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Description of key information

Short description of key information on bioaccumulation potential result:

If C9-C14 aliphatic, <2% aromatic hydrocarbon fluids are absorbed, they are typically metabolized by side chain oxidation to alcohol and carboxylic acid derivatives.  These metabolites can be glucuronidated and excreted in the urine or further metabolized before being excreted.  The majority of the metabolites are excreted in the urine and to a lower extent, in the feces.  Excretion is rapid with the majority of the elimination occurring within the first 24 hours of exposure.  As a result of the lack of systemic toxicity and the ability of the parent material to undergo metabolism and rapid excretion, bioaccumulation of the test substance in the tissues is not likely to occur.

Short description of key information on absorption rate:

C9-C14 aliphatic, <2% aromatic hydrocarbon fluids are poorly absorbed dermally with an estimated overall percutaneous absorption rate of approximately 2ug/cm2/hr or 1% of the total applied fluid. Regardless of exposure route, C9-C14 aliphatic, <2% aromatic hydrocarbon fluids are rapidly metabolized and eliminated.

Key value for chemical safety assessment

Additional information

C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids are readily absorbed when inhaled or ingested.  C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids are poorly absorbed dermally with an estimated overall percutaneous absorption rate of approximately 2ug/cm2/hr or 1% of the total applied fluid.  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.

Discussion on bioaccumulation potential result:

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 were 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. Paraffin having more than 29 carbon atoms thus would not be absorbed to a significant extent under these conditions.

 

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.

 

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.  

 

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.

OVERVIEW OF PERCUTANEOUS ABSORPTION OF HYDROCARBON SOLVENTS

There are no studies of repeated dose toxicity of hydrocarbon solvents using the dermal route of administration. Accordingly, where it is necessary to calculate dermal DNELs, systemic data from studies utilizing other routes of administration, normally inhalation but also oral data, can be used in some situations.  In accordance with ECHA guidance, read across from oral or inhalation data to dermal should account for differences in absorption where these exist (R8, example B.6). In fact, hydrocarbon solvents are poorly absorbed in most situations, in part because some are volatile and do not remain in contact with the skin for long periods of time and also because, due to their hydrophobic natures, do not partition well into aqueous environments and are poorly absorbed into the blood. 

 

           If these differences in relative absorption are introduced into the DNEL calculations to calculate external doses, the DNELs based on systemic effects are highly inflated. This seems potentially misleading as it implies that substances have different intrinsic hazards when encountered by different routes whereas in fact the differences are due ultimately to differences in absorbed dose. Accordingly, it is our opinion that it would be more transparent if the differences in absorption were taken into account in the exposure equations rather than in DNEL derivation. 

 

           Shown below is a compilation of percutaneous absorption information for a number of hydrocarbon solvent constituents covering carbon numbers ranging from C5 to C14 as well as examples of both aliphatic and aromatic constituents. The low molecular weight aliphatic hydrocarbons (n-pentane, 2-methylpentane, n-hexane, n-heptane, and n-octane) were tested by Tsuruta (1982) using rat skin in an in vitro model system. As shown (Table 1), the highest percutaneous absorption value was 2 ug/cm2/hr for pentane. Lower values (< ~ 1 ug/cm2/hr) were reported for aliphatic hydrocarbons ranging from hexane to octane. Several authors have assessed the percutaneous absorption of higher molecular weight aliphatic constituents including Baynes et al. (2000), Singh and Singh (2003), Muhammad et al. (2005), and Kim et al., (2006). The first three of these authors used porcine skin models and reported that, except for one anomalous result with tridecane, the percutaneous absorption values for aliphatic constituents ranging from nonane to tetradecane were well below 1 ug/cm2/hr. Rat and human skin are considered to be more permeable than human skin (Kim et al., 2006), so these numbers can be considered conservative. 

