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Administrative data

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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. Benzene is the lead marker substance for worker risk characterisation, with retention of around 50% of an inhaled dose while dermal uptake is lower at 1%. No measured information is available on bioaccumulation potential of these streams, however calculated log BCF values for the marker substances are in a range 0.73-4.15 i.e. indicative of a low potential for bioaccumulation.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
1
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 ‘High Benzene Naphthas’ 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.

 

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).

 

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 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 metabolism and kinetics of xylene isomers has been reviewed extensively by ATSDR (2007c).All the xylene isomers are well absorbed via the oral route. They are rapidly distributed through the body and any unmetabolised compound quickly eliminated in exhaled air. In gavage dosing experiments in animals, 90% absorption has been estimated. In humans, inhalation absorption has been estimated at about 60-65% based on human data. The major pathway of xylene metabolism in humans involves mixed function oxidases in the liver, with minor metabolism occurring in the lung and kidneys. Xylenes are transformed primarily to methylbenzoic acid followed by conjugation with glycine to form the main metabolites, the corresponding methylhippuric acid isomers, which are eliminated in the urine.

 

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 components; 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 detectable contamination of the milk or meat.

 

The toxicokinetic profile of cyclohexane including absorption, metabolism, distribution and elimination is considered in this endpoint summary.  The primary source is the RAR (2004). 

 

Non-human information

The toxicokinetics of cyclohexane have been studied in rat (RTI, 1984), rabbit (Elliott et al., 1959) and mouse (Naruse, 1984).

Absorption

Although absorption was not determined specifically, minimum values can be estimated from the total of the amounts excreted in exhaled volatiles and urine and that retained in tissue. Using this approach, estimates for absorption of cyclohexane after gavage dosing are approximately 91% for rats (100 - 2000mg/kg bodyweight) and 95% for rabbits (0.3 - 400mg/kg bodyweight).

Distribution

Following administration of 200mg [14C]-cyclohexane per kg bodyweight to rats, concentrations of total 14C in whole blood and plasma were similar; there was considerable inter-animal variation in concentrations when the same dose was administered on three separate occasions to different rats. Peak concentrations of total 14C in blood and plasma were attained by 6 - 12 hours after dosing. Concentrations of total 14C in all studied tissues were greatest 6 hours after dosing and were significantly lower by 72 hours after dosing. Tissue residues of total 14C at 72 hours after administration accounted for approximately 0.4% of a dose of 200mg [14C]-cyclohexane per kg bodyweight. Following dosing by either intravenous (10mg/kg) or oral (200, 1000 or 2000mg/kg) routes, the highest concentrations of 14C at 72 hours after dosing were in adipose tissue. The ratios of the concentrations of 14C in adipose to those in blood ranged from approximately 16:1 for the 10mg/kg intravenous and 100mg/kg oral doses to 41:1 and 47:1 for the 1000 and 2000mg/kg oral doses (RTI, 1984).

The tissue distribution of [14C]-cyclohexane was not determined in rabbit tissues; 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 vapour at concentrations of 8000, 14000 and 17500ppm had peak blood concentrations of cyclohexane of 27, 69 and 122µg/mL respectively; blood concentrations had fallen to 2 - 4% of peak values by 2 hours after the end of exposure (Naruse, 1984).

Metabolism

Following an intravenous dose of 10mg [14C]-cyclohexane per kg bodyweight to rats, 79.5% of the dose was exhaled unchanged during the initial 24 hours after dosing with a further 1.27% and 1.43% exhaled during the 24 - 48 and 48 -72 hour periods respectively. 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 of 100, 200 or 1000mg/kg, unchanged cyclohexane exhaled during the 72 hour period following dosing accounted for 59.4, 59.8 and 92.1% of the doses respectively. The corresponding values for 14C exhaled as either cyclohexanone or cyclohexanol were 0.09, 0.62 and 0.24% of the dose respectively. The report authors commented that the high value for cyclohexane after a dose of 1000mg/kg may have been due to an error in estimating the dose. No significant amounts of 14CO2 were detected after any of the doses.

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.

Plasma contained minor amounts of unchanged cyclohexane along with cyclohexanone, cyclohexanol and five unidentified metabolites that accounted for at least half the total 14C present.

Unchanged cyclohexane in adipose accounted for 79 and 94% of the total 14C present 72 hours after the 10mg/kg intravenous and 1000mg/kg oral doses respectively; small amounts of cyclohexanone and cyclohexanol were also detected. The majority of the total 14C present in muscle, liver and skin was not extractable; small amounts of cyclohexane, cyclohexanone and cyclohexanol were detected (RTI, 1984).

