National Toxicology Program

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

Names (NTP)

• n-Hexane
• HEXANE (8CI)(9CI)

Human Toxicity Excerpts

• HUMAN EXPOSURE STUDIES: Inhalation of 5000 ppm for 10 minutes produces marked vertigo; 2500-1000 ppm for 12 hours produces drowsiness, fatigue, loss of appetite, paresthesia in distal extremities; 2500-500 ppm produces muscle weakness, cold pulsation in extremities, blurred vision, headache, anorexia, and onset of polyneuropathy. [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 1800]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Slightly toxic by ingestion and inhalation. Human systemic effects include: hallucinations, structural change in nerve or sheath... may be irritating to respiratory tract and narcotic in high concentrations. [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 1800]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Nerve conduction blocks, defined by a significant reduction in amplitude or area of the compound muscle action potential at proximal compared with distal sites of stimulation, have been described in glue-sniffers and in workers with industrial exposure at an early stage of n-hexane neuropathy. The frequency with which this focal conduction anomaly appears is described and discussed in the case of a very homogeneous group of 10 young workers diagnosed with n-hexane polyneuropathy. Partial conduction blocks occurred in only two workers and may have been related to the intensity and duration of toxic exposure. [Pastore C et al; Muscle Nerve 26 (1): 132-5 (2002)]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: ... The study involved 26 workers diagnosed as having polyneuropathy following n-hexane exposure. The FM-100 Hue test was used to determine color discrimination in study volunteers. Their results were compared with a control group of 50 people who had not been exposed to n-hexane. The mean total error score for the exposed group was 168.3 (SD = 70.5) for the right eye and 181.5 (SD = 103.0) for the left eye. The mean total error scores for the control group for the right and left eyes were 36.0 (SD = 19.8) and 35.6 (SD = 18.2), respectively. Differences between total and partial error scores for exposed and control groups were statistically significant (P < 0.001). These results may indicate a relationship between n-hexane exposure and development of defects in color vision, and would support a recommendation for periodic assessment of workers exposed to n-hexane and chemically related solvents. [Issever H et al; Occup Med (Lond) 52 (4): 183-6 (2002)]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: In an offset printing factory with 56 workers, 20 (36%) developed symptomatic peripheral neuropathy due to exposure to n-hexane. Another 26 workers (46%) were found to have subclinical neuropathy. The initial change in the nerve conduction study was reduced amplitude of the sensory action potentials, followed by reduced amplitude of the motor action potentials, reduction in motor conduction velocities and increase in distal latencies. These changes indicate primary axonal degeneration with secondary demyelination. Sural nerve biopsy in a severe case showed giant axonal swellings due to accumulation of 10nm neurofilaments, myelin sheath attenuation and widening of nodal gaps. The development of neuropathy bore no direct relationship to the duration of exposure, hence factors such as individual susceptibility may be important. Optic neuropathy and CNS involvement were uncommon and autonomic neuropathy was not encountered. [Chang CM et al; J Neurol Neurosurg Psychiatry 56 (5): 538-42 (1993)]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: ... n-Hexane could cause overt polyneuropathy in workers exposed to more than 100 ppm time-weighted average concentrations (TWA). [Takeuchi Y; Environ Res 62 (1): 76-80 (1993)]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: To estimate the quantitative relation between exposure to airborne n-hexane and various markers of immune function, 35 male workers were examined and compared with unexposed controls. Urinary 2,5-hexanedione concentrations were significantly higher in the exposed group than in the unexposed. A significant suppression was observed in the serum immunoglobulin (IgG, IgM and IgA) levels between two populations. Also, a significant correlation was found between urinary 2,5-hexanedione concentrations and serum Ig level of the exposed group. 4. No significant difference between white blood cell counts was found in the two groups. [Karakaya A et al; Hum Exp Toxicol 15 (1): 56-8 (1996)]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES:... Hexane neuropathy is associated with giant axonal swellings containing accumulations of neurofilaments along the course of the nerve fibers. Nerve fibers degenerate distal to the site of the swelling and myelin loss may occur, producing secondary demyelination. [Rom, W.N. (ed.). Environmental and Occupational Medicine. 2nd ed. Boston, MA: Little, Brown and Company, 1992., p. 566]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Chronic hexane intoxication has been decribed by several investigators. The clinical course includes a slow-developing bilateral, symmetrical, sensimotor, and peripheral neuropathy. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 3]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: In humans, inhaling 2,000 ppm for 10 min resulted in no effects, but 5,000 ppm caused dizziness and... giddiness. ...Slight nausea, headache, eye and throat irritation /occurred/ at 1,400-1,500 ppm. ...No ocular or mucous membrane irritation /was found/ at 5,000 ppm in unacclimated subjects. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 3]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: A ...mild central nervous depressant in acute exposures. ...Vapor causes anesthesia of short duration without sequelae. ...It tends to vaporize when swallowed or aspirated into the tracheobronchial tree. The result can be a rapid dilution of alveolar air and a marked fall in its oxygen content, with asphyxia and consequent brain damage or cardiac arrest. The irritative pulmonary lesions occurring after the aspiration of higher homologues (e.g. octane, nonane, decane, etc) and of mixtures thereof (e.g. kerosene) do not appear to be a problem with... hexane. ...Toxic neuropathies including quadraplegia have occurred among juvenile glue sniffers. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-150]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: ...Solvents such as ...hexane ...may contact the eye in industrial or lab accidents. These substances... dissolve fats. ...They cause pain on contacting the eye, and exam after generous splash of solvent shows dulling of the cornea. ...Damage appears to be scattered loss of epithelial cells due to solution of some of the fats that occur in these cells. [Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986., p. 481]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: 3 women had motor polyneuropathy following industrial exposure to adhesive agent containing 80.4% n-hexane. In the nerve, there were polymorphous changes in the myelin sheaths and axons of large diameter fibers. Muscles showed denervation atrophy and degenerative changes, with lymphocytic infiltrates and phagocytosis. [Scelsi R et al; J Neurol Sci 47 (1): 7-20 (1980) ]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Visual evoked potentials and averaged extraocular electroretinograms were recorded from 15 workers occupationally exposed to n-hexane for 5-21 yr and 10 controls. The changes in exposed subjects indicated cerebral dysfunction. [Seppalainen AM et al; Electroencephalogr Clin Neurophysiol 47 (4): 492-8 (1979) ]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: 93 of 1662 workers exposed to organic solvents, which consisted mainly of n-hexane and a small amount of toluene, were found to have sensory polyneuropathy (53), sensorimotor polyneuropathy (32), or sensorimotor polyneuropathy with amyotrophy (8). Cranial nerve involvements such as visual disorders and facial numbness were observed. About 50% showed denervation and reinnervation of the nerves. [Sobue I et al; Int J Neurol 11 (4): 317-30 (1978) ]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Among 93 cases of n-hexane polyneuropathy during a large outbreak in 1968, 44 were studied. Over a few yr most of the cases completely recovered, except for a few with mild sensory impairment, after providing for 100 ppm as the maximal allowable concn of n-hexane and well equipped ventilation systems in individual houses. During the rescreening in 1981, before which there occurred only 2 pt, 21 cases with mild n-hexane polyneuropathy were observed, revealing mostly the same features as in the previous outbreak in 1968. From these data it may be suggested that, in spite of less than 50 ppm of n-hexane concn in a room, the sandal workers have suffered from neurotoxicity from this organic solvent. [Iida M; Electroencephalogr Clin Neurophysiol (Suppl) 36: 671-81 (1982)]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Acute exposure to hexane causes central nervous system depression. Chronic exposure to an average air concn of 450-650 ppm for as little as 2 months may result in peripheral neuropathy, characterized by muscular weakness, loss of sensation, and impaired gait. [Baselt, R.C. Biological Monitoring Methods for Industrial Chemicals. 2nd ed. Littleton, MA: PSG Publishing Co., Inc. 1988., p. 172]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Hexane may be the most highly toxic member of the alkanes. ... When ingested, it causes nausea, vertigo, bronchial and general intestinal irritation, and CNS depression. Concns of about 50 g may be fatal to humans. ... In studies in human volunteers, ... exposure to 5,000 ppm for 10 min caused marked vertigo and nausea. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4 36]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: "Blurred vision" ... has been mentioned in association with hexane polyneuropathy ... changes in the macula, particularly macular edema, may be produced by solvent vapors from shoemaker's cement, such as n-hexane. Fifteen people who were exposed industrially to hexane for a mean of 12 years ... had normal visual acuity and visual fields, but only 3 were thought to have normal color discrimination. ... There seemed to be vague disturbances in the appearance of the macula areas in 11 of the pt, and vague abnormalities were suspected in retinal fluoroangiograms in some pt. Visual evoked potentials in industrial workers are said to have been found abnormal. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 482]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: ... /It was/ concluded that n-hexane vapor levels of < 100 ppm for 8 hr/day were not likely to produce a clinical neuropathy, but mild subclinical changes in muscle strength and nerve conduction velocity may occur. ... Levels below 100 ppm may be neuropathic if extensive skin exposures also occur. [O'Donoghue, J.L. (ed.). Neurotoxicity of Industrial and Commercial Chemicals. Volume II. Boca Raton, FL: CRC Press, Inc., 1985., p. 63]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: ... The more important manifestations, which develop insidiously, are those of chronic peripheral neuropathy. Both sensory and motor symptoms have been reported as the initial manifestation of peripheral nervous system damage. Touch perception seems to be somewhat more impaired than vibratory or position sense. Distal symmetric motor weakness is common in the majority of cases and may progress to involve pelvic and thigh muscles in severely affected persons. ... As with other toxic solvents, deterioration of nerve function may persist for several weeks after removal from exposure to the chemical. [Rom, W.N. (ed.). Environmental and Occupational Medicine. 2nd ed. Boston, MA: Little, Brown and Company, 1992., p. 566]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Inhalation causes irritation of respiratory tract, cough, mild depression, cardiac arrhythmias. Aspiration causes severe lung irritation, coughing, pulmonary edema; excitement followed by depression. Ingestion causes nausea, vomiting, swelling of abdomen, headache, depression. [Prager, J.C. Environmental Contaminant Reference Databook Volume 2. New York, NY: Van Nostrand Reinhold, 1996., p. 460]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Acute inhalation effects of hexane are euphoria, dizziness, and numbness of limbs. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4 36]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Occupational exposures to hexane concns of 1,000-25,500 for 30-60 min caused drowsiness. Two workers at an hexane extraction facility reported transient paraesthesia following excessive acute exposure to hexane. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4 36]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Chronic effects from glue sniffing over a period of 5-15 months have been described as distal symmetrical motor sensory polyneuropathy. Degeneration of axons and nerve terminals has also been observed as a result of glue sniffing. /Hexane-containing glues/ [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4 36]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: A "stocking and glove" anesthesia that results in sensory impairment and muscular weakness in the feet and hands usually develops. Nerve biopsies show morphological changes of neurofilament-filled axonal swellings and degeneration of the distal axon. There is a marked reduction in conduction velocity in sensory and motor nerves. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4 37]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Hexane caused eye lesions in the macula of 11 of 15 workers exposed for 5-21 yr in an adhesive bandage factory. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4 37]**PEER REVIEWED**
  
