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Whilst there are no toxicokinetic data for this intermediate, the major components in their pure form, have well-defined toxicokinetic parameters. Information for cyclohexane, n-hexane, toluene and 4-vinylcyclohexene is presented below.

Cyclohexane toxicokinetics were reviewed in the EU RAR (2004). The toxicokinetics of cyclohexane have been studied in rat (RTI, 1984), rabbit (Elliott et al., 1959) and mouse (Naruse, 1984). In animals, by oral and inhalation routes, cyclohexane is almost completely absorbed; estimates for absorption of cyclohexane after gavage dosing are approximately 91% for rats and 95% for rabbits. Following administration, mean concentrations in whole blood and plasma were similar and peak concentrations were attained 6 - 12 hours after dosing; concentrations in all studied tissues were greatest 6 hours after dosing and were significantly lower by 72 hours after dosing. Tissue residues at 72 hours after administration accounted for approximately 0.4% of the dose of cyclohexane. Following dosing by either intravenous or oral routes, the highest concentrations at 72 hours after dosing were in adipose tissue (RTI, 1984). In rabbits, total residues in tissue at termination (3 - 6 days after administration) were approximately 2.5% of the dose (Elliott et al., 1959). Mice, exposed for 1 hour by inhalation to cyclohexane had peak blood concentrations of cyclohexane; blood concentrations had fallen to 2 - 4% of peak values by 2 hours after the end of exposure (Naruse, 1984). Following an intravenous dose to rats, 79.5% of the dose was exhaled unchanged during the initial 24 hours after dosing, 14C exhaled as either cyclohexanone or cyclohexanol only accounted for a total of 0.22% of the dose over the 0 - 72 hour period after dosing. Following oral administration, unchanged cyclohexane exhaled during the 72 hour period following dosing accounted for up to 92% of the dose. Similar urinary metabolite profiles were observed after both intravenous and oral administration and at all oral dose levels. Only trace quantities of cyclohexane, cyclohexanone and cyclohexanol were present, the majority of the 14C was present as four unidentified polar metabolites. In rats the major route of excretion of 14C was in exhaled volatiles following intravenous or oral dosing, urinary excretion accounted for up to 30% of the dose. Only minor amounts were excreted in faeces. Elimination half lives for total 14C from plasma and tissues were 10 - 15 hours with a slightly longer value for skin (RTI, 1984).

Human volunteer studies involving exposure by inhalation to cyclohexane vapour are reported (Mraz et al., 1998). Volunteers were exposed by inhalation to cyclohexane vapour, urine was collected for 72 hours, glucuronide conjugates were hydrolysed and cyclohexanol (CH-ol), cyclohexane-1,2, diol (CH-1,2 diol) and cyclohexane-1, 4, diol (CH-1,4 diol) excretion was determined using gas chromatography. Urinary excretion of CH-ol, CH-1,2 diol and CH-1,4 diol accounted for up to 11.3% of the absorbed dose. Excretion of CH-ol declined rapidly after exposure but elimination of the CH-diols reached maximal values a few hours after exposure and then declined with a half life of approximately 17 hours. No sex difference in metabolite profile or excretion rates was observed. Very low concentrations of cyclohexane and cyclohexanone were detected in urine. The volunteers were also dosed orally with the diols and the urinary excretion monitored. Peak excretion rates occurred within 4 hours; the elimination half lives were15 and 19 hours for the 1,2 and 1,4 diols respectively. The 1,2 diol was excreted predominantly (>95%) as the glucuronide conjugate whereas the 1,4 diol was excreted unconjugated. An in-vitro experiment showed that there is negligible binding of the diols to plasma proteins. Several investigators have monitored occupational exposure to cyclohexane. Concentrations of cyclohexane in environmental air, alveolar air and blood and urinary excretion of cyclohexanol were measured in shoe factory workers (Perbellini and Brugnone, 1980). Concentrations of cyclohexane in alveolar air were 78% of those in environmental air, blood concentrations of cyclohexane 4 hours after exposure were 53 - 78% of those in environmental air. Urinary excretion of cyclohexanol accounted for 0.1 - 0.2% of the absorbed dose and was correlated with blood concentrations. Mutti et al., (1981) investigated lung uptake during exposure (6 hour) and alveolar excretion of cyclohexane during the 6 hours post exposure period volunteers and workers at a shoe factory. Alveolar retention of cyclohexane was found to be 34% of the inhaled dose corresponding to a lung uptake of 23%. Post exposure alveolar excretion was less than 10% of the total uptake. After high exposures, 40% of the dose was excreted unchanged in exhaled air with an additional 10% present as CO2; after lower exposures, the corresponding values were 10 and 5% respectively. Urinary excretion of cyclohexanol and cyclohexanone accounted for only about 1% of the absorbed dose.