In rabbits unchanged [14C]-cyclohexane in exhaled volatiles accounted for 25 - 38% of a dose of 360 - 390mg [14C]-cyclohexane per kg bodyweight; an additional 8 - 10% of the dose was eliminated as 14CO2; after a low dose of 0.3 mg[14C]-cyclohexane per kg bodyweight all exhaled radioactivity (6% of dose) was present as 14CO2. No cyclohexanone or cyclohexanol was detected in exhaled volatiles.

Excretion

In rats the major route of excretion of 14C was in exhaled volatiles accounting for 83.2, 63.4, 61.8, 96.8* and 78.5% of the dose following 10mg/kg intravenous, 100, 200, 1000 or 2000mg/kg oral doses respectively; the corresponding values for urinary excretion were 13.5, 28.8, 28.6, 19.3* and 12.0% of the dose (* the high values after the 1000mg/kg oral dose may be due to an error in estimating the dose). A preliminary experiment showed that as only minor amounts of 14C ( <0.3% of the dose) were excreted in faeces; samples were not analysed for the remainder of the studies. Elimination half lives for total 14C from plasma and tissues were 10 - 15 hours with a slightly longer value for skin (RTI, 1984).

In rabbits administered 360 - 390mg [14C]-cyclohexane per kg bodyweight, 35 – 47% of the dose was eliminated in exhaled volatiles; at 0.3mg [14C]-cyclohexane per kg bodyweight the corresponding values was 6% of the dose. Urinary excretion of radioactivity at the high and low dose levels was 33 - 56% and 87% of the doses respectively. Faecal excretion of radioactivity (0.1-0.2% of dose) was minimal (Elliott et al., 1959).

 

 

Human Information

Human Volunteer Studies

Human volunteer studies involving exposure by inhalation to cyclohexane vapour have been conducted (Mraz et al., 1998; 1999). 

In the initial study, 4 male and 4 female volunteers were exposed by inhalation to cyclohexane vapour (1010mg/m3) for 8 hours. 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 0.5, 23.4 and 11.3% of the absorbed dose respectively. 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. Additionally, volunteers were 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.

Occupational Exposure Monitoring

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 (16 - 1929mg/m3) were 78% of those in environmental air (17 - 2484 mg/m3), blood concentrations of cyclohexane (29 - 367µg/L) 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 in 3 volunteers and 5 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 weighted environmental concentration in the breathing zone over a 4 hour exposure period at the start of work was measured in a group of 43 workers using a personal passive dosimeter (Ghittori et al., 1987). Urine was collected post-exposure and analysed for cyclohexane by gas chromatography. The investigators reported a linear relationship between the weighted environmental concentration and urinary cyclohexane concentrations.

Yasugi et al.(1994) monitored 33 female workers who either applied glue containing cyclohexane or worked in the vicinity of glue application. The geometric mean and highest cyclohexane concentrations measured in environmental air using diffusion samplers were 27 and 274 ppm (93 and 943mg/m3) respectively. There was a significant correlation between atmospheric concentrations of cyclohexane and both concentrations of cyclohexanol in urine and cyclohexane in blood and serum; urinary concentrations of cyclohexanone were less well correlated. Only <1% of the absorbed dose was excreted in urine as cyclohexanol almost exclusively as the glucuronide; the half life was estimated at 5 hours.

Perico et al. (1999) monitored atmospheric concentrations of cyclohexane in shoe and leather factories and the excretion of cyclohexane-1,2 diol and cyclohexane-1,4 diol in the urine of exposed workers. Atmospheric concentrations of cyclohexane were measured throughout the 6 - 7 hour working shift using active personal samplers. Urine samples were collected throughout a working week as follows; Monday pre-shift (n=29), Monday post-shift (n=86), Thursday post-shift (n=70) and Friday pre-shift (n=70); metabolite concentrations were determined by gas chromatography after hydrolysis of conjugates. Urine samples were also obtained from subjects not occupationally exposed to cyclohexane to determine whether background concentrations of the metabolites were present. Individual exposure to cyclohexane ranged from 7 - 617mg/m3 (geometric mean - 60mg/m3). Urinary concentrations of cyclohexane-1,2 diol (geometric means) were 3.1, 7.6, 13.2 and 6.3mg/g creatinine for the Monday pre- and post-shift samples, Thursday post-shift sample and Friday pre-shift samples respectively. The corresponding values for cyclohexane-1,4 diol were 2.8, 5.1, 7.8 and 3.7mg/g creatinine. There was a good correlation between environmental exposure to cyclohexane and Monday post-shift values for the diols but poor correlation with the samples taken on Thursday and Friday. The poor correlation after repeated exposure was attributed to accumulation of the diols during the week (half lives were approximately 18 hours). Workers not occupationally exposed to cyclohexane had urinary concentrations (geometric means) of 0.4 and 1.2mg/g creatinine for cyclohexane-1,2 diol and cyclohexane-1,4 diol respectively.