• CASE REPORTS: /The case of/ a 55-year-old male parkinsonian patient with chronic exposure to n-hexane for 17 years /is described/. The results of neurophysiological (electromyography, evoked potentials), neuroradiological (MRI) and neuropsychological tests performed on the patient suggest a role of this solvent at the level of the central nervous system. Biological susceptibility to neurotoxic compounds is discussed briefly. [Vanacore N et al; Neurol Sci 21 (1): 49-52 (2000)]**PEER REVIEWED**
  
• CASE REPORTS: This report describes our second case of parkinsonism in a subject exposed to n-hexane. Positron emission tomography studies demonstrated regional striatal abnormalities of the nigrostriatal dopaminergic system and of glucose metabolism that were different from those found in idiopathic Parkinson's disease. [Pezzoli G et al; Mov Disord 10 (3): 279-82 (1995)]**PEER REVIEWED**
  
• CASE REPORTS: n-Hexane neuropathy was studied in 20 workers exposed for prolonged periods to this solvent, and with urinary 2,5-hexanedione concentrations exceeding the biological exposure index recommended by the American Conference of Governmental Industrial Hygienists (5 mg/L) with a mean of 11.02 mg/L (range 5.3-24.2 mg/L). Although neurological examination did not detect significant anomalies in any of the patients, and the conduction velocity and F waves of all the nerves tested were normal, neurographic studies revealed significant differences in the amplitude of sensory nerve action potentials (SNAP) recorded from the sural (mean 14.0 microV), median (mean 17.3 microV), and ulnar (mean 7.9 microV) nerves when compared with normal values from healthy adults of the same age range, examined under identical conditions. The amplitude of the SNAP in sural and median nerves correlated significantly with the number of years worked. The notable decrease in mean amplitude of the SNAP appeared to reflect the primary neurotoxic effects of 2,5-hexanedione. [Pastore C et al; Muscle Nerve 17 (9): 981-6 (1994)]**PEER REVIEWED**
  
• CASE REPORTS: ... This report describes the case of a worker who developed peripheral neuropathy, with a histologic pattern characteristic of n-hexane toxicity, after chronic on-the-job exposure to n-hexane at concentrations less than 450 ppm... [Ruff RL et al; Clin Toxicol 18 (5): 515-9 (1981)]**PEER REVIEWED**
  
• CASE REPORTS: Three women developed a predominantly motor polyneuropathy following industrial exposure to an adhesive agent containing 80.4% of n-hexane as a volatile substance. Histological and electron-microscopic studies were carried out on sural nerve and on soleus muscle. In the nerve, there were polymorphous changes in both myelin sheaths and axons of large diameter fibres. Irregular and swollen myelin sheaths and segmental swelling of axons with dissolution of neurotubules and evident increase of neurofilaments were frequently observed. Polymorphous inclusion bodies were often present in Schwann cell cytoplasm. The small myelinated and unmyelinated fibres did not show significant changes. The muscles showed denervation atrophy and focal degenerative myopathic changes, with presence of lymphocytic infiltrates and phagocytosis. This study confirms the noxious effect of n-hexane on the peripheral nerve, with development, in our cases, of a toxic polyneuropathy and denervation muscular atrophy with consistent myopathic changes. [Scelsi R et al; J Neurol Sci 47 (1): 7-19 (1980)]**PEER REVIEWED**
  
• CASE REPORTS: Electroneurographic (ENeG) and evoked potential (EP) studies were regularly performed on 11 printing workers with n-hexane polyneuropathy after cessation of exposure. At the initial examination, the ENeG studies simulated a demyelinative process. Further slowing of nerve conduction velocity, or further decreasing of action potential amplitude, or both in the follow up ENeG study were found in about half the patients. The motor distal latency did not worsen. Nerve conduction returned to normal earlier in the sensory than in the motor nerves. After the patients had regained full motor capability, conduction velocities in motor nerves were still significantly slowed. These ENeG characteristics correlate with the pathological and pathophysiological changes in experimental hexa-carbon neuropathies. The initial findings from the EP studies indicated a conduction abnormality in the central nervous system (CNS). Delayed worsening occurred in the amplitude of visual EPs in three patients. On serial follow up, the interpeak latency and interpeak amplitude of visual EPs improved little. Residual abnormalities were also found in the interpeak latency of auditory EPs in the brainstem and in the absolute latency of scalp somatosensory EPs from the peroneal nerve. Astroglial proliferation in the CNS probably impedes recovery of the abnormalities in EP. [Chang YC; Br J Ind Med 48 (1): 12-7 (1991)]**PEER REVIEWED**
  
• CASE REPORTS: A 19-year-old man with an asymptomatic history of recreational gasoline vapor inhalation presented with subacute progressive quadriparesis. For 2 weeks, he had intensely inhaled Coleman fuel oil vapor, which contains n-hexane. Nerve conduction studies including near-nerve needle stimulation showed focal conduction block in the bilateral median and ulnar nerves. Sural nerve biopsy was consistent with giant axonal neuropathy. Conduction block as seen in this case has not heretofore been described in n-hexane polyneuropathy. [Chang AP et al; Muscle Nerve 21 (7): 964-9 (1998)]**PEER REVIEWED**
  
• CASE REPORTS: Somatosensory, brainstem auditory and pattern-reversal visual evoked potentials (SEP, BAEP and PVEP) were studied in 5 patients with n-hexane polyneuropathy to determine if the CNS was affected. In SEPs, the median central conduction (N13-to-N20) was normal but the tibial central conduction (N22-to-P40) was delayed. The central conduction time (I-to-V interval) of the BAEP was also prolonged. However, the P100 latency of the PVEP was normal. The present data indicate that the spinal cord and the brainstem are primarily affected in chronic n-hexane intoxication. [Huang CC, Chu NS; Clin Electroencephalogr 20 (3): 162-8 (1989)]**PEER REVIEWED**
  
