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Description of key information

No experimental information is available on the toxicokinetic behaviour of the streams comprising this category, however equivalent information is available for the marker substances that are present. For substances that drive risk characterisation, around 50% of an inhaled dose of benzene is retained by the body while dermal uptake of n-hexane is approx. 50%. No measured information is available on bioconcentration potential of these streams, however calculated log BCF values for the marker substances are in a range 1.1-2.4 i.e. indicative of a low bioconcentration potential.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
50

Additional information

The toxicokinetic behaviour of some pure substances 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 ‘Aliphatics and Cyclics C5 and Higher’ category the marker substances, in their pure form, have well-defined toxicokinetic parameters.

The worker DN(M)ELs for this category are driven by benzene and n-hexane.

The toxicokinetics of benzene has been extensively studied and was recently reviewed by ATSDR (Toxicological profile for benzene, ATSDR, 2007). 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 partition into 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).

The toxicokinetics of n-hexane is less well studied. The ATSDR review for n-hexane (ATSDR, 1999) stated “Little toxicokinetic information exists for oral or dermal exposure to n-hexane in humans or animals. Inhaled n-hexane is readily absorbed in the lungs. In humans, the lung clearance (amount present which is absorbed systemically) of n-hexane is on the order of 20-30%. Absorption takes place by passive diffusion through epithelial cell membranes. Absorption by the oral and dermal route has not been well characterized. Inhaled n-hexane distributes throughout the body; based on blood-tissue partition coefficients, preferential distribution would be in the order: body fat>>liver, brain, muscle>kidney, heart, lung>blood. n-Hexane is metabolized by mixed function oxidases in the liver to a number of metabolites, including the neurotoxicant 2,5-hexanedione. Approximately 10-20% of absorbed n-hexane is excreted unchanged in exhaled air, and 2,5-hexanedione is the major metabolite recovered in urine. n-Hexane metabolites in the urine and n-hexane in exhaled air do not account for total intake, suggesting that some of the metabolites of n-hexane enter intermediary metabolism.”

References

ATSDR (1999). Toxicological profile for n-hexane . Agency for Toxic Substances and Disease Registry. Department of Health and Human Services, Public Health Service.

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

Modjtahedi, B. S. and Maibach, H. I. (2008). In vivo percutaneous absorption of benzene in man: Forearm and palm. Food Chem. Toxicol., 46, 1171-1174.

ten Berge, W. (2009). A simple dermal absorption model: derivation and application. Chemosphere, 75, 1440-1445.