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Key value for chemical safety assessment

Additional information

Toxicokinetic data is available for constituents of the C9-C14 aliphatic, 2-25% aromatic hydrocarbon fluids; principally the C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids and the C9 aromatic fluids. Based on the data from the constituents, C9-C14 aliphatic, 2-25% aromatic hydrocarbon fluids, can be absorbed when inhaled, ingested, or when dermally exposed. C9-C14 aliphatic, 2-25% aromatic hydrocarbon fluids are expected to be rapidly metabolized and eliminated with little possibility of bioaccumulation.

 

C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids

C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids are readily absorbed when inhaled or ingested.  C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids can be dermally absorbed. Regardless of exposure route, C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids are rapidly metabolized and eliminated. Bioaccumulation of C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids is not expected.

 

C9 aromatic fluids

C9 aromatic fluids are readily absorbed when inhaled or ingested.  C9 Aromatic fluids can be dermally absorbed. Bioaccumulation of C9 Aromatic fluids is not expected.

Discussion on bioaccumulation potential result:

Toxicokinetic data is available for constituents of the C9-C14 aliphatic, 2-25% aromatic hydrocarbon fluids; principally the C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids and the C9 aromatic fluids. 

C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids

C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids are apparently well absorbed if ingested or inhaled. C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids undergo metabolism and rapid excretion; bioaccumulation of the test substance in the tissues is not likely to occur. 

 

C9 to C14 isoalkanes are taken up into the blood and distributed to the internal organs including brain, liver, kidney and fat.  Twelve hours after the exposure, levels in blood, brain, liver and kidney were below detection levels; levels in fat were about half those found at the end of the exposure period.  These data demonstrate that isoalkanes are rapidly eliminated and do not accumulate. The concentration of isoalkanes in blood, brain, liver and fat increased with increasing number of carbon atoms. The C9 and C10 isoalkanes showed increasing concentrations in fat during the exposure period and high concentrations 12 hr after cessation of exposure.

 

Inhaled n-alkanes, nC9-nC13, are taken up into the blood and distributed to the internal organs including the brain.  There is also a corresponding reduction in the blood/air and brain/air ratios with increasing carbon numbers up to C10.  At high carbon numbers the ratios decrease suggesting blood/brain barrier effects for high molecular weight hydrocabons (Nilsen et. al 1988). Thus the efficiency of uptake into both blood and brain also decreases with increasing carbon number. A brain/blood ratio of 11.4 and a fat/blood ratio of 113 was determined for n-nonane. n-Decane was found to have a half-life of 2 hours. The percentage retention of n-alkanes showed an inverse linear relationship to chain length that was describable by the regression line: (percentage retained) = 115.9-3.94 * (number of carbon atoms). This line had a correlation coefficient of -0.995, standard error of estimate Sy * x= 3.30, t = 30.85 and P < 0.001.  The absorption of paraffins with 9-13 carbons ranges from 65-80%.  

 

Based on a study of jet propellant 8 (JP-8) jet fuel components, the in vitro (rat liver microsomal oxidation) nonlinear kinetic constants for n-nonane and n-decane were V(max) (nmol/mg protein/min) = 7.26 +/- 0.20 and 2.80 +/- 0.35, respectively, and K(M) (micro M) = 294.83 +/- 68.67 and 398.70 +/- 42.70, respectively. Metabolic capacity as assessed by intrinsic clearance, V(max)/K(M), was approximately four-fold higher for nonane (0.03 +/- 0.005) than for decane (0.007 +/- 0.001).

 

The blood/brain ratio and the fat/blood ratios for trimethylcyclohexane were determined to be 11.4 and 135, respectively. A marked decrease in biological concentrations of trimethylcyclohexane during the initial phase of exposure indicates that this hydrocarbon is capable of inducing its own metabolic conversion resulting in lower steady state levels.