• CASE REPORTS: 3 CASES OF N-HEXANE NEUROPATHY IN SHOE INDUSTRY WERE REPORTED. IN MOST SEVERE CASES SYMPTOMS CONSISTED OF DYSARTHRIA, DISPROPORTIONATE ATAXIA OF GAIT, BLURRED VISION, AND SOMETIMES AFTER RECOVERY OF PERIPHERAL NEUROPATHY, APPEARANCE OF LEG SPASTICITY. [RIZZUTO N ET AL; EUR NEUROL 19 (5): 308-15 (1980)]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: In a cross-sectional study, nerve conduction velocities were determined in 59 workers employed in press proofing factories in Taipei. Workers were divided into exposure categories on the basis of air concentration of n-hexane (>100 ppm, 50-99 ppm, <50 ppm), and n-hexane concentration in the cleaning solvent used (>50%, 49%-10%, <10%). Fifteen (25%) of the study group were found to have polyneuropathy. ... In one factory where all 6 employees developed polyneuropathy, the air concentration of n-hexane was 190 ppm. /In other factories/ workers exposed to n-hexane at levels less than 100 ppm showed a significant ... decrease in motor nerve conduction velocities ... possibly explained by the common practice of working overtime. [Wang J et al; Am J Ind Med 10: 111-18 (1986)]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: Kidney function was ... studied in a group of shoe workers exposed on a number of occcasions to >100 ppm hexane, a group of unexposed workers, and a group of historically exposed workers who had left the factory during the previous 5 yr. The mean total urinary protein was significantly higher in the exposed workers than in any control group. Some workers also experienced abnormally high urinary lyzozyme activity or increaed beta-glucuronidase activity. There were no effects on urinary albumin or serum creatinine levels. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 39]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• LABORATORY ANIMALS: Acute Exposure: Hexane is three times as acutely toxic to mice as is pentane; concentrations of 30,000 ppm produced... /CNS depression/ within 30-60 min, and convulsions and death resulted from inhalation of 34,000-42,000 ppm. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 1]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Epicutaneous administration of n-hexane to guinea pigs caused progressing nuclear pyknosis and junctional separation between the basement membrane and the basal cells of the skin. [Kronevi T et al; Environ Res 19 (1): 56-69 (1979) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: ...Sterologenesis was not inhibited in /isolated sciatic/ nerves of rats who had inhaled 1,000 ppm n-hexane for 6 hr. Incorporation of (14)C acetate into triacylglycerols of nerves from rats exposed to n-hexane was increased by 50%. [Gillies PJ et al; Toxicol Appl Pharmacol 54 (2): 217-22 (1980) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Dermal application of 2-5 ml/kg for 4 hr to rabbits resulted in ataxia and restlessness. No deaths occurred @ 2 ml/kg, but lethality was noted at 5 ml/kg. ... Intramuscular injection of hexane in rabbits causes edema and hemorrhaging of the lungs and tissues, with polymorphonuclear leukocytic reactions. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4 34]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: ... 0.2 ml of intratracheal n-hexane produces a fatal chemical pneumonitis in rats ... . [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. 965]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Phenobarbital pre-treatment induces 2- and 3-hydroxylation /of n-hexane/ six-fold; 3,4-benzopyrene suppresses 2- and stimulates 3-hydroxylation. [The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 4: A Review of the Literature Published during 1974 and 1975. London: The Chemical Society, 1977., p. 270]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Adult rats were exposed to hexane at different concn. Lung tissue was then examined. The direct toxic effect to pneumocytes could be demonstrated as definite regressive alterations, such as fatty degeneration and change of lamellar bodies of type II pneumocytes as well as incr detachment of cells. After chronic inhalation of solvents conspicuous aggregation of lamellar discharge material of type II pneumocytes can be seen, and probably, as a result of an irritated fat metab, large lysosome like bodies with densely packed lipid material in type I pneumocytes. [Schnoy N et al; Respiration 43 (3): 221-31 (1982) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: The activity of lactate dehydrogenase, beta-glucuronidase, glucose-6-phosphate dehydrogenase, acid and alkaline phosphatase was studied in lung homogenate from New Zealand rabbits exposed to 3000 ppm of hexane 8 hr/day for 8 days or filtered air. In hexane treated animals, all enzymes examined, except alkaline phosphatase, were markedly incr. High values in lung lysosomal enzymes from treated rabbits reflect the acute inflammation while the incr in lung glucose-6-phosphate dehydrogenase may depend upon reparative process subsequent to hexane-induced lung damage. [Barni-Comparini I et al; Agents Actions 12 (5): 737-42 (1982) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Male and female Fischer 344 rats were exposed to 0, 3000, 6500, or 10000 ppm n-hexane vapors 6 hr per day, 5 days per wk, for 13 wk. The mean body wt gain of male rats in the 10000 ppm group was significantly lower than for controls at 4 wk of exposure and thereafter. In addn to depression of body wt gain, the males exposed to 10000 ppm had slightly but significantly lower brain wt at necropsy. Axonopathy was observed in the tibial nerve in 4 of 5 male rats from the 10000 ppm group and one of five male rats in the 6500 ppm group and in the medulla from one male rat in the 10000 ppm group. These axonal changes were detectable only in teased nerve fiber preparations or in Epon embedded specimens. [Cavender FL et al; Fundam Appl Toxicol 4 (2 Pt 1): 191-201 (1984) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Subchronic exposure of rats for 14 wk resulted in nervous system type disease, including cerebral peripheral distal axonopathy. ... Subchronic exposure of pigeons to 3000 ppm 5 hr/day, for 82 days over 17 wk has shown no pathological nerve tissue alterations. However, exposure of rats to 400-600 ppm, 5 days/wk has resulted in peripheral neuropathy in 45 days. Exposure of rats to 850 ppm for 143 days showed loss in wt and degeneration of myelin and axis cylinders in the sciatic nerve. [Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 3187]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Rats orally admin > or = 650 mg/kg for 90 days or more showed axonal degeneration in peripheral nerve. ... /In another study/ neuropathy /was produced/ in 101 days after giving 3.98 g/kg, 5 days/wk. [Snyder, R. (ed.) Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume 1: Hydrocarbons. Amsterdam - New York - Oxford: Elsevier, 1987., p. 330]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: CD rats were exposed with 99% pure or technical grade /hexane/ by gavage for 17 weeks, or until hindlimb paralysis was observed. The treatment with 4,000 mg technical grade /hexane//kg BW caused severe hindlimb weakness or paralysis, tibial nerve lesions, and atrophy of testicular germinal epithelium. [Sheftel, V.O.; Indirect Food Additives and Polymers. Migration and Toxicology. Lewis Publishers, Boca Raton, FL. 2000., p. 740]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Wistar rats received 0.04-5.0 g commercial /hexane//kg BW for 13 weeks. An incr in relative kidney and liver weights was noted at 0.2-5.0 g/kg BW level. Changes in plasma enzymes, indicative of liver damage and elevated cholesterol and triglyceride levels were also observed. Histological exam revealed changes in the liver and kidneys, adrenals, peripheral nerves, spleen, testes, and thymus at the highest dose level tested. The NOAEL of 0.04 g technical grade /hexane//kg BW was established in this study. [Sheftel, V.O.; Indirect Food Additives and Polymers. Migration and Toxicology. Lewis Publishers, Boca Raton, FL. 2000., p. 740]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: ... n-hexane .../was/ administered i.p. (1 ml/kg body wt) ...in albino rats. After 1, 2, 7 and 45 days of treatment.../hepatic protein content decreased with n-heptane and total sulfhydryl content showed a significant decrease ... A significant increase in lipid peroxidation was observed after 24 h and 48 h exposure... A marked decrease in drug metabolizing activity and an increase in pentabarbitone sleeping time was also observed. Hepatic glucose-6-phosphatase, a microsomal marker enzyme, showed a significant decrease. [Goel SK et al; J Appl Toxicol 8 (2): 81-4 (1988) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: New Zealand rabbits were exposed in inhalation chambers to 3,000 ppm of n-hexane 8h/d for 8 d, and the acute respiratory effects were studied by light and electron microscopy. Animals intoxicated showed morphological changes in the lung parenchyma characterized by centriacinar emphysema and scattered micro haemorrhages. Lung damage was most severe at the transition zone from terminal bronchiole to alveolar ducts. This centriacinar lesion consisted to degenerative and necrotic phenomena in bronchiolar epithelium with cellular desquamation, increased number of macrophages within proximal alveoli of alveolar ducts, increased number and size of lamellar bodies in alveolar type II cells, changes in the vascular endothelium. Focal subpleural atelectasis, alveolar and interstitial oedema were also found. The segmental distribution of the pulmonary lesions were confirmed by transmission electron microscopy. [Lungarella G et al; Res Commun Chem Pathol Pharmacol 29 (1): 129-39 (1980) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Specimens from the left ventricular myocardium of 10 rats that had been exposed to subcutaneously administered hexane for 30 days were morphometrically and morphologically examined. Other than the presence of occasional necrotic fibers in hexane-treated animals, there was little difference in the histological appearance of myofibers in control or experimental specimens. There was a slight reduction in the average diameter of cardiac myofibers after exposure to hexane. Pathological ultrastructural changes of the myofibers were noted in the experimental and not in the control groups. Mitochondrial edema and necrosis and myofilament disorganization and dissolution were significant changes noted in the experimental group. These pathological changes suggest that hexane ... is cardiotoxic. [Maharaj B et al; Int J Exp Pathol 74 (2): 145-150 (1993) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Two kinds of nervous system-specific and muscle-specific proteins, enolase and S-100 protein, were quantitatively determined in peripheral nerves and skeletal muscles of rats ... exposed to ... n-hexane... vapor at three different solvent concentrations (500 ppm, 1200 ppm, 3000 ppm) for 12 h/day, 7 days/week for 16 weeks. The body weight gain and motor nerve conduction velocity (MCV) in exposure groups show progressively concentration-dependent decreases compared to control values. Histopathological examination also demonstrated the degeneration of peripheral nerves in 3000 ppm- and 1200 ppm-exposed rats. The significant decrease in the amount of S-100 protein in peripheral nerves was observed not only in the high level exposure groups (3000 ppm and 1200 ppm), but also in the lowest level group (500 ppm), although the MCV and morphological examination remained unchanged at this level. In addition, the muscle-specific S-100 protein in 3000 ppm exposed rats' soleus also displayed a significant reduction. In contrast to this, however, enolase isozymes were not significantly changed by either dosage level in both nervous tissue and skeletal muscle. The experiment suggests that beta- and alpha-S-100 proteins which are specifically localized in nervous system and muscles, respectively, are more vulnerable than enolase isozymes under treatment with n-hexane, and may possibly serve as a specific indicator to evaluate the neurotoxic effects... [Huang J et al; Arch Toxicol 63 (5): 381-5 (1989) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: .../Technical grade/ ...hexane (2,000 ppm) ...exposures for one to six months produced neurophysiologic effects in Wistar rats and retractions of the myelin nerve sheaths and in some instances rupture of Schwann cell membranes. [Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980., p. 469]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Male rats were exposed by inhalation to several concn of hexane, admin continuously or intermittently. The 5th component of the brainstem auditory-evoked response (BAER) incr in latency and decr in amplitude in rats exposed to 1000 ppm hexane 24 hr/day, 5 days/wk, for 11 wk, reflecting a brainstem dysfunction. Latency returned to normal within 5 wk after termination of exposures, but amplitude did not. Latency of the cmpd action potential of the ventral caudal nerve of the tail of these rats was also incr, and this effect was still present 22 wk after termination of the exposure. [Rebert CS et al; Neurobehav Toxicol Teratol 4 (1): 79-85 (1982) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: There was no evidence for any adverse effect among Wistar rats inhaling n-hexane 8 hours/day, 7 days/week for 40 weeks at 700 ppm. In contrast, nerve conduction velocity measures at 4,8,12,16,20, and 24 weeks in male Wistar rats inhaling n-hexane 12 hours/day at 200 or 500 ppm showed progressive degeneration; light microscopy confirmed myelin and axon degeneration. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 2]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: ...Mice /were exposed/ to commercial hexane (65-70% n-hexane) for 24 hr a day, six days a week for one year. Exposure levels ranged from 100 to 2,000 ppm. Atrophy and degeneration of hind leg muscle fibers was present in animals exposed to 1,000 and 2,000 ppm. ... [Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980., p. 469]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Inhalation of 100 ppm hexane by mice gave no evidence of peripheral polyneuropathy in 7 months; however, 250 ppm resulted in peripheral nerve injury. [Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980., p. 3187]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: New Zealand male rabbits were exposed in an inhalation chamber to 3,000 ppm of n-hexane 8 h/day, 5 days/week for 24 weeks, resulting in a total of 120 exposures. After a further 120 days in clean air, morphologic examination of lungs by light and transmission electron microscopy (TEM) revealed three important exposure-related lesions. These consisted of air space enlargement centered on respiratory bronchioles and alveolar ducts (centriacinar emphysema), scattered foci of pulmonary fibrosis, and papillary tumors of non-ciliated bronchiolar epithelial cells. At TEM examination these tumors were rather homogeneous and were found to consist of cells showing both small and large electron dense ovoid granules in their cytoplasmic matrix, a feature that has been described for Clara cells... [Lungarella G et al; Arch Toxicol 55 (4): 224-8 (1984) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: .../Commercial hexane solvent/ CHS consisted of 52.2% n-hexane (110543) and smaller amounts of methylcyclopentane (96377), pentane (109660), butane (106978), and other hexane isomers. Male and female Sprague-Dawley-rats were exposed continuously to 0, 900, 3,000, or 9,000 parts per million (ppm)CHS vapor through two generations of mating, gestation, and lactation starting 10 weeks before mating of the F0 generation. Body weight gains and mortality were recorded. The effects on reproductive parameters such as the number of impregnated females, gestation length, number of live F1 and F2 generation litters, number of live F1 and F2 pups per litter, and number of F1 and F2 pups surviving for 4, 7, 14, and 28 days were determined. Selected rats from each generation were necropsied. No clinical signs of toxicity were observed in any of the rats and no exposure related changes in any of the reproductive parameters were detected. Exposure to 9,000ppm CHS vapor significantly decreased body weight gains in F1 and F2 offspring. The other concentrations did not affect body weight. Hyaline droplet nephropathy in both generations of adult males exposed to 9,000 ppm CHS vapor was the only treatment related pathological lesion observed. The authors conclude that exposure of rats to CHS vapor over two generations causes decreased body weight gain at the high dose of 9,000 ppm but no adverse effects on reproduction. The hyaline droplet nephropathy seen in high dose males was expected as it has been observed in previous studies in which male rats were treated with a variety of chemicals. It is judged to be a phenomenon unique to male rats and not relevant for human risk assessment purposes... [Daughtrey WC et al; Journal of Applied Toxicology 14 (5): 387-393 (1994) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: The carcinogenic and chronic toxicity potential of commercial hexane solvent was evaluated in F-344 rats and B6C3F1 mice (50/sex/concentration/species) exposed by inhalation for 6 h/day, 5 days/week for 2 years. Target hexane vapor concentrations were 0, 900, 3000, and 9000 ppm. There were no significant differences in survivorship between control and hexane-exposed groups, and clinical observations were generally unremarkable. Small, but statistically significant decreases in body weight gain were seen in rats of both sexes in the mid- and high-exposure groups and in high-exposure female mice. The only noteworthy histopathological finding in rats was epithelial cell hyperplasia in the nasoturbinates and larynx of exposed groups. This response was judged to be indicative of upper respiratory tract tissue irritation. No significant differences in tumor incidence between control and hexane-exposed rats were found. In mice, uterine tissue from the high-exposure females exhibited a significant decrease in the severity of cystic endometrial hyperplasia compared to controls. An increase in the combined incidence of hepatocellular adenomas and carcinomas was observed in high-exposure female mice. The incidence of liver tumors was not increased in the mid- or low-exposure female mice or in male mice exposed to hexane. An increased incidence of pituitary adenomas was observed in female, but not male mice. This finding was not believed to have been treatment-related because the incidence in the control group was unusually low, and the incidence in exposed groups was not dose-related and was within the historical control range. No other neoplastic changes judged to be treatment-related were observed in tissues from male or female mice. In conclusion, chronic exposure to commercial hexane solvent at concentrations up to 9000 ppm was not carcinogenic to F-344 rats or to male B6C3F1 mice, but did result in an increased incidence of liver tumors in female mice. [Daughtrey W et al; Toxicol Sci 48 (1): 21-9 (1999) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: ... mice and rats /were treated/ with n-hexane and its principle toxic metabolite 2,5-hexanedione. The mice underwent a chronic treatment intraperitoneum, the rats were treated stereotaxically into the substantia nigra. At biochemical analysis of the striata, dopamine and homovanillic acid levels were significantly lower compared with control animals; norepinephrine, serotonin, 5-hydroxindolacetic acid levels were unchanged. The rats treated with 2,5-hexanedione showed an apomorphine-induced rotational behavior significantly higher compared to controls... [Pezzoli G et al; Brain Res 531 (1-2): 355-7 (1990) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Testicular and germ cell line morphology in rats were studied 2 weeks, 10 months and 14 months after cessation of a 61-day inhalation exposure to 1000 ppm n-hexane. Androgen biosynthetic capacity of testis, testosterone blood concentration, vas deferens morphology and noradrenaline (NA) concentration, epididymal sperm morphology, and fertility were also studied. Severe testicular atrophy involving the seminiferous tubules with loss of the nerve growth factor (NGF) immunoreactive germ cell line was found. Total loss of the germ cell line was found in a fraction of animals up to 14 months post-exposure, indicating permanent testicular damage. No impairment of androgen synthesis or androgen dependent accessory organs was observed. Simultaneous administration of 1000 ppm n-hexane and 1000 ppm toluene, or 1000 ppm n-hexane and 1000 ppm xylene, did not cause germ cell line alterations or testicular atrophy. Toluene and xylene were thus found to protect from n-hexane induced testicular atrophy. [Nylen P et al; Arch Toxicol 63 (4): 296-307 (1989)]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Testicular damage was induced in rats by respiratory treatment with n-hexane at a concentration of 5000 ppm. The earliest lesions were observed immediately after 24 hr of continuous treatment, and involved primary spermatocytes from the leptotene to the middle pachitene stages and spermatids at late stages of maturation; at the same time numerous exfoliated, injured germ cells reached the epididymis. After the 24-hr treatment was suspended, damage to the seminiferous epithelium increased for the first 7 days, while the epididymis showed also focal infiltration by inflammatory cells; recovery was completed from Days 14 to 30. Intermittent treatment (16 hr/day, 6 days/week) at the same concentration of 5000 ppm for up to 6 weeks induced progressive increases in testicular and epididymal lesions, which, after 5 weeks (when most animals began to show clinical symptoms of polyneuropathy), reached aplasia of the germinal epithelium involving also the spermatogonia. Recovery from clinical symptoms was not paralleled by a regression of testicular pathology. On the contrary, after interruption of the treatment, the testicular lesions became increasingly severe, up to complete atrophy of the seminiferous tubules, suggesting an irreversible sterility of the treated animals. Pair-fed controls did not show histological alterations of the testis or epididymis. [De Martino C et al; Exp Mol Pathol 46 (2): 199-216 (1987)]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Pregnant outbred albino mice (CD-1) received n-hexane once daily be gavage at doses up to 2.20 g/kg/day on days 6-15 of gestation. Other pregnant mice received higher hexane doses (up to 9.90 g/kg/day), employing a three times a day injection schedule. At the lower, once-daily doses only one dam died and no teratogenic effects occurred. Higher hexane doses (t.i.d.) were toxic: 2 of 25 dams treated with 2.83 g/kg/day, 3 of 34 treated with 7.92 g/kg/day and 5 of 33 treated with 9.90 g/kg/day died. At the 7.92 and 9.90 g/kg/day doses, the average fetal weight was significantly (p less than 0.05) reduced, but the incidence of malformations in treated and vehicle (cotton-seed oil) control groups did not differ significantly. Thus, n-hexane was not teratogenic even at doses toxic to the dam. [Marks TA et al; Drug Chem Toxicol 3 (4): 393-406 (1980)]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ...Severe testicular effects were seen after exposure with n-hexane in concentrations at 1000 ppm and above, if the daily or weekly exposure was long e.g. 16 h/d in 6 days or continual exposure. Even at the lowest concentration severe testicular atrophy has been described. A slight congestion of the testis was found in a single study with a concentration of 850 ppm 6 days/week for 20 weeks... In one study no effects on the androgen synthesis and accessory organs were found. Similar effects on the testes as found after n-Hexane exposure are seen after 2,5-hexanedione(the main metabolite)exposure in rats. In studies with 2,5-hexanedione, the effect on testes is found in subneurotoxic doses. The degree of intoxication and not the total dose had an influence on the testicular injury. Studies on pregnancy and lactation in rats and mice after inhalation or oral administration do not show an increased incidence of malformations. In some of the studies a higher incidence of minor anomalies such as misaligned sternebrae and reduction in fetal weight were seen. In one study in mice a statistically significant effect on early and late resorptions were seen. Most effects in these studies could be related to a toxic effect on the dams... [Hansen E; TA:KemI Report: 31-47 (1991)]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Timed pregnant Sprague-Dawley rats (25/group) and CD-1 mice (30/group) were exposed to commercial hexane (CH) vapor for six hours/day on gestational days (gd) 6 through 15 at target concentrations of 0, 900, 3000, or 9000 ppm. Maternal clinical signs, body weights, food and water consumption were measured. At scheduled sacrifice, maternal liver, kidney and gravid uterine weight were taken. Ovarian corpora lutea of pregnancy were counted and all uterine implantation sites were identified. All live fetuses were examined externally and approximately 50% per litter were examined for craniofacial or skeletal malformations and variations. Maternal toxicity observed in rats at 9000 ppm included a significant reduction in body weight gain and food consumption. At 9000 ppm rats and mice exhibited treatment-related color changes in the lung at necropsy. Gestational parameters including number of viable and non-viable implantations per litter and sex ratio were unaffected by CH exposure for both species. Rat and mouse fetal body weights per litter were equivalent across exposure groups. There were no treatment-related increases in the incidence of individual external, visceral or skeletal malformations and variations at any exposure level for rats. There were treatment-related increases in the incidence of two minor individual skeletal variations at 9000 ppm for mice. In conclusion, exposure to CH vapor during organogenesis in rats resulted in maternal toxicity at 9000 ppm with no apparent developmental toxicity at any exposure level. Exposure to CH vapor during organogenesis in mice resulted in maternal effects at 9000 ppm accompanied by slight developmental toxicity in the absence of malformations at 9000 ppm. [Keenan T et al; Toxicologist 11 (1): 315 (1991)]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Pregnant Fischer 344 rats were exposed for 6 hr/day to 1,000 ppm n-hexane on days 8-12, 12-16 or 8-16 of gestation. Postnatal growth of pups born to dams exposed to 1,000 ppm on days 8-16 of gestation was significantly depressed compared to controls. [Bus JS et al; Toxicol Appl Pharmacol 51 (2): 295-302 (1979) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Agents reported to affect male reproductive capacity: hexane. /From table/ [Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986., p. 454]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Agents reported to affect female reproductive capacity: hexane. /From table/ [Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986., p. 455]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Exposure to high concns (1,000-5,000 ppm) caused progressive testicular toxicity. [Sheftel, V.O.; Indirect Food Additives and Polymers. Migration and Toxicology. Lewis Publishers, Boca Raton, FL. 2000., p. 740]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Definite reductions in peripheral nerve conduction velocity that occurred in male and female baboons given daily oral doses of n-hexane at 0.13 mg/kg/day comfirm the neurotoxicity of the 2,5-hexanedione and its potentiation of n-hexane axonopathy. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 2]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: When Fisher rats inhaled 1000 ppm n-hexane continuously for three weeks, the animals lost 25% of their body weight. By week 11, the animals developed hindlimb paralysis with clear histological evidence of peripheral nerve degeneration. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 1]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Studies in animals show the following decreasing order of neurotoxic potency: 2,5-hexanedione, /methyl n-butyl ketone (MBK)/, 2-hexanol, and n-hexane. ... The pronounced giant anoxal swelling of hexacarbon neuropathy is unique ... Swelling occurs initially in the proximal sides of the nodes of Ranvier in the distal portions of the nerve fiber and then progresses proximally. Nerve fibers may degenerate distal to the swellings, or secondary demyelination may occur distally. Myelin sheaths are inappropriately thin for their axon diameter. Long, distal nerve sections are the most vulnerable. The abnormally large fibers with swollen axons display abnormal accumulations of 10-nm neurofilaments that are involved in rapid protein transport. Studies in cats indicate widespread axonal degeneration in the mammillary body, lateral geniculate nucleus, and superior colliculus in experimental n-hexane neurotoxicity. Greater changes in the peripheral nervous system probably reflect the differential vulnerabilities of the shorter and smaller central nervous system fiber tracts. Prolonged low-level exposure may cause premature deterioration of central nervous system areas responsible for visual perception and behavior. [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. 965]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Rats intoxicated with pure n-hexane ... by inhalation (400-600 ppm) developed clinical signs after forty-five days and displayed giant axonal swellings and fibre degeneration both in the central and peripheral nervous systems. The changes were most striking in tibial nerves supplying calf muscles and in selected areas of the cerebellum, medulla and spinal cord. In contrast to the usual picture associated with dying-back disease, the distal regions of proximal nerve fibres supplying calf muscles degenerated before equivalent regions of longer fibres supplying the hindfeet... [Schaumburg HH, Spencer PS; Brain 99 (2): 183-92 (1976) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: After long-term n-hexane exposure (2000 ppm, 12 h, d-1, 6 d week-1, for 24 weeks) /of rats/, the content of neuron-specific enolase (gamma-enolase), creatine kinase-B and beta-S100 protein ... decreased significantly in the distal segment of sciatic nerve, whereas they remained unchanged in the brain and proximal sciatic nerve. The quantitative decline in these marker proteins in the distal sciatic nerve could be related to neurophysiological deficits in the peripheral nerves...The biochemical changes observed are consistent with the clinical and pathological findings of n-hexane neuropathy. These nerve-specific marker proteins can be used to assess solvent-related peripheral neurotoxicity. [Huang J et al; Hum Exp Toxicol 11 (5): 323-7 (1992) ]**PEER REVIEWED**
  