Additional Data

Cyclohexane was detected but not quantified in 5 samples of human milk collected in different towns and states of the US and analysed for volatile and semi-volatile organic compounds using gas chromatography - mass spectrometry (Pellizzari, 1982).

 

Discussion on absorption rate:

The toxicokinetics of cyclohexane after dermal exposure have been studied in rat (RTI, 1996; Lyadomi et al., 1998).

In the first study, groups of male and female Fisher-344 rats were exposed dermally to occluded doses of 1 or 100mg/cm2[14C]-cyclohexane for 6 hours; an additional group of rats received a single intravenous dose of 10 mg [14C]-cyclohexane per kg bodyweight. The report authors commented that the low dermal dose was present primarily as vapour while the high dose was present primarily as liquid. Exhaled volatiles, urine and blood samples were collected up to 72 hours after dosing and analysed for total14C. Carcasses were retained at termination and analysed for residues of total14C. Lyadomi et al. (1998) measured blood concentrations of cyclohexane in male WBN/ILA-Ht hairless rats using headspace capillary gas chromatography after dermal exposure for 2 hours to 1mL cyclohexane applied to 3.14cm2skin within an affixed chamber.

Absorption

Absorption of cyclohexane after dermal exposure to 1mg/cm2was 36% (0.06mg/cm2/h) and 60% (0.10mg/cm2/h) in male and female rats respectively and 4% (0.65mg/cm2/h) in both sexes after dermal exposure to 100mg/cm2. The small group sizes and considerable inter-animal variability in absorption prevented an assessment of the relevance of the apparent sex difference at the low dose level.  Lyadomi et al. (1998) did not measure absorption rates but demonstrated that cyclohexane rapidly entered the systemic circulation.

Distribution

Neither study measured tissue distribution of absorbed cyclohexane. In the RTI (1996) study, total 14C residues in carcasses at 72 hours after exposure to [14C]-cyclohexane were <0.4% and <0.1% of doses of 1 and 100mg/cm2 respectively.  Lyadomi et al. (1998) found that blood concentrations of cyclohexane reached a peak of approximately 0.24 µmol/L within 1 hour of the start of exposure and then declined until the end of the 2 hour exposure.

Metabolism

No assessment of the metabolism of cyclohexane was made in either study.

Excretion

Exhaled volatiles accounted for 70% of the radioactivity excreted from the 10mg/kg intravenous dose and 78% and 57% of the radioactivity excreted from the 1 and 100 mg/cm2 dermal doses respectively. Urinary excretion of total 14C represented 29%, 20% and 40% of the excreted radioactivity from the intravenous, low dermal and high dermal doses respectively.

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.

