olive oil at 12.5 mg/kg/day for 1, 2, or 4 weeks, a decreased response of the ancoccygeus muscle to noradrenaline was observed relative to vehicle-treated controls ... The response of the muscle to noradrenaline was tested in vitro in a muscle bath. The reduction in sensitivity to noradrenaline increased with increasing duration of exposure. The investigators suggested that the mechanism of decreased noradrenaline responsiveness may be a result of a block of calcium influx, a delay of the calcium efflux, an inhibition of the uptake of calcium, a decreased sensitivity to calcium by the muscle, or a combination of these mechanisms.[DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p59 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• ALTERNATIVE and IN VITRO TESTS: ...The purpose of the present study was to evaluate the functional and histological effects on cardiac myocytes cultured under the condition of carbon disulfide exposure. Cardiac myocytes were isolated from neonatal rat ventricles by trypsin dispersion and cultured for 3 days in a full (Dulbecco's modified eagle medium) medium containing 2% calf serum. Thereafter the myocytes (10(6) myocytes/culture flask) were incubated with carbon disulfide at (CS(2)) the concentrations of 0, 20, 40, and 80 micromol/mL) for 24hr. The beating arrest rate of myocytes for each group was examined and succinodehydrogenase (SDH) activity in the myocardial cells was also assessed by cytochemical method, and morphological examination was also performed. /The authors/ found that the beating arrest rate of cardiac myocytes increased with increasing exposure levels. Vacuolization and pseudopodia may be seen in the cytoplasm of exposure group. SDH activity decreased with increasing exposure levels. [Tan, X et al; Ecotoxicol Environ Saf 55 (2): 168-172 (2003) ]**PEER REVIEWED** PubMed Abstract
  
• GENOTOXICITY: Carbon disulfide was not mutagenic to Salmonella typhimurium strains TA98 and TA100 at 300 to 1000 umol nor to Escherichia coli strain WP2 uvrA at 20 to 600 umol with or without metabolic activation, nor in Drosophila melanogaster at 200 to 800 ppm. [DONNER M ET AL; MUTAT RES 91 (3): 163 (1981) ]**PEER REVIEWED**
  
• GENOTOXICITY: In male and female rats inhaling 63 or 125 mg carbon disulfide/cu m, 7 hr/day for 1 or 5 days, there was no significant increase in the frequency of chromosomal aberrations in bone marrow cells ... In contrast ... oral exposure to carbon disulfide induced chromosomal aberrations and polyploid cells in the bone marrow of female rats and in rat embryos exposed on days 10 to 13 of gestation /were reported/ ... The effective dose was ... one-tenth of the LD50. [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• GENOTOXICITY: ... To study the genotoxicity of carbon disulfide ... DNA damage in mice sperm /was detected/ with single-cell gel electrophoresis assay (SCGE). ...The index of DNA damage, tail length and tail moment were used to evaluate the extent of DNA damage.... the rate of DNA damage (67.14%, 84.29% and 91.00%, respectively), index of DNA damage intensity (507, 656 and 745, respectively), tail length (5.87, 8.81 and 13.49 microm, respectively) and tail moment (1.30, 1.63, 2.66 microm, respectively) were significantly increased, while the percentage of head of the comet was significantly decreased (84.55%, 73.84% and 55.71%, respectively). A significant changes were clearly observed in all dosage groups compared to those of the control group (P<0.05). [Tang GH, Xuan DF; Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 21 (6): 440-3 (2003) ]**PEER REVIEWED** PubMed Abstract
  
• IMMUNOTOXICITY: While short-term /oral/ exposure of mice to between 138 and 1102 mg/kg body weight per day altered thymus weight, it was not immunotoxic, as indicated by white blood cell differentials, spleen weight, and natural killer cell activity ... [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: ... Carbon disulfide-exposed macaque monkeys /were/ used in visual psychophysical, fluorescein angiography, and fundus photography studies as well as post-mortem neuropathologic evaluations ... Markedly decreased contrast sensitivity functions, decreased visual acuity, and degeneration of the retinal ganglion cells /were/observed/, all of which occurred in the absence of retinal microaneurysms or hemorrhages. There was little evidence of effects on the other retinal neurons. These findings indicate that the retinal and optical nerve pathology produced by CS2 are likely a direct neuropathologic action and not the indirect result of vasculopathy. [Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill, 2001., p. 585]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: While it has often been assumed that the cardiovascular effects of carbon disulfide are secondary to its arteriosclerotic effects, the results of several studies in rats suggest that these may be the result of a direct effect on the heart. Short-term /oral/ exposure of restrained and anaesthetized rats to between 126 and 253 mg/kg body weight per day had a cardiodepressive effect on electrophysiological and mechanical parameters and decreased left ventricular contractility, increased blood pressure, and caused electrocardiograph alterations indicative of myocardial ischaemia following administration of epinephrine or norepinephrine ... However, in conscious unrestrained normotensive rats, the highest dose did not alter mean arterial blood pressure or heart rate, although it significantly reduced body weight ... [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: ... The mechanism for carbon disulfide acceleration of arteriosclerotic plaque formation involves direct injury to the vessel epithelium and changes in lipid metabolism. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p77 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 20, 2006. ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: Viscose rayon workers have been reported to develop serious blisters that progressed to hemorrhagic blisters covered by a thin membrane. These blisters appeared on the fingers in spite of wearing rubber gloves ... The implication of carbon disulfide as the causative agent is supported by experiments in rabbits whose ears were dermally exposed to carbon disulfide. Blisters similar to those found in the rayon workers developed on the animals' ears despite protective covering ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p63 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: ... /It was/ found that the effect of sodium phenobarbital pretreatment on rat liver fat accumulation following exposure to carbon disulfide is dependent on the dose and method of ingestion of carbon disulfide. Fat accumulation is significant if the phenobarbital-treated rat is exposed orally to a very high dose of carbon disulfide (1,263 mg/kg body weight); however, inhalation of 20 to 200 ppm of carbon disulfide (8 hours for 2 to 7 days) in a phenobarbital-treated rat did not produce fat accumulation in the liver. Extrapolation to human beings is difficult, but the study authors asserted that the sensitivity of hepatic mixed-function oxidases to carbon disulfide is similar qualitatively and quantitatively in rats and humans. They suggest that it is not hazardous for individuals without hepatic disease to take barbiturate-containing drugs and simultaneously work in 20 to 200 ppm carbon disulfide ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p96 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 21, 2006. ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: Exposure of rats by inhalation to low concentrations of carbon disulfide (20 to 400 ppm for 8 hours) inhibited microsomal drug metabolism. This was reflected by increased hexobarbital sleep times. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p77 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 20, 2006. ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: /It/ was demonstrated that high doses of CS2 in mice can induce the early lesions of atherosclerosis. Data ... also ... suggest protein cross-linking may be involved in the atherosclerotic process. [Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill, 2001., p. 905]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: /Carbon disulfide was applied daily for 3 to 5 days in cotton ear plugs to rabbit(s)/. Blisters were observed within 3 days ... Early epidermal and subepidermal vesicles progressed to ulcers. Degenerative changes noted in sebaceous glands and local nerves. [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: The metabolism for CS2-atheroma production also may involve direct injury to the endothelium coupled with hypothyroidism, because thiocarbamate (thiourea), a potent antithyroid substance, is a principal urinary metabolite of CS2. [Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill, 2001., p. 647]**PEER REVIEWED**
  