• GENOTOXICITY: Hexane was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology program (NTP). Hexane was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S9, at doses of 0.001, 0.0033, 0.010, 0.033, 0.100, and 0.333 mg/plate. The highest negative dose tested in any Salmonella typhimurium strain was 0.333 mg/plate. Some cultures exhibited slight clearing of the background bacterial lawn at the two highest doses tested. [Mortelmans K et al; Environ Mutagen 8:1-119 (1986)]**PEER REVIEWED**
  
• GENOTOXICITY: Hexane was positive for the induction of sister-chromatid exchanges in cultured Chinese hamster ovary cells; /n-hexane/ was negative for the induction of chromosomal aberrations in the Chinese hamster ovaries assay and in the Salmonella assay. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 2]**PEER REVIEWED**
  
• ALTERNATIVE IN VITRO TESTS: In vitro toxicity of n-hexane using isolated perfused rabbit heart is reported. The force of cardiac contraction was significantly reduced following 1 hr perfusion with 9.6 mg/l n-hexane. [Raje RR; J Toxicol Environ Health 11 (4-6): 879-84 (1983) ]**PEER REVIEWED**
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• LD50 Rat (14-day-old) oral 24.0 mgl/kg bw [Kimura ET et al; Tox Appl Pharm 19: 699-704 (1971) ]**PEER REVIEWED**
  
• LD50 Rat adult oral 45 ml/kg [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-150]**PEER REVIEWED**
  
• LC50 Rat inhalation 48000 ppm/< 4 hr [Snyder, R. (ed.) Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume 1: Hydrocarbons. Amsterdam - New York - Oxford: Elsevier, 1987., p. 330]**PEER REVIEWED**
  
• LD50 Rat (young adult) oral 49.0 mg/kg bw [Kimura ET et al; Tox Appl Pharm 19: 699-704 (1971) ]**PEER REVIEWED**
  
• LD50 Rat (older adult) oral 43.5 mg/kg [Kimura ET et al; Tox Appl Pharm 19: 699-704 (1971) ]**PEER REVIEWED**
  
• LC50 Mouse inhalation 48000 ppm/4 hr [O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 837]**PEER REVIEWED**
  
• LD50 Rat oral 28,710 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 1800]**PEER REVIEWED**
  

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Absorption, Distribution and Excretion

• Hexane is absorbed through the lungs and relatively poorly absorbed through the intact skin. [Rom, W.N. (ed.). Environmental and Occupational Medicine. 2nd ed. Boston, MA: Little, Brown and Company, 1992., p. 566]**PEER REVIEWED**
  
• Accumulation in the tissues depends on lipid content in these tissues. n-/Hexane/ is oxidized in the liver. Excretion occurs via the lungs and kidneys. ... Excretion of /hexane/ is related to dose injected. [Sheftel, V.O.; Indirect Food Additives and Polymers. Migration and Toxicology. Lewis Publishers, Boca Raton, FL. 2000., p. 740]**PEER REVIEWED**
  
• The pharmacokinetics of inhaled n-hexane in rat and man were compared. In the rat metabolism was saturable. Up to 300 ppm, the metabolic rate was directly proportional to the concentration in the atmosphere, reaching 47 mumol/(h X kg). Only 17% of n-hexane was exhaled unchanged. Above 300 ppm, the amount of n-hexane in the body rose with increasing atmospheric concentrations from 1.6 up to a limiting value of 9.6, which corresponded to the thermodynamic distribution coefficient of n-hexane between the organism and the atmosphere. Up to 3000 ppm, the rate of metabolism increased to 245 mumol/(h X kg); only a slow further increase was found up to 7000 ppm (285 mumol/(h X kg]. In man the steady-state concentrations of n-hexane were about 1 ppm. The metabolic clearance was 132 1/h, and n-hexane accumulated to a factor of 2.3 in the organism. The thermodynamic distribution coefficient was calculated to be 12. Twenty per cent of n-hexane in the body was exhaled unchanged. At low concentrations the rate of metabolism of n-hexane is limited in both species by transport to the enzyme system. Under these conditions the rate of metabolism of n-hexane should not be influenced by xenobiotics which induce the n-hexane metabolizing enzyme system. [Filser JG et al; Arch Toxicol 60 (1-3): 77-80 (1987)]**PEER REVIEWED**
  
• ... Male Fischer 344 rats were exposed to 500, 1000, 3000 or 10,000 ppm 14C-n-hexane for 6 hr and the elimination of radioactivity followed for 72 hr after exposure. The disposition of radioactivity was dose-dependent, with 12, 24, 38 and 62% of the acquired body burden excreted as n-hexane by the lung with increasing exposure concentration. In contrast, 38, 31, 27 and 18% of the body burden of radioactivity was recovered as expired 14CO2 and 35, 40, 31 and 18% was recovered in the urine with increasing n-hexane concentration. Radioactivity remaining in the tissues and carcass 72 hr after exposure represented 6.1, 8.8, 7.4 and 5.4% of the body burden for the respective exposures. The dose-dependent elimination of radioactivity was apparently due in part to an inhibition of n-hexane metabolism, reflected by a decrease in total 14CO2 and urinary 14C excretion after 10,000 ppm exposure compared to the 3000 ppm exposure. [Bus JS, Deyo D, Cox M; Fundam Appl Toxicol 2 (5): 226-9 (1982)]**PEER REVIEWED**
  
• ... Many studies have shown that n-hexane can readily be absorbed following inhalation of n-hexane vapours and ingestion of n-hexane. Following absorption n-hexane is widely distributed throughout the body, and the highest concentrations are achieved in those tissues having the highest lipid contents, blood being the only exception. In pregnant rats the same levels of n-hexane are found in the fetal tissue as in the maternal blood... [Hansen E; TA:KemI Report: 31-47 (1991)]**PEER REVIEWED**
  
• Lung uptake and excretion of n-hexane were studied in ten workers in a shoe factory. ... According to the experimental data, alveolar retention was about 25% of the inhaled n-hexane, corresponding to a lung uptake of about 17%. The postexposure alveolar excretion was about 10% of the total uptake... [Mutti A et al; Br J Ind Med 41 (4): 533-8 (1984)]**PEER REVIEWED**
  