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.”

The US EPA HPV Challenge Program (2006) reported that data on the toxicokinetics of 4-vinylcyclohexene and its metabolites is available in mice and rats in vivo and in vitro, and on the transformation by human liver preparations in vitro. Urine and exhaled air are the main routes of excretion of 4-vinylcyclohexene following oral (gavage) administration to female rats and mice, with generally low levels of retention in both species. Mice metabolize the chemical to the 1,2 epoxide in vivo and this has been shown to occur more readily in the mouse than the rat. Different microsomal enzymes appear to be involved in the two species; hepatic microsomal cytochrome P450IIA and P450IIB are primarily responsible for the activity in mice, while cytochrome P450IIB present F344 rat liver is also able to perform this function but to a more limited extent. The HPV Challenge Program (2006) also reports that differences in activation and detoxication seen in mice and rats, as well as differences in tissue affinity and distribution, is possibly relevant to differences seen in the susceptibility of rats and mice to 4-vinylcyclohexene-induced ovarian toxicity and neoplasia.

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 (1999). Toxicological Profile for n-Hexane.U.S. Department of Health and Human Services Public Health Service Agency for Toxic Substances and Disease Registry.http://www.atsdr.cdc.gov/toxprofiles/tp113. html

 

Elliott TH, Parke DV and Williams RT (1959). Studies indetoxication. The metabolism of cyclo[14C]hexane and its derivatives. Biochem. J. 72, 193-200.

EU (2003). 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 RAR (2004). European Union Risk Assessment Report: Cyclohexane. EC Joint Research Centrehttp://ecb.jrc.ec.europa.eu/DOCUMENTS/Existing Chemicals/RISK_ASSESSMENT/SUMMARY/cyclohexanesum031.pdf

Naruse, M. (1984) Effects on mice of long-term exposure to organic solvents in adhesives,Nagoya Med. J., 28, 183 - 210.

Mraz, J., Galova, E.,Nohova, H., Vitkova, D. and Tichy, M. (1999) Effect of ethanol on the urinary excretion of cyclohexanol and cyclohexanediols, biomarkers of the exposure to cyclohexanone, cyclohexane and cyclohexanol in humans,Scan. J. Work Environ. Health,25, 233 - 237.

Mutti A, Falzoi M, Lucertini S, Cavatorta A & Franchini I (1981), Absorption and alveolar excretion of cyclohexane in workers in a shoe factory,Journal of Applied Toxicology,1, 220 - 223.

Perbellini, L. and Brugnone, F. (1980) Lung uptake and metabolism of cyclohexane in shoe factory workers,Int. Arch. Occup. Environ. Health,  45, 261 - 269.

Research Triangle Institute (1984). Adsorption, Distribution, Metabolism and Excretion of Cyclohexane. Testing laboratory: Research Triangle Institute,,,. Report no.:/2227/00-05P. Report date: 1984-06-30.

US EPA HPV Challenge Program, November 2006. 4-Vinylcyclohexene, CAS 100-40-3