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Human Toxicity Values

• Most acute carbon disulfide fatalities result from an ingestion of which 15 ml may be fatal to an adult. [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 819]**PEER REVIEWED**
  

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Non-Human Toxicity Values

• LD50 Rat oral 3188 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 706]**PEER REVIEWED**
  
• LC50 Rat inhalation 25 g/cu m/2 hr [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 706]**PEER REVIEWED**
  
• LD50 Rat ip 583 mg/kg [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LD50 Mouse oral 2780 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 706]**PEER REVIEWED**
  
• LD50 Mouse oral 3020 mg/kg/24 hr [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• LD50 Mouse oral 3020 mg/kg [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LC50 Mouse inhalation 10 g/cu m/2 hr [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 706]**PEER REVIEWED**
  
• LC50 Mouse (male) inhalation 690 mg/cu m/1 hr [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• LC50 Mouse inhalation 0.7 mg/L/1 hr [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LD50 Mouse ip 1890 mg/kg [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  
• LD50 Guinea pig oral 2125 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 706]**PEER REVIEWED**
  
• LC50 Rabbit inhalation 16 mg/L/6 hr [European Chemicals Bureau; IUCLID Dataset, Carbon disulphide (CAS No.75-15-0) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of September 21, 2006. ]**PEER REVIEWED**
  

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Absorption, Distribution and Excretion

• Absorption occurs through all portals including the intact skin. ... carbon disulfide vapor is rapidly absorbed when inhaled; an approximate equilibrium between blood and inhaled vapor is reached in 1-2 hours. ... some absorbed carbon disulfide is excreted in expired air ... traces have been found in the blood 80 hr after termination of exposure, about 70% of an inhaled dose is excreted or metabolized within a few hours. The remaining 30% is slowly excreted in the urine as such or as metabolites. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-90]**PEER REVIEWED**
  
• Large concn of both free & bound carbon disulfide are found in brain (guinea pig studies) & peripheral nerves (rat studies) of exposed animals. Ratio of bound to free carbon disulfide in brain is 3:1. Blood & fatty tissues contain mainly bound carbon disulfide, while liver contains mainly free. [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 701]**PEER REVIEWED**
  
• Carbon disulfide can reach fetuses through placenta or babies by way of mother milk when pregnant or breast-feeding during or following exposure. [CAI SX, BAO YS; IND HEALTH 19 (1): 15 (1981) ]**PEER REVIEWED**
  
• Carbon disulfide blood concentrations reached maximum levels after 2 hours of exposure to about 30 ppm of vapor in air and ranged from 0.15-0.28 mg/l. [Baselt RC; Biological Monitoring Methods for Industrial Chemicals p.64-7 (1980)]**PEER REVIEWED**
  
• Blood concentrations of 0.10-0.70 mg/L were observed during exposure to air concentrations on the order of 80 ppm. [Baselt RC; Biological Monitoring Methods for Industrial Chemicals p.64 (1980) ]**PEER REVIEWED**
  
• A study was conducted to determine the: biochemical changes due to carbon disulfide in 11 male New Zealand white rabbits. The rabbits were exposed to carbon disulfide by inhalation for 6 hours/day, 5 days/week, for up to 38 weeks. Concentrations of carbon disulfide were 250 ppm (775 mg/cu m) during the first 16 weeks, 500 ppm (1,555 mg/cu m) for the next 5 weeks, and 750 ppm (2,330 mg/cu m) for the final 17 weeks. ... Carbon disulfide in the exhaled breath averaged 1.4 ppm (4.3 mg/cu m) when the exposure concn was 500 ppm (1,555 mg/cu m) and rose to 3.1 ppm (9.6 mg/cu m) when the exposure concentration was 750 ppm (2,330 mg/cu m). No carbon disulfide was detected in the exhaled breath of rabbits exposed at 250 ppm (775 mg/cu m). [Cohen AE, et al; Am Ind Hyg Assoc J 20: 303-23 (1959) as cited in NIOSH; Criteria Document: Carbon Disulfide p.92-4 (1977) DHEW Pub NIOSH 77-156]**PEER REVIEWED**
  
• Studies in rabbits indicate that an equilibrium concentration of carbon disulfide is reached after inhalation exposure to 20 to 150 ppm for 1.5 to 2.0 hours ... About 70-80% of the inhaled carbon disulfide was absorbed. After termination of exposure, 15 to 30% of the absorbed carbon disulfide was excreted through the lungs and less than 0.1% by the kidneys. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p65 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• Skin absorption of carbon disulfide vapor in male albino rabbits was studied. ... After 3 hours of dermal exposure to carbon disulfide at 1,550 ppm (4820 mg/cu m), the exhaled air of the rabbit contained 2.5 ppm (7.8 mg/cu m) of the cmpd; 0.25 ppm (0.78 mg/cu m) could still be detected 1.5 hours after cessation of the 3-hour exposure. Exposure of one rabbit to carbon disulfide at 1,500 ppm (4665 mg/cu m), 3 hours/day for 8 consecutive days revealed that the concn of carbon disulfide in the exhaled breath increased with the length of exposure. ... [Cohen AE et al; AMA Arch Ind Health 17: 164-9 (1958) as cited in NIOSH; Criteria Document: Carbon Disulfide p.91 (1977) DHEW Pub NIOSH 77-156]**PEER REVIEWED**
  
