Ethylbenzene and Human Health

A comprehensive risk assessment of the potential human health effects of ethylbenzene was published in 2015.

Disposition in the Body

What happens to ethylbenzene in animals and humans following exposure has been well characterized.

Ethylbenzene is well absorbed from the skin, lungs, and gastrointestinal tract, rapidly distributed in the body, metabolized primarily via hydroxylation of the two carbons of the side-chain, and then further oxidized to a range of metabolites that are excreted principally in the urine. Differences are apparent between animal species and sexes in aspects of metabolism and overall clearance of ethylbenzene. Models (physiologically based pharmacokinetic or PBPK) have been developed that describe ethylbenzene disposition in rats, mice, and humans.

Acute Toxicity

Ethylbenzene has low acute toxicity by oral, dermal, and inhalation exposure.

Acute lethality or serious poisoning in humans has rarely been reported in association with ethylbenzene exposure. Multi-gram oral or dermal doses of ethylbenzene per kilogram of body weight or air concentrations in the thousands of parts per million (ppm) were required to produce serious toxicity and deaths in animals. Consistent with the known effects of organic solvents which cause a general and non-specific depression of the nervous system, acute exposure to high concentrations of ethylbenzene can induce acute neurological effects. High vapor concentrations can also be irritating to mucous membranes and liquid ethylbenzene can cause irritation to the skin and eyes.

Allergic Reactions

There is no evidence that ethylbenzene produces allergic skin or respiratory reactions based on human experience.

There are no reports of skin or respiratory allergic reactions caused by ethylbenzene in occupationally exposed workers. A human clinical study that tested a 10% ethylbenzene material in a patch test found no evidence of skin sensitization reactions.

Repeated Exposure and Nervous System Toxicity

Ethylbenzene is ototoxic to rodents and hence could cause effects on hearing in humans. Other toxic effects noted in repeated-exposure studies in rodents reveal target organ effects specific to rodents that are not relevant to human health or occurred at very high dose levels of low relevance to human exposures.

Ethylbenzene can cause hearing impairment (ototoxicity). Ototoxicity indicated by alterations in brainstem auditory evoked responses and outer hair cell was found in a 13-week study in rats at concentrations of ≥ 200 ppm ethylbenzene. Therefore, hearing effects may be a concern for ethylbenzene. No other evidence of nervous system impairment was found in repeated exposure rat studies that tested ethylbenzene at concentrations of 500 ppm vapor or oral dosages of up to 500 mg per kilogram of body weight per day, indicating that ethylbenzene does not produce persistent or progressive damage to the nervous system.

The repeated exposure (non-cancer) systemic toxicity of ethylbenzene has been evaluated in laboratory animals in subchronic and chronic inhalation studies and subchronic oral studies. Overall, ethylbenzene is a moderate repeated exposure toxicity hazard with consistent targeted effects to the rodent liver and kidney at concentrations of ≥ 250 ppm or doses of ≥ 250 mg per kilogram of body weight per day. These effects appear to be specific to rodents and are not relevant to human health or occurred at very high dose levels of low relevance to human exposures.

Immunotoxicity

There is no evidence that ethylbenzene is harmful to the immune system.

Ethylbenzene has been tested for effects on the immune system at concentrations up to 500 ppm and results were negative.

Genotoxicity

Tests conducted in bacteria, mammalian cells, and in animals demonstrate ethylbenzene is not a concern for genotoxicity.

Ethylbenzene has been extensively tested for toxicity to genetic material and was negative for genotoxicity in all in vivo studies that have been conducted and predominately negative for genotoxicity in in vitro studies. The U.S. National Toxicology Program (NTP) reported a positive result for gene mutations in the mouse lymphoma assay; however, this only occurred at the highest non-lethal dose tested, and was accompanied by cytotoxicity. NTP concluded that ethylbenzene gave little indication of mutagenicity in vitro or in vivo.

Carcinogenicity

Long-term toxicity studies conducted in rats and mice have found tumors to occur at high exposure concentrations after inhalation exposure. There is no evidence of a direct genotoxic mode of action involved in the tumor development. The treatment relation of the observed tumors is equivocal in some cases, and other tumor types are of no, or questionable, relevance to humans. Therefore, ethylbenzene is not considered to be of concern with respect to carcinogenicity in humans.

Human Epidemiology Studies

There are no reliable human studies or reports on human carcinogenic potential of ethylbenzene.

Animal Studies

Ethylbenzene was tested by the NTP in a rat and mouse cancer bioassay and was found to be tumorigenic following lifetime exposures to high vapor concentrations. Significant increases in kidney tumors were found in male rats that breathed 750 ppm ethylbenzene, whereas a smaller increase in kidney tumors was also observed in female rats at the same concentration. Chronic progressive nephropathy (CPN) was exacerbated by ethylbenzene in this study. CPN is thought to be the mode of action underlying the development of the rat kidney cancer, and is considered to have no relevance to human health.

The male rats that inhaled 750 ppm ethylbenzene also appeared to have an increase in testicular tumors, a type of tumor that occurs in nearly all aged rats of this strain. In mice, there were increases in lung tumors in males and liver tumors in females that were exposed to 750 ppm ethylbenzene, increases that were greater than those in the on-study controls but were within the NTP historical control ranges, hence their relevance is questionable. To date, there are limited data on why ethylbenzene exposure appears to result in increased lung tumors in mice, but the data indicate that metabolism in the lung by an enzyme, cytochrome CYP2F2, creates toxic metabolites that cause cell death and increased cell production. The human lung is not expected to produce enough of these metabolites to result in adverse effects. The exposure concentration that was carcinogenic in these studies also falls above the point at which ethylbenzene metabolism becomes saturated, whereas the exposure concentrations human experience are much lower producing normal metabolism.

Developmental, Reproductive, and Endocrine Toxicity

Ethylbenzene is not a teratogen or reproductive toxicant. Non-specific effects on development (fetotoxicity) were observed in animal studies but at exposure levels that also caused effects in parental animals indicating that developing animals are not more sensitive to toxicity.

Ethylbenzene did not damage reproduction or offspring development in rats exposed at concentrations up to 500 ppm over two generations. At doses that produced effects in the dams (≥ 1000 ppm), as indicated by adverse clinical signs, reductions in body weight, and increases in organ weights, ethylbenzene was fetotoxic causing decreases in fetal body weights and increases in skeletal variations. No evidence of fetotoxicity was present in developmental toxicity studies at 500 ppm or lower ethylbenzene concentrations.