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Metabolism/Metabolites

• The major urinary metabolite in rat is l-hexanol. [Sheftel, V.O.; Indirect Food Additives and Polymers. Migration and Toxicology. Lewis Publishers, Boca Raton, FL. 2000., p. 740]**PEER REVIEWED**
  
• ...2,5-Hexanedione is principal metabolite of this and other 6-carbon compounds... . [Schaumburg HH, Spencer PS; Ann NY Acad Sci 329 (Public Control Environ Health Hazards): 14-29 (1979) ]**PEER REVIEWED**
  
• 2,5-hexanedione /the principal metabolite of n-hexane/ causes peripheral neuropathy characterized by muscle weakness and wasting, diminished deep tendon reflexes, decreased nerve conduction and paresthesias. [Ford MD, Delaney KA, Ling LJ, Erickson T; Clinical Toxicology. W.B. Saunders Company., Philadelphia, PA. 2001, p. 652]**PEER REVIEWED**
  
• 1. The in vitro metabolism of n-hexane was studied in rat liver, lung, brain and skeletal muscle microsomes and in microsomes prepared from cell lines expressing human cytochrome P-450 2E1 or 2B6. The hydroxylated metabolites of n-hexane were quantified by gas chromatography-mass spectometry. 2. Rat liver and extensor digitorum longus (EDL, fast-twitch skeletal muscle) microsomes and the CYP 2B6 microsomes produced the pre-neurotoxic metabolite of n-hexane, 2-hexanol as a major metabolite in contrast to the other rat tissues examined. 3. Inhibition of 2- and 3-hexanol production from n-hexane by rat lung microsomes using metyrapone, an inhibitor of cytochrome P-450 2B1 activity, resulted in almost complete inhibition of lung microsomal activity. 4. Production of all three hexanols was significantly increased with phenobarbital-induced rat liver microsomes, with a 10-fold increase in 2- and 3-hexanol production. A slight increase in 2-hexanol production with phenobarbital-induced rat EDL and brain microsomes was observed. No increase in n-hexane metabolism was noted following induction with beta-naphthoflavone or with ethanol. [Crosbie SJ et al; Hum Exp Toxicol 16 (3): 131-7 (1997)]**PEER REVIEWED**
  
• The main metabolites of n-hexane were identified and measured by capillary GC/MS in spot urine samples collected before, at the end, and 15 hours after the same working shift /in ten shoe factory workers/. Urinary concentrations were low, though related to n-hexane in the air. 2,5-Hexanedione in the end of shift samples gave the best estimate of overall exposure. About 3 mg/g creatinine of 2,5-hexanedione would correspond to about 50 ppm of n-hexane in the air (mean daily exposure). [Mutti A et al; Br J Ind Med 41 (4): 533-8 (1984)]**PEER REVIEWED**
  
• n-Hexane is metabolised and the main metabolite is 2,5-hexanedione both in humans and in experimental animals. In one experiment the proportionally highest concentration of metabolites was found at the lowest dose levels... [Hansen E; TA:KemI Report: 31-47 (1991)]**PEER REVIEWED**
  

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TSCA Test Submissions

• Chronic toxicity was evaluated in male and female Sprague Dawley rats (6/sex/group) exposed to n-hexane via inhalation at 0, 6, 26 and 129 ppm for 6 hrs/day, 5 days/week for 6 months. There were significant differences between treated and control animals in the following: body weights (increased for males at 26 ppm), hemoglobin levels (decreased in all treated females), hematocrit levels (in females, decreased at 6 and 26 ppm, increased at 129 ppm), erythrocyte counts (decreased in all treated females at 3 months), clotting time (increased for females at 6 ppm at 3 months), and mean fasting glucose levels (increased in males at 129 ppm). All but the first and last observations appeared to be within normal biological limits and some were noted only at 3 months, suggesting that the effects were not treatment related.[Bio/dynamics, Inc.; 26 Week Inhalation Toxicity Study of n-Hexane in the Rat. (1978), EPA Document No. FYI-AX-1081-0137, Fiche No. 0137-0 ]**UNREVIEWED**
  
• Chronic toxicity was evaluated in male and female Sprague Dawley rats (6/sex/group) exposed to n-hexane via inhalation at 0, 5, 27 and 126 ppm for 21 hrs/day, 7 days/week for 6 months. There were significant differences between treated and control animals in the following: hematocrit levels (increased in females at 126 ppm), blood urea nitrogen (decreased in females at 126 ppm). There were no significant differences between treated and control animals in mortality or body weight.[Bio Dynamics, Inc.; 26 Week Inhalation Toxicity Study of n-Hexane in the Rat. (1978), EPA Document No. FYI-AX-1081-0137, Fiche No. 0137-0 ]**UNREVIEWED**
  
• Chronic toxicity was evaluated in male Sprague Dawley rats exposed to n-hexane via inhalation at 0 (24 rats), 125 (14 rats) or 500 ppm (34 rats) for approximately 22 hrs/day, 7 days/week for 6 months. There were significant differences between treated and control animals in the following: body weights (decreased at 125 and 500 ppm at weeks 13 and 11, respectively, and after), absolute and relative kidney weights and relative lung weights (increased at 500 ppm), relative spleen and brain weights (decreased at 125 ppm), relative lung weights (decreased at 500 ppm), axonal degeneration, myelin vacuolation and muscle atrophy (at 500 ppm), and microscopic renal changes including tubular epithelial desquamation, caste formation (degeneration), cytoplasmic basophilia, and decreased tubular diameter (regeneration) (at 500 ppm).[International Research and Development Corp.; Six Month Continuous Inhalation Exposures of Rats to Hexane Mixtures - Phase I. (1983), EPA Document No. FYI-AX-0282-0166, Fiche No. 0166-2 ]**UNREVIEWED**
  
• Chronic toxicity was evaluated in male Sprague Dawley rats (10/group) exposed to n-hexane via inhalation at 0 or 500 ppm for approximately 22 hrs/day, 7 days/week for 6 months. There were significant differences between treated and control animals in the following: decreased absolute body, spleen, liver, heart, and brain weights; increased relative kidney, lung/trachea, testes, brain, and adrenal gland weights, neuronal atrophy and degeneration with secondary skeletal muscle atrophy, chronic nephritis, and peripheral nerve lesions. There were no differences between treated and control animals in mortality.[International Research and Development Corp.; Six Month Continuous Inhalation Exposures of Rats to Hexane Mixtures - Phase II. (1983), EPA Document No. FYI-AX-0282-0166, Fiche No. 0166-2 ]**UNREVIEWED**
  
• The mutagenicity of n-hexane was evaluated in Salmonella tester strains TA98, TA100, TA1535, TA1537 and TA1538, both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on preliminary bacterial toxicity determinations, n-hexane, diluted with 95% ethanol for strain TA1537 and with DMSO for the rest of the strains, was tested for mutagenicity at concentrations ranging from 194 - 33,000 ug/plate using the plate incorporation method. n-Hexane caused a reproducible increase in revertants in tester strain TA100 at all doses tested without activation. No dose-related effect was observed. n-Hexane did not cause a positive response in any of the other bacterial tester strains, either with or without metabolic activation.[Hazelton Laboratories America, Inc.; In Vitro and In Vivo Mutagenicity Studies, Hexane, Final Report Draft. (1979), EPA Document No. FYI-OTS-0381-0106, Fiche No. OTS0000106-0 ]**UNREVIEWED**
  
• The ability of n-hexane to induce specific locus mutations at the TK locus in cultured L5178Y mouse lymphoma cells (Mouse Lymphoma Mutagenesis Assay) was evaluated in the presence and absence of Aroclor-induced rat liver S9 metabolic activation. Based on preliminary toxicity tests, 8 nonactivated cultures were treated with 80, 90, 100, 110, 120, 130, 140, or 150 ug/ml which produced a range of 0 - 140% total growth. Eight activated cultures were treated with 40, 60, 80, 100, 120, 140, 160, or 180 ug/ml which produced a range of 0 - 22% total growth. None of the nonactivated or activated cultures produced mutant frequencies significantly greater than the solvent controls.[Hazelton Laboratories America, Inc.; In Vivo and In Vitro Mutagenicity Studies, N-Hexane (Hexane UV), Final Report. (1980), EPA Document No. FYI-OTS-0381-0106, Fiche No. OTS0000106-0 ]**UNREVIEWED**
  
• The mutagenicity of n-hexane was evaluated in a dominant lethal assay using 3 groups of 12 male CD-1 mice receiving whole body exposures to nominal concentrations of 0, 100 or 400 ppm for 6 hrs/day, 5 days/week for 8 weeks. Following exposure, each male was mated for 5 days/week with 2 untreated females/week for 2 consecutive weeks. A small but statistically significant increase was observed in the fertility index of females mated to the high-dose group males in week two. A significant reduction in the average resorptions/pregnant female was observed for females mated to high-dose group males in week one. There were no differences between females mated to treated and control males with respect to average number of implantations/pregnant female, proportions of females with one or more resorptions, and proportions of females with two or more resorptions.[Litton Bionetics, Inc.; Mutagenicity Evaluation of n-Hexane in the Mouse Dominant Lethal Assay, Final Report. (1980), EPA Document No. FYI-AX-1081-0137, Fiche No. OTS0000137-0 ]**UNREVIEWED**
  
• The ability of n-hexane to cause chromosome aberrations was evaluated in the bone marrow cells of male Sprague-Dawley CD albino rats (5/group) exposed by inhalation to nominal concentrations of 0, 150, 300 or 600 ppm for 6 hrs/day, for 5 consecutive days. The rats were sacrificed on the day following the last administration of test substance and 50 cells/animal were scored for chromosome aberrations. All treated animals exhibited altered breathing and behavioral patterns following exposure to all test doses of n-hexane. There was a significant increase in frequency of chromosomal aberrations in the bone marrow cells of treated animals relative to controls including percent aberrant cells, and average aberrations/cell. Aberrations/cell were increased 3.3, 6.3, and 4.9 fold for the low-, mid-, and high-dose groups, respectively. The aberrations consisted mainly of chromatid breaks and markers, primarily fragments and dicentrics.[Hazelton Laboratories America Inc.; In Vivo and In Vitro Mutagenicity Studies, n-Hexane (Hexane UV), Final Report. (1980), EPA Document No. FYI-OTS-0381-0106, Fiche No. OTS0000106-0 ]**UNREVIEWED**
  