• Exposure of rabbit skin to high concentrations of carbon disulfide vapor (800 ppm and above) for 1 hour resulted in detectable amounts of carbon disulfide in the breath of animals ... A linear relationship was noted between the exposure concentration and the amount of carbon disulfide in the exhaled breath. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p74 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 20, 2006. ]**PEER REVIEWED**
  
• The relationship between carbon disulfide disposition and development of carbon disulfide neurotoxicity is reviewed. Animal studies have indicated that approximately 8 to 30% of the carbon disulfide retained after inhalation exposure is excreted by the lung; amounts less than 0.5% of retained carbon disulfide are excreted by the kidney. Free carbon disulfide reaches steady state concentrations in various tissues within 4 to 5 hours after initiation of exposure. [Bus JS; Neurotoxicology 6 (4): 73-80 (1985)]**PEER REVIEWED**
  
• Six human volunteers were exposed to 10 and 20 ppm carbon disulfide at rest and to 3 and 10 ppm carbon disulfide under a 50 W level of physical exercise during four consecutive periods of 50 min. Every 5 min a sample was taken from the mixed exhaled air in which the concentration of carbon disulfide was determined. It was established that only an apparent steady state was reached during this exposure period. The retention values were established as 0.374 (SD= 0.106; n= 239) for exposure to 10 ppm carbon disulfide at rest and as 0.410 (SD= 0.103; n= 239) for exposure to 20 ppm carbon disulfide at rest. During exposure to 10 ppm and 3 ppm carbon disulfide, combined with a 50 W level of physical exercise, the retention values decreased to 0.286 (SD= 0.083; n= 239) and 0.277 (SD= 0.049; n= 239) respectively. The respiratory uptake of carbon disulfide (mg carbon disulfide) proved significantly influenced by the amount of body fat estimated from skinfold thickness measurements. [Rosier J et al; Int Arch Occup Environ Health 59 (3): 233-42 (1987)]**PEER REVIEWED**
  
• Despite considerable variation between individuals, absorption seems to be proportional to the concentration of carbon disulfide in the inhaled air, and equilibrium between the carbon disulfide content of inhaled and exhaled air is reached in 1-2 hours. At this point, the percentage retained is about 40-50%, and carbon disulfide is distributed in the organism by the bloodstream, where twice as much is taken up by the erythrocytes as by the plasma. As carbon disulfide is readily soluble in fats and lipids, and binds to amino acids and proteins, it disappears rapidly from the bloodstream and has a high affinity for all tissues and organs. The order of affinity for different organs has not been established in man. Between 10 and 30% of absorbed carbon disulfide is exhaled, less than 1% is excreted in the urine ... . [WHO; Environ Health Criteria: Carbon Disulfide p.2 (1979)]**PEER REVIEWED**
  
• ... If workers are previously exposed, about 55% of the inhaled /carbon disulfide/ vapor is absorbed during the first 15 minutes. Excretion through the lungs and the urine is small, with about 92% of carbon disulfide retained in the tissues and metabolized. [Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994, p. 722]**PEER REVIEWED**
  
• Carbon disulfide ... and its metabolite 2-thiothiazolidine-4-carboxylic acid (TTCA) were detected in virtually all samples of breath, blood, urine, and breast milk of subjects with no known occupational exposure in a number of studies ... [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• Dermal absorption can also contribute substantially to occupational exposure ... In a study of German viscose rayon workers ... /it was/ observed that the slope of the regression between levels of carbon disulfide in personal air and of 2-thiothiazolidine-4-carboxylic acid (TTCA) in urine was significantly greater for spinners than for other workers, particularly if they had skin diseases or skin irritation, which /was/ ... attributed to the increased physical requirements and potential for dermal exposure associated with this task. [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• The available data from human and animal studies indicate that carbon disulfide is extensively and rapidly absorbed via inhalation, oral, and dermal routes. Absorbed carbon disulfide is distributed throughout the body. Because of its lipophilic nature, its distribution is greatest in organs such as the brain and liver where it is metabolized to thiocarbamates ... The kidneys are the primary route of excretion of carbon disulfide metabolites. Conjugation of carbon disulfide or carbonyl sulfide with endogenous glutathione results in formation of thiozolidine-2-thione-4-carboxylic acid and 2-oxythiazolidine-4-carboxylic acid, respectively, which are excreted in the urine. The unmetabolized carbon disulfide is excreted unchanged in the breath, and small amounts (
• ... A study /was/ conducted on volunteers exposed to 17 to 51 ppm for l to 4 hours ... The amounts of carbon disulfide retained in the body and excreted by the lungs and kidneys were determined by measuring the carbon disulfide in inspired and expired air, blood, and urine during and after completion of the experiment until it disappeared from the urine and blood. About 80% of the inhaled carbon disulfide was retained during the first 15 minutes of exposure which decreased to about 40% after 45 minutes and remained at that level for the rest of the exposure period. The degree of retention did not depend on the exposure concentration. Only 5% of the retained carbon disulfide at the end of the exposure period was subsequently eliminated in the exhaled air. About 0.06% of the retained carbon disulfide was excreted unchanged in the urine and was detectable 24 hours after exposure. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p64 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• In dogs exposed to 25 to 60 ppm carbon disulfide, equilibrium concentrations in blood were attained after 0.5 to 2.0 hours ... Desaturation of blood carbon disulfide was almost complete within the first 30 to 60 minutes after exposure. Approximately 8 to 13% of the retained carbon disulfide was exhaled, less than 0.5% was excreted in the urine, and none was excreted in the feces. Excretion in the urine occurred within 2 hours of exposure. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p65 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• An equilibrium concentration of carbon disulfide in blood was attained after exposure of rats to 400 ppm carbon disulfide for 1 hour. Equilibrium was reached in liver and blood between 1 and 8 hours after exposure. Elimination of free carbon disulfide from these tissues was rapid, with an estimated half-life in the blood of 35 minutes and in the liver of approximately 1 hour. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p65 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• In rats, intragastric administration of 10 mg/kg (14)C-carbon disulfide resulted in exhalation of 63% of the dose within 4 hours as unchanged carbon disulfide ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p65 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• Rats receiving 19 mg/kg (14)C-carbon disulfide intraperitoneally excreted 58 to 83% free carbon disulfide in expired air in the 3 hours following dosing ... Younger rats expired significantly more free carbon disulfide than older rats. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p75 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 20, 2006. ]**PEER REVIEWED**
  