 

           Kim et al. (2006) reported results of percutaneous absorption studies with human skin under in vivo conditions. In this case, the assessment method was based on tape stripping. The authors reported percutaneous absorption values ranging from 1 – 2 ug/kg/day for decane, undecane and dodecane. These values are higher than those reported by other authors, most likely because this technique measures absorption into the skin but not through the skin as was done in the studies listed above. Accordingly, it seems likely that these numbers are conservative as well.

 

           With respect to aromatic hydrocarbons, most of the reported percutaneous absorption values [Baynes et al. (2000); Singh and Singh (2003); Mohammad et al. (2005); and Kim et al. (2006)] are less than 2 ug/cm2/day. The only exceptions are the values for naphthalene from Mohammad et al. (2005) which range from 4.2-6.6 ug/cm2/hr. 

 

           After considering all of the above, it seems reasonable to assume apparent that across the entire range of hydrocarbon solvent constituents, percutaneous absorption values are less than 2 ug/cm2/day. Accordingly, when systemic dermal DNELs are calculated using route to route extrapolations, the values will not be corrected for differences in absorption. Rather, 2 ug/cm2/hr will be used as a common percutaneous absorption rate for all hydrocarbon solvents for which dermal exposure estimates are provided. 

           

Table 1: Summarized information on percutaneous absorption of hydrocarbon solvent constituents (C5-C16). 

 

Constituent

Molecular Weight

nmol/min/cm2

nmol/hr/cm2

ug/cm2/hr

Reference

Aliphatic Constituents

 

 

 

 

 

Pentane

72

0.52

31.2

2.2

Tsuruta et al. 1982

 

 

 

 

 

 

2-methyl pentane

86

0.02

1.2

0.1

Tsuruta et al., 1982

 

 

 

 

 

 

n-hexane

86

0.02

0.6

0.5

Tsuruta et al., 1982

 

 

 

 

 

 

n-heptane

100

0.02

1.2

0.1

Tsuruta et al., 1982

 

 

 

 

 

 

n-octane

114

0.08 x 10-3

0.005

0.0005

Tsuruta et al., 1982

 

 

 

 

 

 

Nonane

128

 

 

0.03

Muhammad et al., 2005

Nonane

 

 

 

0.38

McDougal et al., 1999

 

 

 

 

 

 

Decane

142

 

 

2

Kim et al., 2006

Decane

 

 

 

1.65

McDougal et al., 1999

 

 

 

 

 

 

Undecane

156

 

 

0.06-0.07

Muhammad et al., 2005

Undecane

 

 

 

1.0

Kim et al., 2006

Undecane

 

 

 

1.22

McDougal et al., 1999

 

 

 

 

 

 

Dodecane

170

 

 

0.02-0.04

Muhammad et al., 2005

Dodecane

 

 

 

2

Kim et al., 2006

Dodecane

 

 

 

0.3

Singh and Singh, 2003

Dodecane

 

 

 

0.51

McDougal et al., 1999

Dodecane

 

 

 

0.1

Baynes et al. 2000

 

 

 

 

 

 

Tridecane

184

 

 

0.00-0.02

Muhammad et al., 2005

Tridecane

 

 

 

2.5

Singh and Singh, 2003

Tridecane

 

 

 

0.33

McDougal et al., 1999

Tetradecane

198

 

 

0.3

Singh and Singh, 2003

Hexadecane

 

 

7.02 x 10E-3

0.00004

Singh and Singh, 2002

 

 

 

 

 

 

Aromatic Constituents

 

 

 

 

 

Trimethyl benzene

120

 

 

0.49 - 1.01

Muhammad et al., 2005

Trimethyl benzene

 

 

 

1.25

McDougal et al., 1999

 

 

 

 

 

 

Naphthalene

128

 

 

6.6 - 4.2

Muhammad et al., 2005

Naphthalene

 

 

 

0.5

Kim et al., 2006

Naphthalene

 

 

 

1.4

Singh and Singh 2002

Naphthalene

 

 

 