• The ability of n-hexane to cause chromosome aberrations was evaluated in the bone marrow cells of male Sprague-Dawley CD albino rats (5/group) exposed by inhalation to nominal concentrations of 0, 100 or 400 ppm for 6 hrs/day, for 5 days/week for 4 weeks for the control and low-dose groups, and for 1 week for the high-dose group. The rats were sacrificed on the day following the last administration of test substance and 50 cells/animal were scored for chromosome aberrations. Significant increases in treated animals relative to controls was observed in the percent total aberrations and percents of marker-type aberrations. There were no significant differences observed between treated and control animal body weights and mitotic indices.[Hazelton Laboratories America Inc.; In Vitro and In Vivo Mutagenicity Studies, Hexane, Final Report. (1980), EPA Document No. FYI-OTS-0381-0106, Fiche No. OTS0000106-0 ]**UNREVIEWED**
  
• N-Hexane was administered to three groups of twenty pregnant [CRL:COBS CD (SD) BR] rats via inhalation at target concentrations of 0, 100, and 400 ppm (actual concentrations were 0+/-0, 93.4+/-17.1, and 408+/-21.5 ppm) on gestational days 6 - 15 (6 hours/day). Body weight, food consumption, and general behavior and appearance were recorded during the exposure period. There were no compound-related deaths and all dams had a normal appearance throughout the study. There were no significant differences between controls and treated animals' mean body weights or food consumption. Necropsy of the dams (day 20 of gestation) revealed enlarged salivary glands in 1 control animal and 2 animals from each of the low- and high-dose groups but was not believed to be compound related. Examination of the fetuses for changes in soft tissues revealed no significant differences between controls and treated groups and the sex ratio was also comparable. Skeletal abnormalities related to delayed bone ossification were seen in both control and treated groups. The study authors concluded that inhalation exposure to n-hexane during gestation did not result in compound-related health effects on dams and that there was no evidence of embryo toxicity or effects on fetal growth and development[Litton Bionetics, Inc; Teratology Study in Rats, n-Hexane: Final Report (01/01/79); EPA Document No. FYI-AX-0183-0231; OTS0000231-0]**UNREVIEWED**
  
• A commercial hexane was administered by whole-body inhalation exposure to groups of male and female Charles River CD rats at target concentrations of 0, 100, 500, and 1500 ppm. In addition, males and females which were to be bred to untreated animals, were exposed to 1500 ppm commercial hexane. Exposures for both sexes took place during a 100 day pre-mating period and a 15-day mating period for 6 hours/day, 7 days/week. Treatment continued (6 hours/day, 7 days/week) for mated females (but not males) during gestational days 1-20 and days 5-20 of lactation. One death, believed to be not treatment-related, occurred among the F0 females during the third week of gestation; no other F0 deaths were reported. There were no significant differences in behavior or appearance between treated and control animals. There were no biologically significant differences from controls in mean weekly body weights for males or female food consumption. Maternal body weight changes were comparable, overall, to controls and any noted differences were not dose related. The body weights of F1 pups were reduced for most treated groups compared to controls. However, analysis showed no dose-relationship. There were no treatment-related effects on male or female fertility indices, and no microscopic, macroscopic, or organ weight changes were noted in any animals necropsied during the course of the study. The no observable effect level for this study was determined to be 1500 ppm.[International Research and Development Corp.; Single Generation Inhalation Reproduction/Fertility Study on Commercial Hexane (09/01/86); EPA Document No. FYI-AX-1086-0459; OTS0000459-1]**UNREVIEWED**
  
• N-Hexane was evaluated for reproductive and developmental effects in timed-pregnant (33/group) and virgin (10/group) Swiss (CD-1) mice exposed by inhalation at target concentrations of 0, 200, 1000, and 5000 ppm for 20 hours/day, 12 consecutive days. Confirmed-pregnant females were also exposed on days 6-17 of gestation. Mean body weight at sacrifice and mean body weight gain for pregnant mice in the 5000 ppm exposure group were significantly reduced compared to controls. Mean gravid uterine weight was also significantly less than controls for females in the 5000 ppm and 200 ppm groups. The number of live implants was reduced for all exposure groups, but the difference was statistically significant for only the 5000 ppm group. The percent incidence of late resorptions was significantly greater than controls in the 5000 ppm group and correlated positively with exposure concentration; however, an increase in the incidence of total resorptions was greater in both the 200 ppm and 5000 ppm groups. A decrease in female mean fetal weight correlated with increasing exposure concentration. There was no evidence of compound-related effects on placental weight at any exposure. There were no statistically significant treatment-related increases in fetal developmental variations.[Pacific Northwest Laboratory; Inhalation Developmental Toxicology Studies: Teratology Study of n-Hexane in Mice (05/1988); EPA Document No. FYI-OTS-0888-0633; OTS0000633]**UNREVIEWED**
  
• n-Hexane, either alone or mixed with C6 isomers, was evaluated for chronic toxicity by inhalation exposure (whole-body)in groups of male Charles River CD rats. Exposure duration was 22 hours/7 days/week for 6 months. Total hexane target concentrations were 0 ppm n-hexane/0 ppm mixed hexane (Group I), 125 ppm n-hexane (Group II), 125 ppm n-hexane/125 ppm mixed hexane (Group III), 125 ppm n-hexane/375 ppm mixed hexane (Group IV), 125 ppm n-hexane/1375 ppm mixed hexane (Group V), and 500 ppm n-hexane (Group VI). One mortality occurred in week 22 from Group III (cause undetermined). General appearance and behavior of animals in Groups II-V were comparable to controls. Abnormal gait was observed in animals from Group VI, increasing in severity and incidence from week 14. Comparison and interpretation of average body weight data was ambiguous due to the unusual growth pattern exhibited by the control group. The average body weight gain of control animals was lower than exposed animals during the first week of exposure, and seemed plateau at week 11, remaining consistently lower than Groups II, III, and IV. Average body weights of animals exposed to 500 ppm (Group VI) were significantly less than controls at the end of 3 weeks and remained lower (although not always significantly lower) until the end of the study. Mean absolute and relative liver weights were significantly lower than controls for Groups V and VI. Groups IV, V, and VI showed significantly lower mean absolute relative kidney weights when compared to control Group I. At necropsy, discoloration of the liver was seen in animals from Groups II, III, V, and VI, and hepatic necrosis was observed during microscopic examination. Evidence of renal degeneration and regeneration was observed in animals exposed to 500 ppm n-hexane and 125 ppm n-hexane/375 and 1375 ppm mixed hexane (Groups IV, V, and VI). Axonal degeneration, myelin vacuolation, and skeletal muscle atrophy was observed in animals receiving 500 ppm n-hexane only (Group VI). No neuropathic or myopathic changes were seen in Groups II, III, IV, or V.[International Research & Development Corp.; Six Month Continuous Inhalation Exposures of Rats to Hexane Mixtures - Phase I (10/12/83); EPA Document No. FYI-AX-1083-0166; OTS0000166-2]**UNREVIEWED**
  
• Commercial hexane (mean percent composition = 51.5% n-hexane, 16.0% methylcyclopentane, 16.1% 3-methylcyclopentane, 12.9% 2-methylcyclopentane, 3.3% cyclohexane, and 0.17% 2,4-dimethylpentane) was evaluated for carcinogenic potential in B6C3F1 mice by whole-body inhalation. Fifty mice/sex/group were exposed to target concentrations of 0, 900, 3000, and 9000 ppm for 6 hours/day, 5 days/week, for approximately 2 years. Survival of exposed animals did not differ significantly from controls. There were no clinical, ophthalmic, or hematologic effects observed that were related to exposure. In male mice, mean body weights and body weight gain were comparable to controls, although animals in the 9000 ppm group had a lower food consumption rate. Females in the 9000 ppm group had significantly lower mean body weight and body weight gain than controls as well as lower food consumption, especially in the beginning of the study. An increase in the number of hepatocellular adenomas and carcinomas was observed in females from the high-exposure group. A similar change was not seen in males from any exposure group. Females in the 9000 ppm group also showed a decrease in the severity and incidence of cystic endometrial hyperplasia of the uterus. Females from all exposure groups showed an increase in the incidence of pituitary proliferative changes, but there was no exposure-related response. The NOEL for neoplastic changes was 3000 ppm.[Bio/Dynamics Inc.; An Inhalation Oncogenicity Study of Commercial Hexane in Rats and Mice, Part II - Mice (06/01/93); EPA Document No. 88-930000110; OTS0537874]**UNREVIEWED**
  
• Commercial hexane (mean percent composition = 51.5% n-hexane, 16.0% methylcyclopentane, 16.1% 3-methylcyclopentane, 12.9% 2-methylcyclopentane, 3.3% cyclohexane, and 0.17% 2,4-dimethylpentane) was evaluated for carcingenicity in Fischer 344 rats by whole-body inhalation. at target concentrations of 0, 900, 3000, and 9000 ppm (measured mean concentrations were 0, 900, 3000, and 9016 ppm) for 6 hours/day, 5 days/week, for approximately 2 years. Survival of exposed animals did not differ significantly from controls (67% for control males, 76% for control females). There were no clinical, ophthalmic, or hematologic effects observed that were related to exposure, except that males exposed to 900 and 9016 ppm exhibited excess lacrimation. Mean body weights and body weight gains were significantly reduced in males and females receiving 3000 and 9016 ppm commercial hexane. Food consumption was also reduced, but not in a dose-related manner. Hyperplasia of the respiratory epithelium and hypertrophy/hyperplasia of goblet cells was observed in males and females exposed to 9016 ppm and 3000 ppm, with greater severity in the high exposure group. The exposures did not produce an carcinogenic effect.[Bio/Dynamics Inc.; An Inhalation Oncogenicity Study of Commercial Hexane in Rats and Mice, Part I - Rats (04/16/93); EPA Document No. 42084 L5-2; OTS0572989]**UNREVIEWED**
  