• intraperitoneal administration of (14)C-carbon disulfide to rats resulted in excretion of carbonyl sulfide by the lungs in greater quantities than carbon dioxide. Pretreatment of rats with phenobarbital, however, resulted in a greater amount of excretion of carbon dioxide than carbon disulfide. In both experiments, excretion of (14)C-carbonyl sulfide and carbon dioxide accounted for 14 to 43% of the total administered radioactivity, with about twice as much carbon dioxide. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p75 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 20, 2006. ]**PEER REVIEWED**
  
• A series of experiments were performed to investigate the rate of absorption of carbon disulfide by immersion of the hand in aqueous solutions of increasing concentrations (0.33 to 1.67 g/L) for 1 hour ... Absorption was calculated indirectly by determining carbon disulfide elimination by the lung or directly by measuring carbon disulfide concentration in the solutions before and after immersion of the hand. Rates of absorption of carbon disulfide, determined from analysis of the solutions, ranged from 0.232 to 0.789 mg/sq cm/hour and were about 10 times higher than rates calculated from lung excretion of carbon disulfide. In the former case, 25% of the absorbed dose was exhaled in the desaturation period; in the latter, only 3% was eliminated in the expired air ... Factors other than absorption through the skin (eg, evaporation) may have accounted for the reduced carbon disulfide concentration ... Nevertheless, these results suggest that rapid absorption of carbon disulfide can occur in humans through skin. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p66 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• Milk from nursing mothers occupationally exposed to carbon disulfide was found to contain an average of 12.3 ug carbon disulfide/l00 mL ... Exposure concentrations of carbon disulfide ranged from 9.3 to 21.1 ppm for a 6.5-hour period. Exposure to 7.4 to 40 ppm for a shorter duration (2 to 4 hours) resulted in a lower average milk concentration of 6.8 ug/l00 mL. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p66 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• Although carbon disulfide was rapidly eliminated from rat tissues during the first 6 to 8 hours after exposure, low concentrations of carbon disulfide were still detected in the tissues 20 hours after exposure ... Anesthetized male Sprague-Dawley rats exposed to 640 ppm carbon disulfide had an exponential increase in carbon disulfide in the blood which reached an apparently steady state after 90 minutes of exposure. After discontinuation of exposure, the blood concentration decreased rapidly, with elimination half-lives reported to be 6 and 85 minutes for the fast and slow components, respectively. In all tissues except fat, the carbon disulfide concentration approached steady state within 4 to 5 hours of exposure. Loss of free carbon disulfide was rapid from all tissues except the liver and kidneys, which retained 25% and 29%, respectively, at 8 hours postexposure ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p67 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• Inhalation exposure of pregnant mice to carbon disulfide during gestation resulted in rapid absorption and distribution of carbon disulfide and its metabolites in embryonic and fetal tissues within 1 hour ... Pregnant mice were exposed via inhalation to 25 microcuries (uCi) (35)S- or (14)C-carbon disulfide for 10 minutes on day 9, 14, or 17 of gestation. The levels of (35)S-labelled metabolites in the embryonic neuroepithelium were higher in the fetal brain than in the maternal brain during early gestation (day 9). The concentrations in the fetal brain, eyes, and skeleton exceeded that of other fetal organs during mid-gestation (day 14). In late gestation (day 17), the levels in the fetal and maternal brain were relatively low, but high uptake of radioactivity was seen in the placenta, fetal blood, liver, and eyes. During early gestation, the distribution of (14)C-labelled metabolites was similar to that of (35)S-labelled metabolites with an immediate higher uptake in the embryo (including neuroepithelium) than in the maternal serum. On days 14 and 17 of gestation, radioactivity was present in the ventricle of the fetal brain. High levels were detected in the fetal liver and blood at late gestation (day 17). In contrast to (35)S-labelled metabolites, (14)C-labelled metabolites were retained longer (up to 24 hours) in the fetal brain and liver. High concentrations of (14)C-labelled metabolites were also seen in the fetal urinary tract. Thus, the distribution pattern varied with the age of the conceptus and also with the radiolabel of carbon disulfide. These results indicate that carbon disulfide and its metabolites pass through the placenta at all stages of gestation and localize selectively in various tissues of the body. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p67 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• The distribution of free carbon disulfide and bound carbon disulfide liberated by acid hydrolysis was investigated in the tissues of white rats after a large, single subcutaneous dose (approximately 361 mg/kg) of carbon disulfide ... Results of these studies indicate that following absorption, free carbon disulfide is rapidly removed from the blood and tissues. Negligible blood levels were present 11 hours after the dose was administered ... Initially, free carbon disulfide accumulated in the blood, adrenals, and brain, but levels in the organs rapidly decreased, and only very small amounts were present after 10 to 16 hours. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p68 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• ... (35)S-carbon disulfide was administered parenterally to guinea pigs ... About 20 to 50% of intracardially injected (35)S-carbon disulfide was retained; the amount of material retained depended on the concentration of dose administered. The largest amount of radiolabel appeared in the liver (0.43 ug) and the least amount in the brain (0.05 ug) at 1.5 hours following injection. Only 10% of the labelled compound remained in the tissues after 48 hours ... In guinea pigs exposed to carbon disulfide vapors (13.6 to 25.7 ppm), the brain and blood contained more (35)S-label relative to the liver. Forty-eight hours later, 30 to 50% of (35)S-label remained in the tissues such as blood, liver, brain, kidney, and skin. The urinalyses revealed that urinary (35)S-label was about 30% of the retained sulfur, with about 85% or 90% of it appearing in the first 24-hour output, the larger part of the metabolized material in the urine being excreted as inorganic sulfate. The feces contained about 5 to 15% metabolized (35)S-label, the amount of which increased with the increasing dose of carbon disulfide ... Inhalation exposure to 14 ppm (35)S-carbon disulfide for 8 hours or to 26 ppm (35)S-carbon disulfide for 40 hours resulted in excretion of the administered dose mainly in the urine (63%) and expired air (30%) within 48 hours of exposure. The metabolized material was excreted in the urine predominantly in the form of inorganic sulfur compounds; some organosulfur derivatives were also present. Most of the unmetabolized carbon disulfide was excreted in the expired air. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p68 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• Carbon disulfide is also found in the saliva and sweat of exposed individuals in small quantities. These measurements have not been shown to quantitatively correlate with carbon disulfide exposure. The concentration of carbon disulfide in the feces is very low [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p87 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 20, 2006. ]**PEER REVIEWED**
  