 

The tissue disposition after 3 weeks of exposure to dearomatised white spirit, mixed aliphatic, and cycloaliphatic constituents was determined. After 3 weeks of exposure the concentration of total white spirit was 1.5 and 5.6 mg/kg in blood; 7.1 and 17.1 mg/kg in brain; 432 and 1452 mg/kg in fat tissue at the exposure levels of 400 and 800 ppm, respectively. The concentrations of n-nonane, n-decane, n-undecane, and total white spirit in blood and brain were not affected by the duration of exposure. Two hours after the end of exposure the n-decane concentration decreased to about 25% in blood and 50% in brain. A similar pattern of elimination was also observed for n-nonane, n-undecane and total white spirit in blood and brain. In fat tissue the concentrations of n-nonane, n-decane, n-undecane, and total white spirit increased during the 3 weeks of exposure. The time to reach steady-state concentrations is longer than 3 weeks. Post-exposure decay in blood could be separated into two phases with half-lives of approximately 1 and 8 hr for n-nonane, n-decane, and n-undecane. In brain tissue two slopes with half-lives of 2 and 15 hr were identified. In fat tissue, only one slope with half-life of about 30 hr was identified. In conclusion, after 3 weeks of exposure the fat:brain:blood concentration coefficients for total white spirit were approximately 250:3:1.

 

Nilsen, O., Haugen, O., Zahlsen, K. Halgunset, J., Helseth, A., Aarset, H., and Eide,1988. Toxicity of n-C9 to n-C13 alkanes in the rat on short term inhalation. Pharmacology and Toxicology 62:259-266.

C9 aromatics

DISTRIBUTION

Human Data: 1,3,5-trimethylbenzene has a very large volume of distribution (30-30 L/kg), implying wide tissue distribution and substantial partitioning in the tissues (2).  One hour post exposure blood levels of 1,3,5-trimethylbenzene in human volunteers exposed to 25 ppm for 4 hours were similar to the steady-state level that occurred during the exposure period (2, 3).  These data, combined with the very high oil:air partition coefficients of trimethylbenzenes (9620-11300) imply substantial redistribution of inhaled trimethylbenzenes to fatty tissues (2, 3, 6)

Animal Data: Tissue levels of 1,2,4-trimethylbenzene following exposure to 100 ppm for 12 hours per day for 3 days are summarized in Table 1.

 

Table 1.  Distribution of 1,2,4-trimethylbenzene in rat tissues (mean value from four animals)following exposure to 100 ppm of the substances 12 h daily for 3 days. Values in parentheses are from animals that had a 12-h recovery period after the last exposure (10).                                                         

                                            

Tissue

Concentration (µmol/kg)

Blood  

17.1

Brain

36.5

Liver

35.4

Kidney

103.6

Fat

1070 (120)

 

Following inhalation exposure in rats, the fat:blood partition coefficient of trimethylbenzenes is around 63 (10, 13). The data in Table 1 is consistent with this partition coefficient given the selective redistribution of 1,2,4-trimethylbenzene to adipose tissue.  Twelve hours following the cessation of exposure, adipose tissue levels of 1,2,4-trimethylbenzene were decreased by a factor of approximately 9, demonstrating rapid mobilization of this substance from body adipose tissue.  Thus normally, long-term accumulation of this material in fat does not occur. Trimethylbenzene does not selectively redistribute to other body tissues other than adipose tissues.

Oral dosing of rats with 14C-1,2,4-trimethylbenzene was associated with a rapid and wide tissue distribution of radioactivity throughout the body, with selective and preferential re-distribution to adipose tissue (14).  There was no preferential uptake of radioactivity into any other organ or tissue (14).

 

Summary: Collectively, these data demonstrate that during inhalation exposure, C9 aromatics undergo substantial partitioning into adipose tissues.  Following cessation of exposure, the level of C9 aromatics in body fats rapidly declines.  Thus, the C9 aromatics are unlikely to bioaccumulate in the body.  Selective partitioning of the C9 aromatics into the non-adipose tissues is unlikely. No data is available regarding distribution following dermal absorption.  However, distribution following this route of exposure is likely to resemble the pattern occurring with inhalation exposure.