1.8

Baynes et al. (2000)

Naphthalene

 

 

 

1.0

McDougal et al., 1999

 

 

 

 

 

 

1 methyl naphthalene

142

 

 

0.5

Kim et al., 2006

Methyl naphthalene

 

 

 

1.55

McDougal et al., 1999

 

 

 

 

 

 

2-methyl naphthalene

 

 

 

0.5

Kim et al., 2006

2-methyl naphthalene

 

 

 

1.1

Singh and Singh, 2002

 

 

 

 

 

 

 

 

 

 

 

 

Dimethyl naphthalene

156

 

 

0.62 – 0.67

Muhammad et al., 2005

Dimethyl naphthalene

 

 

 

0.59

McDougal et al. 1999

 

 

Table 2: Estimated percentages of various hydrocarbon solvent constituents absorbed

 

Based on the information provided below, an overall estimate of 1% for all hydrocarbon solvents seems reasonable. 

 

 

Category

Representative Substance

Estimate of Percent absorption

Proposal for category

Reference for percent value

 

 

 

 

 

1

Trimethyl benzene

0.2%

0.2%

Based on data in Muhammad et al. (2005)

2

Naphthalene

1.2%

1.2%

Riviere et al. 1999

3

Dodecane (75%)

0.63%

0.5%

Riviere et al., 1999

 

TMB (25%)

0.2%

 

Muhammad et al., 2005

 

 

 

 

 

4

Hexadecane (70%)

0.18%

0.5%

Riviere et al., 1999

 

Naphthalene (30%)

1.2%

 

Riviere et al., 1999

 

 

 

 

 

5

Pentane

-

-

 

 

 

 

 

 

6

Hexane

-

-

 

 

 

 

 

 

7

Heptane

0.14%

0.14%

Singh et al. 2003

 

 

 

 

 

8

Dodecane

0.63%

0.63%

Riviere et al. 1999

 

 

 

 

 

9

Hexadecane

0.18%

0.18%

Riviere et al., 1999

 

 

 

 

 

 

References

 

Kim, D., Andersen, M., and Nylander-French (2006). Dermal absorption and penetration of jet fuel components in humans. Toxicology Letters 165:11-21.

 

McDougal, J., Pollard, D., Weisman, W., Garrett, C., and Miller, T. (2000). Assessment of skin absorption and penetration of JP-8 jet fuel and its components. Toxicological Sciences 25:247-255.

 

Muhammad, F., N. Monteiro-Riviere, R. Baynes, and J. Riviere (2005). Effect of in vivo jet fuel exposure on subsequent in vitro dermal absorption of individual aromatic and aliphatic hydrocarbon fuel constituents. Journal of Toxicology and Environmental Health Part A. 68:719-737.

 

Riviere, J., Brooks, J., Monteiro-Riviere, N., Budsaba, K., and Smith, C. (1999). Dermal absorption and distribution of topically dosed jet fuels jet A, JP-8 andJP-8(100). Toxicology and Applied Pharmacology 160:60-75.

 

Singh Somnath, Zhao Kaidi, Singh Jagdish. (2002). In vitro permeability and binding of hydrocarbons in pig ear and human abdominal skin. Drug and chemical toxicology, (2002 Feb) Vol. 25, No. 1, pp. 83-92.

 

Singh, S. and Singh, J. (2003). Percutaneous absorption, biophysical and macroscopic barrier properties of porcine skin exposed to major components of JP-8 jet fuel. Environmental Toxicology and Pharmacology 14:77-85.

 

Singh, S., Zhao, K., Singh, J. 2003. In vivo percutaneous absorption, skin barrier perturbation and irritation from JP-8 jet fuel components. Drug Chem. Toxicol 26:135-146.

 

Tsuruta, H. et al. (1982). Percutaneous absorption of organic solvents III. On the penetration rates of hydrophobic solvents through the excised rat skin. Industrial Health 20:335-345.