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Metabolism/Metabolites

• The metabolism for CS2-atheroma production also may involve direct injury to the endothelium coupled with hypothyroidism, because thiocarbamate (thiourea), a potent antithyroid substance, is a principal urinary metabolite of CS2. [Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill, 2001., p. 647]**PEER REVIEWED**
  
• A small amt of carbon disulfide is apparently converted to hydrogen sulfide, which is rapidly oxidized to sulfate and excreted in the urine. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-90]**PEER REVIEWED**
  
• Carbon disulfide reacts with a variety of nucleophilic functional groups ... amino, to form dithiocarbamic acids ... mercapto, to form trithiocarbamic acids ... hydroxyl, to form xanthogenic acids ... cmpd with two such groups to form heterocycles. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-90]**PEER REVIEWED**
  
• Carbon disulfide admin ip to rats was oxidized to (14)CO2 to an extent proportional to the amount of cytochrome P450 present in the liver at the time of admin. [The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 429]**PEER REVIEWED**
  
• The metabolic formation of carbonyl sulfide from carbon disulfide was confirmed in an in vivo study ... After intraperitoneal injection of (14)C-carbon disulfide in nonpretreated rats, carbonyl sulfide was excreted by the lung in greater quantities than carbon dioxide. Pretreatment with phenobarbital ... resulted in a greater amount of excretion of carbon dioxide than carbonyl sulfide. In both experiments, excretion of (14)C-carbonyl sulfide and carbon dioxide accounted for 14 to 43% of the total administered radioactivity, with about twice as much carbon dioxide. These results indicate that phenobarbital treatment caused induction of cytochrome p-450 which catalyzed the conversion of carbon disulfide to carbonyl sulfide faster in pretreated rats than in rats not pretreated with phenobarbital. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p72 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• Between 10 and 30% of absorbed carbon disulfide is exhaled, less than 1% is excreted in the urine, and the remaining 70-90% undergoes biotransformation before excretion in the urine in the form of sulfur-containing metabolites, only some of which have been identified (eg, thiourea and mercaptothiazolinone). [WHO; Environ Health Criteria: Carbon Disulfide p.2 (1979)]**PEER REVIEWED**
  
• In an attempt to further define the mechanisms involved in carbon disulfide metabolism, the relationship between carbon disulfide and carbonyl sulfide metabolism was explored in male Sprague-Dawley rat hepatocytes and liver microsomes. Pretreatment of animals with cobaltous chloride or phenobarbital decreased or increased, respectively, the extent of carbon disulfide metabolism by hepatic microsomes, as determined by the formation of carbonyl sulfide and nonvolatile sulfur compounds. Carbon disulfide metabolism in microsomes was biphasic in that there was an initial period of rapid metabolite formation followed by a period of slower metabolism. Carbon disulfide metabolism in hepatocytes was biphasic as well. SKF-525A significantly inhibited carbon disulfide metabolism in hepatocytes and microsomes from phenobarbital treated rats. Acetazolamide did not significantly inhibit carbon disulfide metabolism regardless of the metabolite studied. [Chengelis CP, Neal RA; Biochemical Pharmacology 36 (3): 363-8 (1987)]**PEER REVIEWED**
  
• Carbon disulfide is metabolized by two distinctly different pathways: ability of carbon disulfide to spontaneously react with free amine and sulfhydryl groups of amino acids and polypeptides, and microsomal metabolism of carbon disulfide to reactive intermediates capable of covalently binding to tissue macromolecules. Dithiocarbamates are formed during in vitro incubations of carbon disulfide with blood; treatment of the dithiocarbamate products with acid and heat liberates carbon disulfide. Tissue concentrations of acid labile metabolites exceed those of free carbon disulfide at the end of an 8 hour, 2 mg/l carbon disulfide inhalation exposure. Acid labile metabolites may also accumulate in the body after repeated carbon disulfide exposure. [Bus JS; Neurotoxicology 6 (4): 73-80 (1985)]**PEER REVIEWED**
  
• Carbon disulfide (at the micrograms per litre or micrograms per cubic metre level) and its metabolite 2-thiothiazolidine-4-carboxylic acid (TTCA) were detected in virtually all samples of breath, blood, urine, and breast milk of subjects with no known occupational exposure in a number of studies ... At least some of the carbon disulfide and/or TTCA may have arisen from exposure to other chemicals of which they are known to be metabolites, such as disulfiram, captan, or dithiocarbamate fungicides, and TTCA is present naturally in brassica vegetables and may be found in the urine at levels above 10 umol/litre after consumption of such items ... [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• Carbon disulfide is extensively metabolized, with the main metabolites being 2-mercapto-2-thiazolinone-5, thiocarbamide, and 2-thiothiazolidine-4-carboxylic acid (TTCA). TTCA represents 2 to 6% of the total carbon disulfide absorbed in humans and has been utilized for biomonitoring ... Different studies show a constant, close correlation between 8-hr TWA airborne exposure to carbon disulfide and urinary TTCA concentrations. The concentration of TTCA in an after-shift urine specimen collected towards the end of the work week following exposure to an 8-hr TWA of 31 mg carbon disulfide/cu m was approximately 4 mmol/mol creatinine ... [International Programme on Chemical Safety; Concise International Chemical Assessment Document Number 46: Carbon disulfide (2002). Available from: http://www.inchem.org/pages/cicads.html as of September 14, 2006. ]**PEER REVIEWED**
  
