National Toxicology Program

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

Names (NTP)

• Isobutene
• 2-METHYL-1-PROPENE

Human Toxicity Excerpts

• BUTYLENE ISOMERS ARE SIMILAR IN PHARMACOLOGICAL ACTIVITY AS ASPHYXIANTS & WEAK ANESTHETICS. ... ABOUT 4.5 TIMES AS TOXIC AS ETHYLENE. /BUTYLENE ISOMERS/ [Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963., p. 1204]**PEER REVIEWED**
  
• The biotransformation of 2-methylpropene, a gaseous alkene widely used in industry, was investigated in vitro in liver tissue of rats, mice, and humans. Interspecies comparison revealed that the lowest levels of the primary epoxide metabolite were detected in incubations of 2-methylpropene with human liver homogenate, followed by rat and mouse, respectively. Among the human liver samples, however, important interindividual variations were observed. Out of the 16 samples analyzed, only 2 contained measurable epoxide amounts, while in the other samples only traces were detectable. The involvement of rat liver cytochrome P450 2E1 in the activation of 2-methylpropene to its epoxide 2-methyl-1,2-epoxypropane has been established. The lower capacity of the mixed function oxidase system in human liver samples compared to rodents is confirmed. Concerning epoxide detoxifying enzymes, a high microsomal epoxide hydrolase activity was observed in human liver tissue and an intermediate in rat liver, while a low activity was measured in mouse liver. These findings were inversely correlated with the epoxide levels measured in vitro in liver tissue of the three species studied. It can be concluded that, as far as the in vitro metabolism of 2-methylpropene is concerned, neither mouse nor rat represents a good model for the human situation. Although, the same biotransformation pathways are involved, marked quantitative differences in epoxide levels were observed. The results indicate that human liver tissue is exposed in vitro to smaller concentrations of the primary metabolite 2-methyl-1,2-epoxypropane than rodent liver. [Cornet M et al; Chem Res Toxicol 8 (7): 987-92 (1995)]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• 2-Methylpropene or isobutene is a gaseous chemical used on a large scale in the synthetic rubber industry. The present review covers the rather scarce literature on 2-methylpropene with respect to its metabolic fate and toxicity in laboratory animals and humans. It has been shown both in vivo and in vitro that 2-methylpropene is metabolized to the primary metabolite 2-methyl-1,2-epoxypropane by rodent and human liver tissue. The formation of this reactive epoxide intermediate is catalyzed by CYP2E1, while epoxide hydrolase and glutathione S-transferase appear to be involved in its inactivation. In rats, the capacity to absorb and metabolize 2-methylpropene is saturable. 2-Methylpropene is oxidized to compounds that are mainly excreted in urine. Data indicate that rodents can tolerate low levels of 2-methylpropene without apparent toxicity. The primary metabolite 2-methyl-1,2-epoxypropane, however, is able to produce genetic damage in both prokaryotic and eukaryotic cells in vitro. 2-Methylpropene is thus not toxic per se but elicits metabolic activation to become potentially harmful. Consequently, the balance between formation and detoxification of 2-methyl-1,2-epoxypropane plays a key role in determining the potential toxicity of the parent compound [Cornet M, Rogiers V; Crit Rev Toxicol 27 (3): 223-32 (1997)]**PEER REVIEWED**
  
• The toxicity of isobutene is similar to that of other lower alkenes. It is a simple asphyxiant and causes CNS depression at higher concentrations. At 30%, it produces no CNS depression in mice, and excitement and CNS depression in 7 to 8 min at 40%, but immediate CNS depression in 2 to 2.25 min at 50%, or in 50 to 60 sec at 60 to 70%. The 2-hr LC50 in the mouse is 415 mg/L and the 4-hr LC50 in the rat is 620 mg/L. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 1247]**PEER REVIEWED**
  
• ... CONCLUSIONS: Under the conditions of these 2 yr inhalation studies, there was some evidence of carcinogenic activity of isobutene in male F344/N rats based on an incr incidence of follicular cell carcinoma of the thyroid gland. There was no evidence of carcinogenic activity of isobutene in female F344/N rats or male or female B6C3F1 mice exposed to 500, 2,000 or 8,000 ppm. [DHHS/NTP; Toxicology & Carcinogenesis Studies of Isobutene in F344/N Rats and B6C3F1 Mice p.5 Technical Report Series No. 487 (1998) NIH Publication No. 99-3977]**PEER REVIEWED**
  
