Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Key value for chemical safety assessment

Additional information

Toxicokinetic behaviour of some of the stream components has been extensively studied and reported. In many circumstances the body burden of the substance and/or metabolites is dependent upon several factors such as the rate and extent of uptake, distribution, metabolism and excretion. In complex mixtures, however, the toxicokinetics of even well-studied pure substances may vary depending upon interaction with other chemical species available within the mixture. For example, the substances present may compete for the uptake, metabolism, and/or elimination of the complex mixture. This situation, already complicated, is further exacerbated when the composition of the mixture is uncertain and variable.

For this ‘Fuel Oils’ category the marker substances (benzene, toluene, ethylbenzene, styrene, naphthalene, anthracene and biphenyl) in their pure form, have well-defined toxicokinetic parameters that have been taken into account during the derivation of their respective DNEL’s. The overall DNEL of this category is driven by the DNELs for benzene and naphthalene and already incorporates critical information on the toxicokinetic behaviour of these substances, albeit in a pure state.

The toxicokinetics of benzene has been extensively studied and was recently reviewed by ATSDR (ATSDR, 2007a). ATSDR concluded "Inhalation exposure is probably the major route of human exposure to benzene, although oral and dermal exposures are also important. Benzene is readily absorbed following inhalation or oral exposure. Although benzene is also readily absorbed from the skin, a significant amount of a dermal application evaporates from the skin surface. Absorbed benzene is rapidly distributed throughout the body and tends to accumulate in fatty tissues. The liver serves an important function in benzene metabolism, which results in the production of several reactive metabolites. Although it is widely accepted that benzene toxicity is dependent upon metabolism, no single benzene metabolite has been found to be the major source of benzene hematopoietic and leukaemogenic effects. At low exposure levels, benzene is rapidly metabolized and excreted predominantly as conjugated urinary metabolites. At higher exposure levels, metabolic pathways appear to become saturated and a large portion of an absorbed dose of benzene is excreted as parent compound in exhaled air. Benzene metabolism appears to be qualitatively similar among humans and various laboratory animal species. However, there are quantitative differences in the relative amounts of benzene metabolites”. The present analysis confirms the ATSDR statement. More specifically, human inhalation exposure is estimated to be approximately 50%, oral exposure assumed to be 100% (this value used for DN(M)EL calculations). Percutaneous absorption is estimated at 0.1% (Modjtahedi and Maibach, 2008) whereas a QSAR model determined a maximum value of 1.5% (Ten Berge, 2009).For percutaneous absorption of benzene from petroleum streams a value of 1% is considered appropriate. This value is based on experiments with compromised skin and with repeated exposure (Blank and McAuliffe, 1985; Maibach and Anjo, 1981) as well as the general observation that vehicle effects may alter the dermal penetration of aromatic compounds through skin (Tsuruta, et al, 1996).

ATSDR have also reviewed the toxicokinetics of naphthalene (ATSDR, 2005) and report that naphthalene is readily absorbed into the systemic circulation following inhalation or ingestion. Systemic absorption of naphthalene can also occur following dermal contact however, the rate and extent of naphthalene absorption for all routes is unknown in many instances. Naphthalene is initially metabolised into a number of reactive epoxide and quinone metabolites by cytochrome P450 oxidation. Metabolites of naphthalene are excreted in the urine as mercapturic acids, methylthio derivatives and glucuronide conjugates. Glutathione and cysteine conjugates are excreted in the bile. Following ingestion the urinary excretion of naphthalene metabolites is prolonged due to delayed absorption from the gastrointestinal tract.

Toluene toxicokinetics were reviewed by the EU (EU, 2003a). In summary, the major uptake of toluene vapour is through the respiratory system. It is absorbed rapidly via inhalation and the amount absorbed (approximately 50%) depends on pulmonary ventilation. Toluene is almost completely absorbed from the gastrointestinal tract. Liquid toluene can be absorbed through the skin but dermal absorption from toluene vapours is not likely to be an important route of exposure. Dermal absorption of liquid toluene was predicted using a model which considers absorption as a two stage process, permeation of the stratum corneum followed by transfer from the stratum corneum to the epidermis. The model predicted a maximum flux of 0.0000581 mg/cm2/min giving a dermal absorption value of approximately 3.6% of the amount applied as liquid toluene. Toluene is distributed to various tissues, the amount depending on the tissue/blood partition coefficient, the duration and level of exposure, and the rate of elimination. Biotransformation of toluene occurs mainly by oxidation. The endoplasmic reticulum of liver parenchymal cells is the principal site of oxidation which involves the P450 system. Analysis of blood and urine samples from workers and volunteers exposed to toluene via inhalation in concentrations ranging from 100 to 600 ppm (377-2,261 mg/m3) indicate that of the biotransformed toluene, ~ 99% is oxidised via benzyl alcohol and benzaldehyde to benzoic acid. The remaining 1% is oxidised in the aromatic ring, forming ortho-, meta- and para-cresol. In the rat, elimination of toluene is rapid with most toluene eliminated from fat after 12 hours. Within a few hours after termination of exposure the blood and alveolar air contains very little toluene. A proportion (around 20%) of the absorbed toluene is eliminated in the expired air. The remaining 80% of the absorbed toluene is metabolised in the liver by the P450 system, mainly via benzyl alcohol and benzaldehyde to benzoic acid. Benzoic acid is conjugated with glycine and excreted in the urine as hippuric acid.

