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Endpoint summary

Description of key information

Benzene is absorbed by all physiological routes (inhalation, dermal and oral), the inhalation route is considerably the most important route of exposure (DECOS, 2014). Absorbed benzene is rapidly distributed throughout the body and tends to partition into fatty tissues. The liver serves an important function in benzene metabolism.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Toxicokinetic behaviour of some pure constituents of Distillates (Petroleum), steam-cracked, dimerised (C5-12, C10-rich) have 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 Distillates (Petroleum), steam-cracked, dimerised (C5-12, C10-rich) the marker substances (dicyclopentadiene, benzene and toluene), in their pure form, have well-defined toxicokinetic parameters that have been considered during the derivation of their respective DNEL’s. The overall DNEL of Distillates (Petroleum), steam-cracked, dimerised (C5-12, C10-rich) is driven by the DNELs for benzene and dicyclopentadiene and already incorporates critical information on the toxicokinetic behaviour of these substances, albeit in a pure state.

The toxicokinetics of dicyclopentadiene has been evaluated in rats, mice and dogs (Litton Bionetics, 1976). Elimination from plasma was biphasic in all three species; terminal half-lives were 18 to 27 hours. Radioactivity was rapidly and widely distributed into tissues in all three species; the highest concentrations were found in the body fat, adrenal glands and urinary bladder in the rat; in the urinary bladder, gall bladder and body fat in the mouse; and in the bile, gall bladder and bladder in the dog. In all three species, the majority of the radioactivity was excreted in the urine. Urinary radioactivity was present as 6 -7 constituents; conjugates but no unchanged dicyclopentadiene were present. A further study was carried out in a lactating Jersey cow (Ivie, 1980). On the basis of this study it was concluded that exposure of livestock to small quantities of dicyclopentadiene would not result in perceptible contamination of the milk or meat.

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).

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.

References

ATSDR (2007a). Toxicological profile for benzene. 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

Ivie GW and Oehler DD (1980). Fate of dicyclopentadiene in a lactating cow. Bull. Environm. Contam. Toxicol. 24, 662-670.

Litton Bionetics (1976). Mammalian toxicological evaluation of DIMP and DCPD. Testing laboratory: Litton Bionetics Inc.5516 Nicholson Ave. Report no.: DAMD 17. 75-C-5068. Owner company: U. S. Army Med. Res. and Dev. Command,, D. C. 20314,. Report date: 1976-06-25.