• ... Distribution /of carbon disulfide/ is greatest in organs such as the brain and liver where it is metabolized to thiocarbamates. Carbon disulfide is metabolized by cytochrome p-450 to an unstable oxygen intermediate which either spontaneously degrades to atomic sulfur and carbonyl sulfide or hydrolyzes to form atomic sulfur and monothiocarbonate. Carbonyl sulfide is converted to monothiocarbonate by carbonic anhydrase. Monothiocarbonate degrades to generate carbonyl sulfide or forms carbon dioxide and hydrogen sulfide. Unlike in animals, oxidation of sulfur to inorganic sulfate does not contribute significantly to the metabolism of carbon disulfide in humans. Despite the differences in the metabolism of carbon disulfide between animals and humans, dithiocarbamates are the common metabolites formed in these species after reaction with amino acids. These metabolites contribute in part to the neurotoxic effects of carbon disulfide. The kidneys are the primary route of excretion of carbon disulfide metabolites. Conjugation of carbon disulfide or carbonyl sulfide with endogenous glutathione results in formation of thiozolidine-2-thione-4-carboxylic acid and 2-oxythiazolidine-4-carboxylic acid, respectively, which are excreted in the urine. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p64 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• Inhalation exposure of pregnant mice to carbon disulfide during gestation resulted in rapid absorption and distribution of carbon disulfide and its metabolites in embryonic and fetal tissues within 1 hour ... Pregnant mice were exposed via inhalation to 25 microcuries (uCi) (35)S- or (14)C-carbon disulfide for 10 minutes on day 9, 14, or 17 of gestation. The levels of (35)S-labelled metabolites in the embryonic neuroepithelium were higher in the fetal brain than in the maternal brain during early gestation (day 9). The concentrations in the fetal brain, eyes, and skeleton exceeded that of other fetal organs during mid-gestation (day 14). In late gestation (day 17), the levels in the fetal and maternal brain were relatively low, but high uptake of radioactivity was seen in the placenta, fetal blood, liver, and eyes. During early gestation, the distribution of (14)C-labelled metabolites was similar to that of (35)S-labelled metabolites with an immediate higher uptake in the embryo (including neuroepithelium) than in the maternal serum. On days 14 and 17 of gestation, radioactivity was present in the ventricle of the fetal brain. High levels were detected in the fetal liver and blood at late gestation (day 17). In contrast to (35)S-labelled metabolites, (14)C-labelled metabolites were retained longer (up to 24 hours) in the fetal brain and liver. High concentrations of (14)C-labelled metabolites were also seen in the fetal urinary tract. Thus, the distribution pattern varied with the age of the conceptus and also with the radiolabel of carbon disulfide. These results indicate that carbon disulfide and its metabolites pass through the placenta at all stages of gestation and localize selectively in various tissues of the body. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p67 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• ... (35)S-carbon disulfide was administered parenterally to guinea pigs ... About 20 to 50% of intracardially injected (35)S-carbon disulfide was retained; the amount of material retained depended on the concentration of dose administered. The largest amount of radiolabel appeared in the liver (0.43 ug) and the least amount in the brain (0.05 ug) at 1.5 hours following injection. Only 10% of the labelled compound remained in the tissues after 48 hours ... In guinea pigs exposed to carbon disulfide vapors (13.6 to 25.7 ppm), the brain and blood contained more (35)S-label relative to the liver. Forty-eight hours later, 30 to 50% of (35)S-label remained in the tissues such as blood, liver, brain, kidney, and skin. The urinalyses revealed that urinary (35)S-label was about 30% of the retained sulfur, with about 85% or 90% of it appearing in the first 24-hour output, the larger part of the metabolized material in the urine being excreted as inorganic sulfate. The feces contained about 5 to 15% metabolized (35)S-label, the amount of which increased with the increasing dose of carbon disulfide. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p69 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• High levels of thiocarbamide and trace amounts of 2-thio-5-thiazolidinone were identified by chromatographic analysis of the urine of workers exposed to carbon disulfide by inhalation ... High concentrations (approximately 320 mM) of thiazolidine-2-thione-4-carboxylic acid (TTCA) were detected in the urine of women exposed to approximately 32 ppm (100 mg/cu m) carbon disulfide through inhalation ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p71 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• Only metabolites of carbon disulfide were found 3 hours after a dose of (14)C- or (35)S-labeled carbon disulfide was intraperitoneally administered ... Distribution varied with the age of the rat and the radiolabel injected. Following intraperitoneal administration of (14)C-carbon disulfide, 4 to 9% of the dose was metabolized to carbon dioxide depending on age. Significantly more carbon disulfide was metabolized to carbon dioxide by 30- and 40-day-old rats than by 1 to 20-day-old rats. The biotransformation products of carbon disulfide which were covalently bound remained in tissues from rats of all ages. Twenty-four hours after dosing with (35)S-labeled carbon disulfide, up to 13 times more labeled metabolites were covalently bound in organs from 1-day-old rats than in similar organs from 40-day-old rats. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p69 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• Carbon disulfide is oxidized by the liver mixed-function oxidase (MFO) system to carbonyl sulfide, which then undergoes further desulfurization, releasing elemental sulfur. This reaction has been shown to occur in vitro ... Following intraperitoneal administration of approximately 100 mg carbon disulfide/kg, about 5% of the total dose was excreted in the breath as carbon dioxide. This amount was increased to 13% in animals pretreated with phenobarbital to induce liver microsomal enzymes ... /It was/ found that 4 to 9% of an intraperitoneally administered dose of (14)C-carbon disulfide was excreted as (14)CO2 in expired air, with 30- and 40-day-old rats excreting more (9% versus 4%) (14)CO2, than 1 to 20-day-old rats. This was attributed to the increased hepatic MFO of carbon disulfide to carbon dioxide in 30 to 40-day-old rats. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p71 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• The role of the cytochrome p-450 monooxygenase system in catalyzing carbonyl sulfide formation was also confirmed by in vitro studies ... The rate of carbonyl sulfide formation was NADPH-dependent and increased with microsomes obtained from phenobarbital-treated rats. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p72 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• In a study designed to examine the effect of p-450 induction on the metabolism of carbon disulfide to thiazolidine-2-thione-4-carboxylic acid (TTCA), rats were treated with nothing, ethanol, phenobarbital, 3-methylcholanthrene, or phenobarbital and ethanol before being exposed to carbon disulfide at 50 ppm for 6 hours ... After 7 days the pretreatment regimens were repeated in the same rats, and the rats were again exposed to carbon disulfide at 500 ppm for 6 hours. None of the inducers had any effect on urinary excretion of TTCA. About 7.6% and 2.3% of the dose was excreted as TTCA at 50 and 500 ppm, respectively, suggesting saturation ... Satuation of TTCA production was observed in an oral study in rats ... treated with a single gavage dose of 1, 10, 30, or 100 mg/kg, 4.6%, 2.4%, 1.7%, and 0.8%, respectively, of the dose was excreted in the urine as TTCA. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p72 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 19, 2006. ]**PEER REVIEWED**
  