 

METABOLIC TRANSFORMATION

 

Human Data: The major metabolites of trimethylbenzenes most commonly identified in urine are the dimethylbenzoic acid and dimethylhippuric acid derivatives of the parent molecule (1-3, 5, 15-20).  Both the dimethylbenzoic and hippuric acid metabolites of the trimethylbenzenes are commonly used for biomonitoring of human exposures.

 

Animal Data: In rats, urinary metabolites of 1,2,4-trimethylbenzene consist of a complex mixture of isomeric triphenols, the sulphate, glucuronide and mercapturic conjugates of dimethylbenzyl alcohols, dimethylbenzoic acids and dimethylhippuric acids (14).  The major metabolites are 3,4-dimethylhippuric acid (30.2% of the dose), sulphate and glucuronide conjugates of 2,4-dimethylbenzyl alcohol (12.7% of the dose), and sulphate and glucuronide conjugates of 2,5-dimethylbenzyl alcohol (11.7% of the dose) (14).

 

In rats, approximately 78% of an oral dose of 1,3,5-trimethylbenzene is excreted as 3,5-dimethylhippuric acid; an additional 7.6 and 8.2% were excreted as glucuronic and sulphuric acid conjugates (21). The corresponding values for the glycine, glucuronic and sulphuric acid conjugates of 1,2,4-trimethylbenzene and 1,2,3-trimethylbenzene were 43.2, 6.6, and 12.9% and 17.3, 19.4, and 19.9%, respectively (21). In rabbits, the major urinary metabolites of 1,2,4-trimethylbenzene following oral dosing are 2,4-dimethylbenzoic acid and 3,4-dimethylhippuric acid (22).

 

Biotransformation of 1,2,4-trimethylbenzene to dimethylbenzoic acids in the rat follows the Lineweaver-Burk equation with Km ranging from 7-28 mg/l and Vmax ranging from 23-96 mg/h/kg depending on the particular species of dimethylbenzoic acid formed (7). Biotransformation to 3,4-dimethylbenzoic acid is favoured, given its Km of 28 mg/l and Vmax of 96 mg/h/kg.  Notably, in rats, the biotransformation of trimethylbenzenes is inhibited by pre-treatment with ethanol and enhanced by ethyl acetate (8, 23). In rats, 1,3,5-trimethylbenzene is an inducer of cytochrome p450, cytochrome b5, aminopyrine N-demethylase, aryl hydrocarbon hydroxylase, aniline hydroxylase,and NADPH-cytochrome c reductase in the rodent liver (24).  In the kidney, 1,3,5-trimethylbenzene induces cytochrome P-450 and cytochrome b5 (24).  Thus, trimethylbenzenes are inducers of their own metabolism in the rat.  These data are consistent with the low propensity for bioaccumulation of trimethylbenzenes in mammals.

 

Summary: Collectively these data demonstrate that C9 aromatics may undergo several different Phase I dealkylation, hydroxylation and oxidation reactions which may or may not be followed by Phase II conjugation to glycine, sulphation or glucuronidation.  However, the major predominant biotransformation pathway is typical of that of the alkylbenzenes and consists of: (1) oxidation of one of the alkyl groups to an alcohol moiety; (2)oxidation of the hydroxyl group to a carboxylic acid; (3) the carboxylic acid is then conjugated with glycine to form a hippuric acid. The minor metabolites can be expected to consist of a complex mixture of isomeric triphenols, the sulphate and glucuronide conjugates of dimethylbenzyl alcohols, dimethylbenzoic acids and dimethylhippuric acids.  Consistent with the low propensity for bioaccumulation of the C9 aromatics, these substances are likely to be significant inducers of their own metabolism. 

