Cyclohexane

Cyclohexane (also known as Benzene Hexahydride, Hexahydrobenzene or Hexamethylene), is a colorless flammable liquid with a petroleum-like odor that is used as solvent and paint remover, in analytical chemistry, and in the making of adhesives and perfumes. (1) Cyclohexane is considered a dangerous fire hazard because its container can explode in fire causing poisonous gases. This solvent is also classified as an irritant, health hazard and environmental hazard. This alicyclic hydrocarbon is used as a raw material for the manufacturing of nylon. (2) Let discuss more about its toxic effects!

Figure 1. Chemical safety classifications of Cyclohexane. (National Center for Biotechnology Information, 2024)

Source

Exposure to Cyclohexane can occur in the workplace or the environment following its release to air, water, or land. Exposure can also occur by using products that contain Cyclohexane or by smoking cigarettes. It can enter the body by inhalation of contaminated air, by consumption of poisoned food or water, or by adsorption through the skin. Sources of exposure in the industry include petroleum refining, automotive repair shops, and commercial printing and publishing. Natural sources of exposure include crude petroleum, and naturally occurring as plant volatile and release from volcanoes. (3)

Mechanism of Action and Biotransformation

Cyclohexane is metabolized by the liver through hydroxylation producing Cyclohexanol. The metabolic pathway of Cyclohexane is insufficient and not well studied. A mechanism of action has not been proposed for Cyclohexane to explain its toxic effects. (4) Its metabolite Cyclohexanol or a product of it is considered to be responsible for Cyclohexane nephrotoxic and spermatotoxic effects. (5)

Toxicokinetics

The uptake of Cyclohexane occurs mainly by inhalation of their vapors and has a pulmonary retention of about 20%. Cyclohexane can be absorbed by the lungs, GI tract and skin. After uptake the substance ends in the bloodstream and is metabolized by the liver. Their metabolites are then excreted in the urine. Uptake by the lungs can also be excreted by exhalation. Cyclohexane also has neurotoxic effects causing depression of the central nervous system (CNS) and narcotic effects with high concentrations. (4)(5) Irritation to the lungs and nasal mucosa after inhalation can occur, as well as irritation to the skin after exposure. Toxicity to the kidneys, liver and male sperm is possible by the effects of the Cyclohexane metabolites. (5)

Target Organs

As shown in Figure 2, Cyclohexane can produce toxicity in the brain and CNS, the lungs, the liver, the kidneys, the skin and the male reproductive system.

Figure 2. Target organs of Cyclohexane toxicity. (Obtained from Home Health UK)

Sign and Symptoms of Toxicity (Acute and Chronic)

Acute exposure to Cyclohexane can cause irritation and burn of the skin and eyes by contact. Prolonged or repeated exposure to the skin can cause rash, dryness, itching, and/or redness. Irritation of the nose, throat and lungs can occur by inhalation of Cyclohexane causing cough and wheezing. Exposure in general can cause headache, dizziness, nausea and vomiting, lightheadedness, drowsiness, and passing out. (1) Breathing large amounts of Cyclohexane can also cause tremors and convulsions. The effects of chronic exposure to Cyclohexane are unknown but repeat exposure to large amounts of this toxicant can cause damage to the eyes and respiration issues. (3) Figure 3 shows some behavioral and histological changes observed after inhalation of Cyclohexane in humans and rodents.

Figure 3. Effects observed in humans and rodents after inhalation of Cyclohexane. (Campos-Ordonez & Gonzalez-Perez, 2016)

Carcinogenicity, Genetic susceptibility and Heritable traits

Cyclohexane has not been tested for carcinogenic effects or the data available is insufficient to determine its human carcinogenic potential. (1)(4) One skin exposure study found the potential of Cyclohexane to cause skin tumors after skin exposure. (5) No genotoxic effects or reproductive effects have been found beside the ability of the metabolite Cyclohexanol to cause spermatotoxicity. (5)

Treatments

Removing contaminated clothes, flushing eyes and washing skin with soap and water is the first step in treatment to remove the source of exposure. If breathing problems are present oxygen or artificial ventilation is used. Liver and kidney function tests are performed to discard damage to these organs. (1) There is no specific treatment besides removing the source of exposure and supportive care until the symptoms resolve.

Historical or unique exposure

The following video shows the historical exposure of Cyclohexane caused by the Flixborough disaster in 1974. A chemical plant that used Cyclohexane to produce nylon, exploded after the temporary use of a bypass pipe to replace a compression cylinder that was cracked.

  References

  1. New Jersey Department of Health. (2016, March). Cyclohexane Hazardous Substance Fact Sheet. Retrieved from New Jersey Department of Health: https://nj.gov/health/eoh/rtkweb/documents/fs/0565.pdf 
  2. National Center for Biotechnology Information (2024). PubChem Compound Summary for CID 8078, Cyclohexane. Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/Cyclohexane.
  3. Department of Climate Change, Energy, the Environment and Water. (2022, June). Cyclohexane. Retrieved from Australian Government DCCEEW: https://www.dcceew.gov.au/environment/protection/npi/substances/fact-sheets/cyclohexane#:~:text=Natural%20sources,can%20be%20released%20from%20volcanoes. 
  4. U.S Environmental Protection Agency. (2003, August). Toxicological Review of Cyclohexane. Retrieved from EPA: https://iris.epa.gov/static/pdfs/1005tr.pdf 
  5. Cyclohexane. (n.d.). Retrieved from Wiley Online Library: https://onlinelibrary.wiley.com/doi/pdf/10.1002/3527600418.mb11082e0013#:~:text=1%20Toxic%20Effects%20and%20Mode%20of%20Action&text=It%20causes%20depression%20of%20the,is%20distributed%20via%20the%20bloodstream.
  6. Campos-Ordonez, T., & Gonzalez-Perez, O. (2016, January). Cyclohexane, a Potential Drug of Abuse with Pernicious Effects on the Brain. Retrieved from Frontiers: https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2015.00291/full 
  7. The Raven’s Eye. (2024, March 4). Temporary Bypass Pipe Failed – The Result Was Catastrophic (Flixborough Chemical Explosion 1974) [Video]. YouTube. https://www.youtube.com/watch?v=_v3__0fq-IE