Isoprene is formed endogenously in humans; the sources proposed include mevalonic acid via the intermediate product dimethylallyl pyrophosphate (precursors of cholesterol), the peroxidation of squalene and from the decomposition of farnesyl (3 isoprene units) or geranylgeranyl residue (4 isoprene units) of prenylated proteins. Isoprene exhibits saturation kinetics in rats and mice For humans at low concentrations, the rate of isoprene metabolism to its epoxide metabolites is about 8-14 times lower than in rodents. The rate of metabolism was directly proportional to the exposure concentration at concentrations up to 300 ppm. Saturation of isoprene metabolism was nearly complete at about 1000 ppm in rats and at about 2000 ppm in mice. The maximal metabolic elimination rate in mice was determined to be at least 400µmol/hr/kg, which is about three times faster than that found in rats (130µmol/hr/kg). The whole body half-life of isoprene was 6.8 minutes in rats and 4.4 minutes in mice. The internal dose of isoprene was found to be greater in mice than rats after exposure to the same concentration. At concentrations above 1000 ppm, mice absorb three times more isoprene per kg body weight compared to rats, though at lower concentrations, the species difference in uptake became smaller (approx. two-fold at 700 ppm). Metabolites of isoprene were detected in the blood, nose, lungs, liver, kidneys, and fat of male F344/N rats exposed to 1,480 ppm [14C]-labelled isoprene. In liver microsomes, isoprene is metabolized by cytochrome P450 oxidation to the monoepoxide metabolites, 3,4-epoxy-3-methyl-butene and 3,4 -epoxy-2-methyl-butene. Both monoepoxides can be further metabolized to the diepoxide metabolite, 1,2:3,4-diepoxy-2-methyl-butane. The epoxides can also be hydrolysed or can be conjugated with glutathione. It is also expected that epoxide diols can be formed. A physiologically-based toxicokinetic (PT) -model has been constructed and used to simulate the inhalation of isoprene, its distribution by the blood flow, its metabolism, endogenous production, and exhalation as unchanged isoprene (Filser et al, 1996; Csanady and Filser, 2001). The model compartments consist of air, lung, richly perfused tissues, fat, muscle, and liver. Mouse, rat and human partition coefficients were determined experimentally. The endogenous production of isoprene was considered to occur only in the human liver and was described by zero-order kinetics. Taking into account species-specific partition coefficients and physiological processes (ventilation or blood flow), pulmonary uptake, accumulation in the blood and tissues, exhalation and rates of isoprene metabolism were comparable in rodents and humans. The PT model predicted that for exposure concentrations up to 50 ppm, the rate of isoprene metabolism are about 14 times faster in mice and about 8 times faster in rats than in humans. At 0 ppm atmospheric isoprene, the rate of metabolism in humans is 0.31 μmol/hr/kg body weight and represents the part of endogenously produced isoprene that is metabolized. About 90% of the endogenously produced isoprene is metabolized, and only about 10% is exhaled unchanged. Because of the rapid isoprene metabolism, Csanady and Filser (2001) concluded that isoprene cannot accumulate in humans at low exposure concentrations. Dermal absorption is low, with model prediction giving absorption of approximately 0.3%

 

The EU Risk Assessment Report (EU, 2002) contains a comprehensive review of the toxicokinetic information on 1,3-butadiene. In summary, various animal studies have shown rapid absorption of 1,3-butadiene by the lungs. In rodents, uptake and metabolism obeys simple first order kinetics at concentrations up to about 1,500 ppm, above which saturation of the process appears to occur. There are no data on the toxicokinetics of 1,3-butadiene following oral or dermal exposure, and their contribution to uptake and metabolism of 1,3-butadiene is anticipated to be negligible. After inhalation exposure both rats and mice show high concentration of 1,3-butadiene and its metabolites in their body tissues. The highest concentration are observed in the fat with lower levels in the blood, heart, lung, liver, bone marrow, thymus and kidney, with levels consistently higher in the target tissues of mice than rats. Available data indicate that metabolism is qualitatively similar among the various species (including humans) studied, although there may be quantitative differences in the metabolic rates and the proportion of metabolites generated. The major metabolic pathway involves initial oxidation of 1,3-butadiene via cytochrome P-450 enzymes (predominantly P-450 2E1, although other isozymes may also be involved) to the reactive metabolite, 1,3-butadiene monoxide (or epoxybutene). Epoxybutene can be further activated via cytochrome P-450 mediated transformation to another active metabolite 1,2,3,4-diepoxide (or diepoxybutane). The epoxybutene and diepoxybutane can be detoxified by hydrolysis or glutathione conjugation and is mediated by epoxide hydrolase and glutathione S-transferase. Epoxybutene, diepoxybutane and crotonaldehyde are all-reactive and known mutagens and are believed to be responsible for the toxic effects of butadiene. Extensive data indicate that the active epoxide metabolites (including diepoxide) are formed to a greater degree in mice than in rats exposed similarly to 1,3-butadiene. A comparison of butadiene epoxide levels in target tissues (blood, bone marrow, lung, heart, fat, spleen and thymus) of rats and mice following low level exposure to 1,3-butadiene showed consistently higher epoxide levels in mouse than in rat tissues. The greater susceptibility of mice to the toxic effects of 1,3-butadiene may be related to the higher rate of formation of epoxybutene and limited detoxification, resulting in greater accumulation of the active metabolites in this species. 1,3-butadiene is excreted via the respiratory tract, urine or faeces. In rodents, urinary excretion takes place in two phases with 77-99% of the inhaled dose excreted with a half-life of a few hours, while the remainder is excreted with a half-life of several days. There is no evidence for bioaccumulation of 1,3-butadiene.

In an in vivo percutaneous absorption study using hairless mice and a direct method for volatile chemicals, total absorption of ethylbenzene was 3.61% of the achieved dose. A breath decay curve indicated absorption was complete 15 minutes after application. Evaporation rates were used to derive an estimated contact time of 5 min and the percutaneous absorption rate was calculated to be 37 µg/cm2/min.

 

Key References

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.