 

ELIMINATION AND EXCRETION

Human Data: The identified routes of excretion of the trimethylbenzenes following inhalation exposure in humans include: (1) exhalation of the unchanged volatile parent substance (3); (2) urinary excretion of the unchanged volatile parent substance(25); and (3) urinary excretion of metabolites (1-3, 5, 15-20).  Post-exposure exhalation of unmetabolized trimethylbenzenes accounts for 20-37% of the absorbed amount (2).  Urinary excretion of unmetabolized trimethylbenzenes is low (= 0.002%) (2).  Overall urinary excretion of metabolites (predominantly 3,4-dimethylhippuric acid) of 1,2,4-trimethylbenzene in the first 24 hours post-exposure accounts for 22% of the inhaled dose (18). Urinary excretion of unconjugated dimethylbenzoic acid metabolites accounts for only small percent of the inhaled dose of trimethylbenzenes (18). The bulk of the absorbed dose of trimethylbenzenes is metabolized and excreted in urine, predominantly as their dimethylhippuric acids or conjugated (sulphated or glucuronidated) dimethylbenzoic acid derivatives (1-3, 5, 15-20).  The urinary excretion of dimethylhippuric acids is well-correlated with exposure to trimethylbenzenes and has been commonly used for biomonitoring purposes. 

 

The initial blood clearance of trimethybenzenes in man is 0.6-1 l/hr/kg (2). However, trimethylbenzenes have longer terminal half-lives in blood (T½ 78-120 hr) due to their extensive partitioning into adipose tissues (2).  The kinetics of urinary elimination of unmetabolized 1,3,5-trimethylbenzene follows a biphasic pattern with a T½ for Phase I of 0.45-0.88 hr and a T½ for Phase II of 6.7-19.2 hr.25  Elimination of unmetabolized 1,3,5-trimethylbenzene in exhaled air is biphasic with an initial T½ of 1 hr (3).  Urinary elimination of dimethylbenzoic acids following inhalation exposure to 1,3,5-trimethylbenzene is biphasic with a T½ for Phase I of 13 hr and a T½ for Phase II of 60 hr (3).  Notably, co-exposure to white spirits interferes with the metabolic elimination of 1,2,4-trimethylbenzene (5, 16).

 

Animal Data: Following oral administration of 14C-1,2,4-trimethylbenzene, > 99% of the administered radioactivity was excreted in urine within 24 hours (14).  The predominant urinary species being the 3,4-dimethylhippuric acid metabolite (14).  Likewise, urine is the major route of excretion of trimethylbenzene metabolites in rats following inhalation exposure. As in humans, there is a strong correlation between the level of trimethylbenzene inhalation exposure and the concentration of metabolites in urine.

 

Summary: Collectively these data demonstrate that the predominant route of excretion of C9 aromatics following inhalation exposure involves either exhalation of the unmetabolized parent compound, or urinary excretion of its metabolites.  When oral administration occurs, there is little exhalation of unmetabolized C9 aromatics, presumably due to the first pass effect in the liver.  Under these circumstances, urinary excretion of metabolites is the dominant route of excretion.

 

References

1.            Kostrzewski P, Wiaderna-Brycht A, Czerski B. Biological monitoring of experimental human exposure to trimethylbenzene. Sci Total Environ 1997;199:73-81.

2.            Jarnberg J, Johanson G, Lof A. Toxicokinetics of inhaled trimethylbenzenes in man. Toxicol Appl Pharmacol 1996;140:281-288.

3.            Jones K, Meldrum M, Baird E, et al. Biological monitoring for trimethylbenzene exposure: a human volunteer study and a practical example in the workplace. Ann Occup Hyg 2006;50:593-598.

4.            Jarnberg J, Johanson G. Physiologically based modeling of 1,2,4-trimethylbenzene inhalation toxicokinetics. Toxicol Appl Pharmacol1999;155:203-214.

5.            Jarnberg J, Johanson G, Lof A, Stahlbom B. Inhalation toxicokinetics of 1,2,4-trimethylbenzene in volunteers: comparison between exposure to white spirit and 1,2,4-trimethylbenzene alone. Sci Total Environ 1997;199:65-71.

6.            Jarnberg J, Johanson G. Liquid/air partition coefficients of the trimethylbenzenes.Health 1995;11:81-88.

7.            Swiercz R, Rydzynski K, Wasowicz W, Majcherek W, Wesolowski W. Toxicokinetics and metabolism of pseudocumene (1,2,4-trimethylbenzene) after inhalation exposure in rats. Int J Occup Med Environ Health2002;15:37-42.