The metabolism of ethylbenzene has been reviewed in the recent transitional RAR (EU, 2008b). Absorption via inhalation and the oral route was considered and it was concluded that for risk characterisation purposes inhalation absorption of 65 % was applicable for humans and 45 % for animals. For inhalation via the oral route, 100% oral absorption should be assumed for animals and humans. Although ethylbenzene is rapidly distributed through the body, there is no evidence of ethylbenzene accumulation in fat or fat-rich tissues (EU, 2008a). There are some species differences in metabolism. Side-chain oxidation leads to major metabolites in humans being e.g. mandelic acid, phenylglyoxylic acid with hippuric acid and benzoic acid being the major metabolites in rats. Ring oxidation is a minor metabolic pathway. With rapid metabolism, ethylbenzene and its metabolites are eliminated rapidly, mainly as urinary metabolites with minor loss via exhalation and excretion in faeces. Following exposure, excretion is virtually complete within 24 hrs.

ATSDR have also reviewed the toxicokinetics of styrene (ATSDR, 2007b) and report that styrene is well absorbed by the inhalation and oral routes and poorly absorbed through the skin. Once absorbed, styrene is widely distributed throughout the body, with the highest levels detected in fat. There are several metabolic pathways for styrene; the primary pathway is oxidation of the side chain by cytochrome P450 to form styrene 7,8-oxide. The styrene oxide is further metabolized to ultimately form mandelic acid or phenylglyoxylic acid or can be conjugated with glutathione. Styrene is rapidly eliminated primarily in the urine as mandelic acid and phenylglyoxylic acid.

Anthracene is a polycyclic aromatic hydrocarbon (PAH) and its toxicokinetic were reviewed in the RAR (EU, 2009). The RAR summarised “Most studies of the toxicology of PAH have been carried out with compounds other than anthracene, and indicate that PAH are in general absorbed through the lung, the gastrointestinal tract, and the skin. Once absorbed by any route, they are widely distributed in the body and are found in almost all internal organs, particularly those rich in lipids. They can cross the placenta and have been detected in fetal tissues. The metabolism of PAH is complex, and involves mainly conversion via intermediate epoxides to phenols, diols, and tetrols, which can subsequently form phase II conjugates (esters with sulfuric or glucuronic acids or with glutathione). Metabolites and their conjugates are excreted via the urine and feces, but conjugates excreted in the bile can be reabsorbed after being hydrolysed by enzymes of the gut flora. After inhalation or intratracheal instillation of PAH, the largest part of metabolites was recovered in the feces, suggesting significant hepatobiliary recirculation following pulmonary absorption. PAH do not persist in the body and their turnover is rapid. The molecular basis of the genotoxicity and carcinogenicity of PAH has been extensively investigated, and the ability to undergo metabolism to a bay-region diol epoxide is believed to constitute an important structural feature of it. It is important, from this point of view, to note that the anthracene molecule does not contain a bay region.”



ATSDR (2005). Toxicological profile for naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene. U.S. Department of Health and Human Services Public Health Service Agency for Toxic Substances and Disease Registry.

ATSDR (2007a). Toxicological profile for benzene. U. S. Department of Health and Human Services Public Health Service Agency for Toxic Substances and Disease Registry.

ATSDR (2007b). Draft toxicological profile for styrene. U. S. Department of Health and Human Services Public Health Service Agency for Toxic Substances and Disease Registry.

EU (2003a). European Union Risk Assessment Report for Toluene. EC Joint Research Centre http: //ecb. jrc. ec. europa. eu/DOCUMENTS/Existing- Chemicals/RISK_ASSESSMENT/REPORT/toluenereport032. pdf

EU (2008b). Draft Risk Assessment Report for Ethylbenzene.

EU (2009). European Union Risk Assessment Report for Anthracene.

Filser JG, Csanady GA, Denk B, Hartmann M, Kauffmann A, Kessler W, Kreuzer PE, Putz C, Shen JH and Stei P (1996). Toxicokinetics of isoprene in rodents and humans. Toxicology, 113, 278-287.