Solvent Blog Entry: Cyclohexane

Introduction:

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Cyclohexane is a cycloalkane and colorless, flammable liquid at room temperature. It it primarily used in the production of nylon, but it is also used in solvents, insecticides, and plasticizers (1). Cyclohexane is also used in crude oil and in gasoline (2).

 Figure 1: Structure of Cyclohexane (3)

Cyclohexane is can be found naturally in petroleum, but it is also manufactured from benzene. The primary exposure to cyclohexane is through inhalation from its presence in gasoline vapors that are present in the ambient air (4).

Biotransformation:

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Cyclohexane is absorbed into the blood through the lungs, gastrointestinal tract, and skin (4). Once absorbed into the bloodstream, as a non polar, organic compound, Cyclohexane partitions preferentially to lipid-rich tissues such as fat, the liver, and the brain (4). In the liver, Cyclohexane is hydroxylated to Cyclohexanol (4). Cyclohexanol is the main primary metabolite, although Cyclohexanone and 1,2-cyclohexane-diol have also been identified in vivo (4).  

Figure 2: Biotransformation of cyclohexane into cyclohexanol, which can then transform into other metabolites (5)

While cyclohexanol is the main metabolite in rabbits, in humans cyclohexanol tends to be further hydroxylated into cyclohexanediols (6).

 

Toxicokinetics and Mechanism of Action:

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Compared to benzene, cyclohexane is relatively nontoxic and does not have the same adverse effects on the blood (6). The most common form of exposure is the inhalation of its vapors, but it can also be ingested. Once it is distributed into the blood stream, it is hydroxylated into cyclohexanol and its derivatives (6). The metabolite cyclohexanol is responsible for the nephrotoxic effects (6). Cyclohexane and its metabolites end up distributed in the liver, kidney, brain, and fat cells. Cyclohexane can also be absorbed by the skin and cause skin irritation (6). In mice, it has been shown to be a tumor promotor, but so far no genotoxic effects have been seen in multiple tests (6). Cyclohexane and its metabolites are later excreted in urine, as cyclohexanol or cyclohexadiols (6).

 

Target Organs and Signs and Symptoms:

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Cyclohexane is usually inhaled, and then distributed into the blood stream. From there it targets the:

• Brain
• Kidney
• Liver

It can also be absorbed through the skin, and can cause skin irritation. While there are not many lethal toxic effects, there are effects of cyclohexane exposure, and some of these effects can make cyclohexane a potential drug of abuse. 

Figure 3: Cyclohexane Effects in both Animals and Humans (7)

 

Cyclohexane’s main effect on the body is CNS depression. Because cyclohexane is a lipophilic compound, it can easily diffuse through different regions of the brain and cause different neural effects. It has been linked to cognitive deterioration (8). However, because most commercial exposure is from products with mixed amounts of cyclohexane, n-hexanes, toluene, and benzene, it is difficult to clarify how big of a part cyclohexane plays in recreational use effects.

 

Toxicity:

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Carcinogenicity

• Unclear if irritant effects cause tumor promotion
• No studies show clear carcinogenicity

Genotoxicity

• No signs of genotoxicity in vitro

Reproductive and Developmental Toxicity

• Cyclohexanol has been shown to be spermatotoxic in rats
• No statistically significant results show any developmental toxicity at any dose range

Neurotoxicity

• There are many neural effects caused by cyclohexane toxicity
• Neural dysfunction is common from cyclohexane exposure

 

Summary:

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Cyclohexane is widely to be considered to be a safer alternative to benzene and toluene. However, there are not enough studies on chronic exposure effects in humans. Also, because most exposures are from a mixture of solvents, it can be difficult to clarify what role cyclohexane plays in the overall toxicity.

Most of the symptoms of acute toxicity effect the nervous system. The biggest symptoms caused by cyclohexane effect the nervous system, although I could not find a mention of any trend of cyclohexane being lethal to humans historically, meaning that it is excreted from the body fairly efficiently. Overall, more studies need be done on the toxicological profile of cyclohexane to better understand its effects on humans, especially as it is being used more extensively in manufacturing because it is considered a safer alternative to other solvents.

Resources:

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