• The metabolism and distribution of commercial hexane containing [14C]n-hexane(mean percent composition = 51.5% n-hexane, 16.0% methylcyclopentane, 16.1% 3-methylcyclopentane, 12.9% 2-methylcyclopentane, 3.3% cyclohexane, and 0.17% 2,4-dimethylpentane) was evaluated in male and female F-344 rats. Groups of 4 males and 4 females received 1.2 mg/cm2 of the compound applied to clipped, unabraided skin by a syringe equipped with a blunt needle through a Teflon-faced septum seal of a specially designed apparatus providing complete occlusion of the site. The apparatus was left in place for 6 hours during which time each animal was housed in a metabolism cage. After 6 hours, the air was flushed and collected from the metabolism cages. The residual dose was collected from the interior of the apparatus, the apparatus removed and the exposed skin was gently scrubbed to recover as much of the unabsorbed dose as possible. The animals were returned to the metabolism cages for continued collection of excreta. Animals were sacrificed at the end of 24 hours. Exhaled air was collected by passing air from each metabolism cage through a series of solvent filters. Exhaled volatiles were collected from the filters at the end of 0, 3, 6, and 24 hours. Radio-labeled CO2 was collected at the end of 0, 6, and 24 hours after dosing. Feces and urine were collected at 24 hours. Total recovery of radio-labeled dose was low for both males and females: 89% and 86%, respectively. Male rats exhaled an average of 65% of the applied dose as volatiles and 3% as radio-labeled CO2, while 2.3% of the dose was excreted in the urine. Females exhaled an average of 61% of the applied dose as volatiles, 3% as radio-labeled CO2, and 1.5% excreted in the urine. Excretion in the feces accounted for less than 1% and the residual dose recovered from the apparatus and skin washing averaged 8.25% for both males and females. Overall retention of radiolabel in the tissues, including carcass, skin dose site, and gastrointestinal tract, was minimal for both sexes: 0.4% for males, 0.3% for females. [Research Triangle Inst.; Final Report: Volume 1 of 4, Disposition and Pharmacokinetics of Commercial Hexane Following IV Bolus, Dermal Absorption, or Nose-Only Inhalation (08/11/92); EPA Document No. 40-9289454; OTS0558678 ]**UNREVIEWED**
  
• The metabolism and distribution of commercial hexane containing [14C]n-hexane(mean percent composition = 51.5% n-hexane, 16.0% methylcyclopentane, 16.1% 3-methylcyclopentane, 12.9% 2-methylcyclopentane, 3.3% cyclohexane, and 0.17% 2,4-dimethylpentane) was evaluated in male and female F-344 rats. Groups of 4 males and 4 females received 11 mg/cm2 of the compound applied to clipped, unabraided skin by a syringe equipped with a blunt needle through a Teflon-faced septum seal of a specially designed apparatus providing complete occlusion of the site. The apparatus was left in place for 6 hours during which time each animal was housed in a metabolism cage. After 6 hours, the air was flushed and collected from the metabolism cages. The residual dose was collected from the interior of the apparatus, the apparatus removed and the exposed skin was gently scrubbed to recover as much of the unabsorbed dose as possible. The animals were returned to the metabolism cages for continued collection of excreta. Animals were sacrificed at the end of 24 hours. Exhaled air was collected by passing air from each metabolism cage through a series of solvent filters. Exhaled volatiles were collected from the filters at the end of 0, 3, 6, and 24 hours. Radio-labeled CO2 was collected at the end of 0, 6, and 24 hours after dosing. Feces and urine were collected at 24 hours. Total recovery of radio-labeled dose was low for both males and females: 89% and 86%, respectively. Male rats exhaled an average of 45% of the applied dose as volatiles and 4% as radio-labeled CO2, while 3.3% of the dose was excreted in the urine. Females exhaled an average of 44% of the applied dose as volatiles, 3% as radio-labeled CO2, and 1.2% excreted in the urine. Excretion in the feces accounted for less than 1% for males and females. Kidney, liver, and thymus had the highest concentration of radiolabel 24 hours after administration in males. In females, the highest average concentrations were found in the kidneys, liver, and skin. Overall retention of radiolabel at sacrifice was minimal for both sexes with males retaining 0.49% and females 0.47% in the carcass. [Research Triangle Inst.; Final Report: Volume 1 of 4, Disposition and Pharmacokinetics of Commercial Hexane Following IV Bolus, Dermal Absorption, or Nose-Only Inhalation (08/11/92); EPA Document No. 40-9289454; OTS0558678 ]**UNREVIEWED**
  
• The metabolism and distribution of commercial hexane containing [14C]n-hexane(mean percent composition = 51.5% n-hexane, 16.0% methylcyclopentane, 16.1% 3-methylcyclopentane, 12.9% 2-methylcyclopentane, 3.3% cyclohexane, and 0.17% 2,4-dimethylpentane) was evaluated in male and female F-344 rats via nose-only inhalation. The average atmospheric concentration was 920+/-54 ppm for a 6-hour exposure. Following exposure, animals were placed in metabolism chambers for collection of excreta. Selected tissues and the residual carcass were analyzed for total radioactivity 168 hours following the beginning of the exposure. Male rats exhaled an average of 20% of the inhaled dose as unchanged radio-labeled n-hexane and 35% as radio-labeled CO2. Thirty seven percent of the dose was excreted in the urine as a complex mixture of metabolites (unidentified), while excretion in the feces accounted for only 2.8%. At sacrifice, males were shown to retain an average of 4% radiolabel in the carcass with muscle, skin, and adipose tissue showing slightly elevated tissue to blood ratios (TBR) of radiolabel concentration. Females exhaled an average of 18% of the dose as unchanged radio-labeled n-hexane, 47% as radio-labeled CO2, and 25% excreted in the urine as an unidentified mixture of n-hexane metabolites. Excretion in the feces accounted for 2.5% of the dose in females. Females had slightly raised radiolabel TBR in adipose tissue, liver, skin, and ovaries., while females retained an average of slightly more than 6% in residual carcass tissues. [Research Triangle Inst.; Final Report: Volume 1 of 4, Disposition and Pharmacokinetics of Commercial Hexane Following IV Bolus, Dermal Absorption, or Nose-Only Inhalation (08/11/92); EPA Document No. 40-9289454; OTS0558678 ]**UNREVIEWED**
  
• The metabolism and distribution of commercial hexane containing [14C]n-hexane(mean percent composition = 51.5% n-hexane, 16.0% methylcyclopentane, 16.1% 3-methylcyclopentane, 12.9% 2-methylcyclopentane, 3.3% cyclohexane, and 0.17% 2,4-dimethylpentane) was evaluated in male and female F-344 rats by nose-only inhalation. The average atmospheric concentration was 8949+/-1520 ppm for 6 hours. Following exposure, animals were placed in metabolism chambers for collection of excreta. Animals were sacrificed and selected tissues and the residual carcass were analyzed for total radioactivity at 96 hours following the beginning of the exposure. Male rats exhaled an average of 58% of the inhaled dose as unchanged n-hexane and 1% as radio-labeled CO2, while 35% of the dose was excreted in the urine as a mixture of unidentified metabolites. Approximately 5% of the total dose was eliminated in the feces. Overall males eliminated 99% of the total dose prior to sacrifice. Females exhaled an average of 59% of the dose as radio-labeled n-hexane and 1% as 14C-labeled CO2. Thirty four percent was excreted in the urine as a mixture of unidentified metabolites, while slightly more than 5% was eliminated in the feces. Females excreted 99% of the total dose within 96 hours from the beginning exposure. Thymus and adipose tissue were shown to have the highest concentration of radioactivity in both sexes and also had the highest tissue to blood ratios of radio-labeled compound. At sacrifice, males were shown to retain an average of 4% radiolabel, while females retained an average of slightly more than 5% in residual carcass tissues. [Research Triangle Inst.; Final Report: Volume 1 of 4, Disposition and Pharmacokinetics of Commercial Hexane Following IV Bolus, Dermal Absorption, or Nose-Only Inhalation (08/11/92); EPA Document No. 40-9289454; OTS0558678 ]**UNREVIEWED**
  
• The metabolism and distribution of commercial hexane containing [14C]n-hexane(mean percent composition = 51.5% n-hexane, 16.0% methylcyclopentane, 16.1% 3-methylcyclopentane, 12.9% 2-methylcyclopentane, 3.3% cyclohexane, and 0.17% 2,4-dimethylpentane) was evaluated in male and female F-344 rats by intravenously administered single bolus doses of (10.3+/-0.1 and 9.3+/-0.9 mg/kg, respectively) radio-labeled commercial hexane. Following dose administration, the animals were placed in metabolism chambers for collection of excreta. Animals were sacrificed and selected tissues and the residual carcass were analyzed for total radioactivity at 72 hours. Male rats exhaled an average of 49% of the inhaled dose as unchanged n-hexane and 21% as radio-labeled CO2, while 16% of the dose was excreted in the urine as a mixture of unidentified metabolites. Excretion in the feces was slightly less than 1%, and analysis of tissues at sacrifice showed about a 3% retention in the carcass of the total recovered dose. Females exhaled an average of 40% of the dose as unchanged parent compound, 28% as 14C-labeled CO2, and 12% excreted in the urine as a mixture of unidentified metabolites. Excretion in the feces accounted for slightly less than 1% of the total recovered dose and less than 3% was retained in the carcass. No specific tissues were found to concentrate radioactivity in either males or females. [Research Triangle Inst.; Final Report: Volume 1 of 4, Disposition and Pharmacokinetics of Commercial Hexane Following IV Bolus, Dermal Absorption, or Nose-Only Inhalation (08/11/92); EPA Document No. 40-9289454; OTS0558678 ]**UNREVIEWED**
  

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Footnotes

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