Raffinates (Fischer-Tropsch), C10-25-branched

Endpoint summary

Description of key information

Raffinates (Fischer-Tropsch), C10-C25-branched 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, Raffinates (Fischer-Tropsch), C10-C25-branched hydrocarbon fluids, are rapidly metabolized and eliminated. 

Additional information

There have not been any in vivo dermal absorption studies of Raffinates (Fischer-Tropsch), C10-C25-branched hydrocarbon fluids, but there have been in vitro studies of some constituents, particularly dodecane and hexadecane.  Due to the structural similarity of these molecules to Raffinates (Fischer-Tropsch), C10-C25-branched 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 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.

 

The percutaneous absorption and cutaneous disposition of topically applied neat Jet-A, JP-8, and JP-8(100) jet fuels (25 uL/5 cm2) was examined by monitoring the absorptive flux of the marker components 14C naphthalene and 4H dodecane simultaneously applied non-occluded to isolated perfused porcine skin flaps (a = 4). Absorption of 14C hexadecane was estimated from JP-8 fuel. Absorption and disposition of naphthalene and dodecane were also monitored using a nonvolatile JP-8 fraction reflecting exposure to residual fuel that might occur 24 h after a jet fuel spill. In all studies, perfusate, stratum corneum, and skin concentrations were measured over 5 h. Naphthalene absorption had a clear peak absorptive flux at less than 1 h, while dodecane and hexadecane had prolonged, albeit significantly lower, absorption flux profiles. Within JP-8, absorption was (mean +/- SEM; % dose) hexadecane (0.18 +/- 0.08).  The area under the curve (AUC) was determined to be (mean +/- SEM; % dose-h/mL): hexadecane (0.0017 +/- 0.0003).

 

The flux, permeability coefficient (Kp), and binding of hexadecane for porcine skin was determined to be 8.80 +/- 0.00 (nmol/cm2/h) x 10E-3. The permeability coefficient (Kp), and binding of hexadecane for human skin were determined to be 7.02 +/- 0.00 (nmol/cm2/h) x 10E-3. Factor of difference (FOD) in the permeability of pig and human skin was 1.28 for hexadecane. The FOD in binding of hexadecane to pig and human skin was found to be 0.76.

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, S., Zhao, K., Singh, J. (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.