• The effect of p-450 induction or glutathione depletion on carbon disulfide metabolism to thiozolidine-2-thione-4-carboxylic acid (TTCA) in rats following oral exposure has also been studied ... The rats were pretreated with nothing, acetone, phenobarbital, 3-methylcholanthrene, or three inhibitors of glutathione production, namely phorone, diethylmaleate, or buthionine sulfoximine, before being given a single gavage dose of carbon disulfide at 26 to 34 mg/kg. Phenobarbital decreased the output of TTCA by 21% during the first 12 hours of the urine collection. None of the other p-450 inducers had any effects on TTCA excretion, and the investigators suggested that the effect of phenobarbital may have been a result of cytochrome p-450 aggregation. Buthionine sulfoximine, an inhibitor of glutathione production, reduced the total output of TTCA by about 40%. Phorone and diethylmaleate pretreatment, which transiently reduce glutathione, decreased TTCA excretion. [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p72 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 20, 2006. ]**PEER REVIEWED**
  
• Carbon disulfide combines readily with the amine groups of amino acids to produce dithiocarbamates, which are water-soluble metabolites. Such reactions have been demonstrated with free amino groups in serum in vivo ... The formation of acid-labile carbon disulfide, readily destroyed at low pH, was also consistent with significant in vivo formation of dithiocarbamate metabolites ... Following absorption of inhaled carbon disulfide by the lung, free carbon disulfide is distributed to various tissues where it is either eliminated, primarily by the lung, or further metabolized to acid-labile carbon disulfide metabolites. The formation of acid-labile carbon disulfide metabolites may continue to increase at steady-state concentrations of carbon disulfide as long as free carbon disulfide is available to the tissue and amine substrates are available. This was demonstrated in rats exposed to 640 ppm carbon disulfide for 8 hours in which acid-labile carbon disulfide metabolites continued to accumulate in several tissues after steady-state levels of carbon disulfide were reached ... [DHHS/ATSDR; Toxicological Profile for Carbon Disulfide (CAS# 75-15-0) p76 (1996). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp82.pdf as of September 20, 2006. ]**PEER REVIEWED**
  
• Carbon dioxide and carbon monoxide are metabolites. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 3:503]**PEER REVIEWED**
  

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TSCA Test Submissions

• Carbon Disulfide (CAS RN 75-15-0) was evaluated for inhalation toxicity in male and female B6C3F1 mice. Three groups of 10 male and 12 female mice were exposed to target concentrations of 50, 300, or 800 ppm atmospheres of carbon disulfide vapor for 6 hrs/5 days/wk for at least 89 days. The corresponding time-weighted average concentrations were 49.3, 297.1, and 798.4 ppm, respectively. A control group of 10 males and 12 females was exposed to clean air only and animals were handled in a manner similar to the test animals. Mortalities included 4 mice from the high concentration group (800 ppm, sex unknown), a control female was killed accidently, and one female from the group receiving 300 ppm was discovered missing. Exposure to 800 ppm carbon disulfide produced a treatment-related decrease in body weight gain in both sexes, with a significant reduction in food consumption among only females at 13 weeks. Significant decreases in erythrocyte counts, total hemoglobin, and hematocrit, in conjunction with increased iron positive brown pigment in the spleens were seen in all high dose animals. Significant decreases in brain weight was found in both sexes in the high concentration group, and the males of this group exhibited a significant decrease in mean kidney weight along with renal lesions, mineralization, and tubular epithelial syncytia. The high dose group also exhibited neural effects of treatment, including segmental degeneration of the peripheral nerves, and axonal swelling in the ventral and lateral funiculi of the thoracic and lumbar spinal cord. [Toxigenics; 90-Day Vapor Inhalation Toxicity Study of Carbon Disulfide in B6C3F1 Mice (1983); EPA Doc. No. FYI-OTS-0983-0255; Fiche No.OTS0000255-0 ]**UNREVIEWED**
  
• Carbon Disulfide (CAS RN 75-15-0) was evaluated for inhalation toxicity in male and female Sprague-Dawley rats. Three groups of 15 male and 15 female rats were exposed to target concentrations of 50, 300, or 800 ppm atmospheres of carbon disulfide vapor for 6 hrs/5 days/wk for at least 89 days. The corresponding time-weighted average concentrations were 49.3, 297.1, and 798.4 ppm, respectively. A control group of 15 males and 15 females was exposed to clean air only and animals were handled in a manner similar to the test animals. In addition, 5 rats/sex/group were designated for neuropathological examination, while the remaining 10/sex/group received routine clinical and histopathological examinations. Mortalities occurring during the course of the study included one high dose male found dead, and one low-dose male sacrificed in extremis. Ataxia and occasional occurrences of slight to severe foot-drag were observed in the high dose group. Males and females in the 800 ppm group exhibited treatment-related decreases in body-weight gain, and males showed a significant decrease in food consumption. Males receiving 800 ppm and females at 800 and 300 ppm showed a significant decrease in brain weight. Histopathological examination revealed slight axonal swelling of the ventral and lateral funiculi of the spinal cord in the majority of high-dose males and females, and segmental degeneration in the peripheral nerves in 6 of 10 males and 6 of 10 females. Examination of nerve fibers revealed axonal swelling of the muscular and sural nerves in all animals receiving 800 ppm with the exception of one female, and single instances in males from the 300 ppm group. Animals in the low dose group exhibited no treatment-related effects of exposure. [Toxigenics; 90-Day Vapor Inhalation Toxicity Study of Carbon Disulfide in Sprague-Dawley Rats(1983); EPA Doc. No. FYI-OTS-0983-0255; Fiche No.OTS0000255-0 ]**UNREVIEWED**
  