8.            Romer KG, Federsel RJ, Freundt KJ. Rise of inhaled toluene, ethyl benzene, m-xylene, or mesitylene in rat blood after treatment with ethanol. Bull Environ Contam Toxicol 1986;37:874-876.

9.            Dahl AR, Damon EG, Mauderly JL, et al. Uptake of 19 hydrocarbon vapors inhaled by F344 rats. Fundam Appl Toxicol 1988;10:262-269.

10.          Zahlsen K, Nilsen AM, Eide I, Nilsen OG. Accumulation and distribution of aliphatic (n-nonane), aromatic (1,2,4-trimethylbenzene) and naphthenic (1,2,4-trimethylcyclohexane) hydrocarbons in the rat after repeated inhalation. Pharmacol Toxicol 1990;67:436-440.

11.          Korinth G, Geh S, Schaller KH, Drexler H. In vitro evaluation of the efficacy of skin barrier creams and protective gloves on percutaneous absorption of industrial solvents. Int Arch Occup Environ Health 2003;76:382-386.

12.          McDougal JN, Pollard DL, Weisman W, Garrett CM, Miller TE. Assessment of skin absorption and penetration of JP-8 jet fuel and its components. Toxicol Sci 2000;55:247-255.

13.          Eide I. A review of exposure conditions and possible health effects associated with aerosol and vapour from low-aromatic oil-based drilling fluids. Ann Occup Hyg 1990;34:149-157.

14.          Huo JZ, Aldous S, Campbell K, Davies N. Distribution and metabolism of 1,2,4-trimethylbenzene (pseudocumene) in the rat. Xenobiotica1989;19:161-170.

15.          Fukaya Y, Saito I, Matsumoto T, Takeuchi Y, Tokudome S. Determination of 3,4-dimethylhippuric acid as a biological monitoring index for trimethylbenzene exposure in transfer printing workers. Int Arch Occup Environ Health 1994;65:295-297.

16.          Jarnberg J, Johanson G, Lof A, Stahlbom B. Toxicokinetics of 1,2,4-trimethylbenzene in humans exposed to vapours of white spirit: comparison with exposure to 1,2,4-trimethylbenzene alone. Arch Toxicol 1998;72:483-491.

17.          Kostrewski P, Wiaderna-Brycht A. Kinetics of elimination of mesitylene and 3,5-dimethylbenzoic acid after experimental human exposure. Toxicol Lett 1995;77:259-264.

18.          Jarnberg J, Stahlbon B, Johanson G, Lof A. Urinary excretion of dimethylhippuric acids in humans after exposure to trimethylbenzenes. Int Arch Occup Environ Health 1997;69:491-497.

19.          Stahlbom B, Jarnberg J, Soderkvist P, Lindmark D. Determination of dimethylhippuric acid isomers in urine by high-performance liquid chromatography. Int Arch Occup Environ Health 1997;69:147-150.

20.          Ichiba M, Hama H, Yukitake S, et al. Urinary excretion of 3,4-dimethylhippuric acid in workers exposed to 1,2,4-trimethylbenzene. Int Arch Occup Environ Health 1992;64:325-327.

21.          Mikulski PI, Wiglusz R. The comparative metabolism of mesitylene, pseudocumene, and hemimellitene in rats. Toxicol Appl Pharmacol1975;31:21-31.

22.          Cerf J, Potvin M, Laham S. Acidic metabolites of pseudocumene in rabbit urine. Arch Toxicol 1980;45:93-100.

23.          Freundt KJ, Romer KG, Federsel RJ. Decrease of inhaled toluene, ethyl benzene, m-xylene, or mesitylene in rat blood after combined exposure to ethyl acetate. Bull Environ Contam Toxicol1989;42:495-498.

24.          Pyykko K. Effects of methylbenzenes on microsomal enzymes in rat liver, kidney and lung. Biochim Biophys Acta 1980;633:1-9.

