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Toxicological information

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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 (%):
Absorption rate - inhalation (%):

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.”


Isoprene studies demonstrate a clear species difference between rats and mice with respect to toxicity with the mouse being the more sensitive species. This species difference is thought to be due primarily to differences in the rates of formation and/or deactivation of the biological active epoxide metabolites, with the mouse producing higher levels than the rat (SIDS, 2005; MAK, 46 Lieferung 2009).

In relation to establishing the DNEL for isoprene, the endogenous production and fate of isoprene is considered. Using a physiological toxicokinetic model, the rate of endogenous production of isoprene in a 70 kg man was estimated to be 23.8 umol/h (0.34umol/h/kg); approximately 90% is metabolised, the remaining 10% is exhaled unchanged.The model predicts that endogenous production of isoprene will result in blood concentrations of 9.5 nmol/l in humans.For man, the estimated area under the blood concentration versus time curve (AUC) following exposure by inhalation to 10 ppm isoprene for 8h is 4-fold higher than the 24h AUC resulting from exposure to endogenous isoprene (Csanady and Filser, 2001).

An extensive survey of published values for endogenous isoprene exhaled by the general population has been conducted. The weighted mean and standard deviation of values published since 1990 is 0.064 ± 0.049 ml/m3; older values were excluded due to doubts regarding the specificity of the analytical methods used.A physiological toxicokinetic (PT) model was used to calculate the life time (80 years) exposure to endogenous isoprene; this value, expressed as the area under the venous blood concentration versus time curve (AUC0-80) is 3.6 ± 2.8 mmol h/L.The PT model was then used to calculate the acceptable occupational exposure (8 hours/day, 5 days/week, 48 weeks/year for 40 years) such that the mean AUC for occupational exposure remained within the standard deviation of the endogenous AUC; this gave a value of 2.9 ml/m3(MAK,46 Lieferung 2009).


In animals, by oral and inhalation routes, cyclohexane is almost completely absorbed and a figure of 100% absorption will be taken into account for any hazard and risk assessment. Dermal absorption of cyclohexane in liquid phase (i.e. by direct contact with liquid) in rats can be estimated as 5%, as concluded in the RAR (2004). Cyclohexane expected to have low potential for bioaccumulation, based on an estimated BCF of 167 calculated using an experimental log Kow of 3.44.


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.