• The epoxidation of the gaseous alkene 2-methylpropene or isobutene was studied in vitro in rat lung tissue in comparison with rat liver. Pulmonary tissue appears to be less exposed to the toxic epoxide metabolite than is the case for hepatic tissue. The results are correlated with the low capacity of the mixed function oxidase system, expressed by means of the cytochrome p450 content and the 7-ethoxycoumarin O-deethylase activity, to form reactive intermediates. The activities of the principal epoxide detoxifying enzymes glutathione S-transferase and epoxide hydrolase represent only 5-10% of the values measured in rat liver. [Cornet M et al; Arch Toxicol 70 (1): 64-7 (1995)]**PEER REVIEWED**
  
• There was a linear relationship between the degree of CNS depression and the cerebral concentrations. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 1247]**PEER REVIEWED**
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• LC50 Mouse oral 415 mg/L/2 hr [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 1247]**PEER REVIEWED**
  
• LC50 Rat oral 620 mg/L/4 hr [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 1247]**PEER REVIEWED**
  
• LC50 Rat ihl 620 g/cu m/4 hr [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 1952]**PEER REVIEWED**
  
• LC50 Mouse ihl 415 g/cu m/2 hr [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 1952]**PEER REVIEWED**
  

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Absorption, Distribution and Excretion

• FASTED RATS EXHALE THE HYDROCARBONS @ RATE OF APPROX 1.7 NMOL/KG/HR. THROUGH AN IMPROVED ANALYTICAL PROCEDURE OTHER VOLATILE HYDROCARBONS COULD BE DETECTED IN BREATH OF ANIMALS. [FRANK H ET AL; TOXICOL APPL PHARMACOL 56 (3): 337 (1980)]**PEER REVIEWED**
  
• In metabolic studies on rats and mice, inhaled isobutene levels in the brain and parenchymatous organs were similar, but the level in the fatty tissue was significantly higher than in the brain, liver, kidneys, or spleen. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 1247]**PEER REVIEWED**
  

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Metabolism/Metabolites

• The effect of age and gender on the in vitro biotransformation of 2-methylpropene, an alkene metabolized to 2-methyl-1,2-epoxypropane, was studied. The epoxide concentration and the epoxide metabolizing enzymatic activities were investigated in male and female Brown Norway rats of different ages. Liver tissue of senescent rats was exposed to smaller 2-methyl-1,2-epoxypropane concentrations than that of young animals, although changes during ageing were rather modest. With advancing age a feminization of male glutathione S-transferase and cytosolic epoxide hydrolase activities was found, as well as a significant decline of the female microsomal epoxide hydrolase activity and an increase of the cytochrome p450 content in the oldest female rats. [Cornet M et al; Mech Ageing Dev 74 (1-2): 103-15 (1994)]**PEER REVIEWED**
  
• Total uptake, excretion patterns, and metabolic conversions were studied in rats exposed for up to 6 hr to 0, 2, 40, 400, or 4000 ppm 14(C)isobutene. Absorption of the inhaled isobutene was approximately 8% up to 40 ppm isobutene, but decreased at the higher concentrations. The amount of isobutene metabolized per ppm.hr of exposure was also linear up to 40 ppm but decreased at higher concentrations. Over 90% of the absorbed isobutene was metabolized at exposure concentrations up to 400 ppm, but the exposure to approximately 4000 ppm isobutene resulted in approximately 20% of the absorbed dose exhaled as the unmetabolized isobutene. Two urinary metabolites were identified as isobutenediol and 2-hydroxyisobutyric acid. Two other urinary metabolites were tentatively identified as sulfate conjugates of isobutenediol. [Henderson RF et al; Toxicol Appl Pharmacol 123 (1): 50-61 (1993)]**PEER REVIEWED**
  

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TSCA Test Submissions

• None found

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Footnotes

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