25.          Janasik B, Jakubowski M, Jalowiecki P. Excretion of unchanged volatile organic compounds (toluene, ethylbenzene, xylene and mesitylene) in urine as result of experimental human volunteer exposure. Int Arch Occup Environ Health2008;81:443-449.

26.          Hissink, A. et al. (2007).  Model studies for evaluating the neurobehavioral effects of complex hydrocarbon solvents III.  PBPK modeling of white spirit constituents as a tool for integrating animal and human data.  Neurotoxicology 28:751-760.

27.          Muhammad, F. et al. (2005).  Effect of in vivo jet fuel exposure on subsequent in vitro dermal absorption of individual aromatic and aliphatic hydrocarbon fuel constituents.  Journal of Toxicological and Environmental Health Part A, 68:719-737.

Discussion on absorption rate:

There have not been any in vivo dermal absorption studies of C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids, but there have been in vitro studies of some constituents, particularly dodecane.  Due to the structural similarity of these molecules to other constituents of the C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids, it seems reasonable to assume that the solvents would have toxicokinetic properties similar to those of these constituents.  There is also dermal absorption studies available for the C9 aromatics.

C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids 

IN VIVO

 

Ten healthy adult volunteers (five males and five nonpregnant females) with no occupational exposure to jet fuel were recruited for participation. One of the volunteer’s forearms was placed palm up inside the exposure chamber, and two aluminum application wells (10 cm2 per well) were pressed against the skin to prevent JP-8 from spreading during the experiment. Neat JP-8 (1.0 mL) was applied to the volar forearm. The exposure chamber was sealed for the duration of the experiment (0.5 h). At the end of the exposure period, the two exposed skin sites were wiped with a gauze pad and tape-stripped as many as 10 times. Blood samples were drawn from the unexposed arm at baseline, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, and 3.5 h.

 

The permeability coefficients (cm/h) of the aliphatic hydrocarbons were determined to be: Decane 6.5E-06, Undecane 4.5E-07, and Dodecane 1.6E-06.

 

A simple mathematical model based on Fick’s laws of diffusion was used to predict the spatiotemporal variation of undecane and dodecane in the stratum corneum of human volunteers using the same data as above. The estimated values of the diffusion coefficients (Dsc, cm2/min×10E-8 +/- S.D.) were determined to be: undecane, 4.2 +/- 1.2 and Dodecane, 5.0 +/- 0.7.

 

IN VITRO

Several in vitro studies used porcine skin flaps to determine the absorption and disposition of several aliphatic compounds. There are some general conclusions of the absorption and disposition of C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids. All of the tested chemicals showed a lag time of about 1 h. The retention of aliphatic chemicals in stratum corneum is much higher than epidermis and dermis at all time points. Under infinite dose conditions, the chemicals diffused rapidly into stratum corneum and reached plateau levels within 1 h. The absorption of chemicals in stratum corneum at all time points were in the following order: tetradecane > dodecane > nonane. This shows a linear relationship between the carbon chain length and the absorption of the chemicals in the stratum corneum. The absorption pattern of chemicals in epidermis and dermis, in contrast to stratum corneum, demonstrated a parabolic relationship between the molecular weight of the hydrocarbon and their skin retention.

 

Dermal absorption values for several of the C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids have been experimentally determined. The permeability coefficients (cm/h) for decane, undecane, and dodecane were determined to be 6.5*10E-6, 4.5*10E-07, and 1.6*10E-06, respectively. In a second experiment, the diffusion coefficient values (cm2/h) of for dodecane (DOD), tridecane (TRI), and tetradecane (TET) were determined to be (0.21 +/-0.02)*10E-6, (6.849 +/- 0.57)*10E-6, (0.209 +/- 0.04)*10E-6, respectively.

 

Binding to the stratum corneum can be determined by calculating the Log PC (octanol/water) values. There is an increase in binding of the aliphatic JP-8 components to with increasing Log PC value. Log PC values are 8.76 +/- 0.74, 13.15 +/- 1.05, 15.85 +/- 1.36 for dodecane (DOD), tridecane (TRI), and tetradecane (TET), respectively.