• Carbon Disulfide (CAS RN 75-15-0) was evaluated for inhalation toxicity in male and female Fischer 344 rats. Three groups of 15 male and 15 female rats were exposed to target concentrations of 50, 300, or 800 ppm atmospheres of carbon disulfide vapor for 6 hrs/5 days/wk for at least 89 days. The corresponding time-weighted average concentrations were 49.3, 297.1, and 798.4 ppm, respectively. A control group of 15 males and 15 females was exposed to clean air only and were handled in a manner similar to the treated animals. In addition, 5 rats/sex/group were designated for neuropathological examination (Dedicated animals), while the remaining 10/sex/group received routine clinical and histopathological examinations (Principle animals). There were no mortalities during the course of the study. Ataxia was observed in 29 of 30 animals in the 800 ppm group. Male rats receiving 800 ppm and 300 ppm and female rats in the 800 ppm group exhibited a significant decrease in body weight gain, and males and females receiving 800 ppm displayed a significant decrease in total food consumption. High-dose males exhibited a slight increase in red blood cell removal and a mild decrease in platelet counts, and both sexes displayed a mild increase in neutrophils and decrease in lymphocytes. There was a significant, dose-related decrease in brain weight. Histopathology studies from Principle animals revealed axonal swelling of nerve fibers from the ventral and lateral funiculi of the spinal cord in high-dose animals and one mid-dose male. Segmental degeneration of the sciatic nerve was observed in 3 high-dose males and 2 females receiving 800 ppm. No treatment related signs or lesions were seen in rats receiving 50 ppm carbon disulfide. Teased fiber preparations from Dedicated animals revealed axonal swelling of the muscular and sural nerves and clumping and loss of myelin sheathing in muscular nerves in the 800 ppm group. One female receiving 300 ppm exhibited axonal swelling of the fibers in Epon sections of the muscular nerve, and one female had equivocal results. The group receiving 50 ppm were not examined for neuropathological effects. [Toxigenics; 90-Day Vapor Inhalation Toxicity Study of Carbon Disulfide in Fischer 344 Rats(1983); EPA Doc. No. FYI-OTS-0983-0255; Fiche No.OTS0000255-0 ]**UNREVIEWED**
  
• A dose range-finding study was conducted with carbon disulfide (CAS RN 75-15-0) in pregnant New Zealand White rabbits to determine the dose range for a definitive developmental toxicity study. Groups of 6 rabbits were exposed by whole-body inhalation to 0, 100, 300, 1000, or 3000 ppm carbon disulfide on gestation days 6-18. Surviving rabbits were sacrificed on gestation day 29 and uterine examinations were conducted. The high concentration exposure (3000 ppm) produced 100% mortality, while 1000 ppm produced a suggestion of transient anoxia. No other clinical signs were noted. Exposure to 1000 ppm did produce a significant increase in post-implantation losses and incidences of developmental anomalies, and a significant increase in mean fetal body weight. [Pathology Assc., Inc.; Developmental Inhalation Toxicity Study of Carbon Disulfide in the New Zealand White Rabbit, Final Report (1991); EPA Doc. 86940000785; Fiche No. OTS0557195 ]**UNREVIEWED**
  
• Carbon disulfide (CAS RN 75-15-0) was evaluated for developmental toxicity in New Zealand White rabbits. A total of 144 animals were placed into one of two staggered exposure periods (72/period). Groups of naturally inseminated does (24/group) were exposed by whole-body inhalation to 0 (filtered air control), 60, 100, 300, 600, or 1200 ppm carbon disulfide vapor on gestation days 6-18 for 6 hours per day. Surviving animals were sacrificed on gestation day 29. Clinical signs of toxicity reported for the 1200 ppm group included ataxia, low food consumption, scant feces, labored respiration, wheezing, tremors, and abortion with bloody excretion involving two maternal deaths. Also noted were decreased maternal absolute body weight gain and reduced mean body weight relative to controls. Evidence of embryo- and fetal toxicity at 600 and 1200 ppm were seen as significant treatment-related increase in postimplantation loss and reduced mean fetal body weights. A statistically significant increase in the number of cumulative skeletal and visceral malformations was observed in the 1200 ppm exposure group, although the incidence of individual malformations was not statistically significant. Under the conditions of this study, the NOEL for maternal toxicity was considered to be 600 ppm, while the NOEL for developmental toxicity was 300 ppm. [Pathology Assc., Inc.; Developmental Inhalation Toxicity Study of Carbon Disulfide in the New Zealand White Rabbit, Final Report (1991); EPA Doc. 86940000785; Fiche No. OTS0557195 ]**UNREVIEWED**
  
• Carbon disulfide (75-15-0) was evaluated for adverse effects on reproduction in female Sprague-Dawley Crl: CD-BR rats (15/exposure) group. Survival, growth and developmental effects on the F1 generation were also assessed. Groups of 15 female rats were exposed whole-body to CS2 at target concentrations of 125, 250, or 400 ppm (39, 78, and 155 mg/m3) for 6 hours per day for 14 days prior to mating, throughout mating, and continuing to gestational day 19. A control group of 24 females were exposed to clean, filtered air on a comparable schedule. The females were mated (1:1) with unexposed males, and allowed to deliver and raise their offspring to lactation day 21. The females were necropsied after weaning, and the F1 offspring were necropsied on day 42. There were no treatment-related mortalities. Females exposed to 500 ppm exhibited clear material around the eyes and red material around the nose. Mean body weights and body weight gains were reduced in this group throughout gestation, and mean food consumption was reduced through gestational days 15-20. Mating and fertility indices were comparable between all treatment groups and controls, but three females in the 500 ppm group experienced 100% litter loss. Pup viability and mean litter size were also reduced on days 1-4, prior to selection, for dams exposed to 500 ppm. Pup physical development indicators were unaffected by maternal exposure to CS2. Necropsies did not reveal any remarkable findings in either the dams or pups. The NOEL for maternal and neonatal toxicity was considered to be 250 ppm. [WIL Research Labs.; An Assessment of Reproduction in Female Rats Exposed to CS2 via Inhalation (1992); EPA Doc 86940000786; Fiche No. OTS0557196 ]**UNREVIEWED**
  

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Footnotes

¹ Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.