 

The flux, JSS (nmol/cm2 per h)*10E-2, values were determined to be 1.94 +/- 0.39, 13.80 +/- 0.82, and 1.40 +/- 0.20 for DOD, TRI, and TET, respectively. The permeability coefficients, Kp (cm/h)*10E-4, were 0.37 +/- 0.13, 18.46 +/- 1.50, 0.64 +/- 0.20 for DOD, TRI, and TET, respectively. The diffusion coefficient values, D (cm/h)*10E-6, were determined to be 0.21 +/- 0.02, 6.84 +/- 0.57, and 0.20 +/- 0.04 for DOD, TRI, TET, respectively. The lag time (hours) was determined to be 1.33 +/- 0.07, 0.89 +/- 0.17, and 1.62 +/- 0.34 hours for DOD, TRI, and TET, respectively. FTIR results suggest that all of the test chemicals significantly (P<0.05) extracted SC lipid and protein in comparison to control. TRI exhibited greater extraction of the SC lipid and protein as well as greater transport through the skin than other chemicals.

C9 aromatic fluids

  ABSORPTION

INHALATION EXPOSURE

 

Human Data

Exposure of human volunteers to trimethylbenzene vapour concentrations ranging from 5 -150 mg/m3 resulted in pulmonary retentions between 56-71% depending on the chemical species and the study (1, 2). Absorption into the blood stream of human volunteers exposed to a 25 ppm vapour of 1,3,5-trimethylbenzene for a period of 4 hours was rapid, and resulted in a mean steady-state blood level of 0.85 micromol/l after 1-2 hours of exposure(3). Similar results were observed in human volunteers exposed to 100 ppm (26). Likewise, rapid pulmonary absorption of 1,2,3-trimethylbenzene in human volunteers has also been demonstrated (4, 5).

In vitro human blood:gas partition coefficients for the trimethylbenzenes are high, ranging from 40.8 to 69.3, depending on the chemical species (6).  Thus the pulmonary absorption of trimethylbenzenes is ventilation-limited.  This is consistent with the apparent high rate of uptake of the trimethylbenzenes from the alveoli into the blood and the apparent slow rate of equilibration of 1,3,5-trimethylbenzene partial pressures in alveolar and inspired air in man (3).

 

Animal Data : The systemic absorption of inhaled trimethylbenzenes in rats is rapid with blood levels reaching a plateau after about 2 hours of exposure (7, 8).   The rate of uptake of inhaled 1,2,4-trimethylbenzene rats is 13.6 nmol×kg-1×min-1×ppm-1during nose-only exposure (9, 10). As in humans, 1,2,4-trimethylbenzene has a relatively high blood:gas partition coefficient and its uptake is ventilation-limited (10).  

 

Summary: The available human and animal data imply that: a high proportion of inhaled C9 aromatic substances are available for absorption; that rapid systemic absorption of C9 aromatics following inhalation exposure can be expected; and that pulmonary absorption of the C9 aromatic substances is ventilation limited.

 

DERMAL EXPOSURE

 

Human Data: Attempts at dermal absorption determinations in humans with trimethylbenzenes has been difficult due to their acute primary skin irritancy (3). Slow, low-level skin penetration of 1,2,4-trimethylbenzene through excised human skin in vitro, as measured using Franz static diffusion cells, can occur although steady state absorption conditions were not established following an 8 hour exposure period (11)

 

Animal Data: The mean in vitro rat dermal absorption flux of trimethylbenzenes present in a kerosene-based fuel (JP-8), was 1.25 micrograms/cm2/hour with a breakthrough time of 1 hour, as determined in Franz static diffusion cells.12 Similarly, in a study in which pigs were treated dermally with jet fuel for 1-4 days, and then skin removed and tested for dermal penetration under in vitro conditions, values of 0.49-1.01 micrograms/cm2/hour were reported for trimethylbenzene (27).

 

Summary: The available in vitro and animal data imply that C9 aromatics will be systemically absorbed following dermal exposure, albeit at low levels.