Hydrocarbons, C14-C20, n-alkanes,

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
C14-C20 aliphatic, <2% aromatic hydrocarbon fluids 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: 
C14-C20 aliphatic, <2% aromatic hydrocarbon fluids can be dermally absorbed, although they tend to partition into the stratum corneum. When dermally absorbed, C14-C20 aliphatic, <2% aromatic hydrocarbon fluids are rapidly metabolized and eliminated.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Approximately 34% of C14¿C20 aliphatic, <2% aromatic hydrocarbon fluids are absorbed when ingested. C14¿C20 aliphatic, <2% aromatic hydrocarbon fluids is poorly dermally absorbed. Absorption following inhalation is assumed to be similar to ingestion since exposures will be to aerosol. Regardless of exposure route, C14¿C20 aliphatic, <2% aromatic hydrocarbon fluids are rapidly metabolized. Bioaccumulation of C14¿C20 aliphatic, <2% aromatic hydrocarbon fluids is not expected.

Discussion on bioaccumulation potential result:

C14-C20 aliphatic, <2% aromatic hydrocarbon fluids are absorbed if ingested. C14-C20 aliphatic, <2% aromatic hydrocarbon fluids undergo metabolism and rapid excretion and low deposition, bioaccumulation of the test substance in the tissues is not likely to occur.

 

The fate of pristane (2, 6, 10, 14-tetramethylpentadecane) was studied in rats after a single per os administration of 3H-labeled pristane. The balance study showed extensive fecal excretion (66%) mainly as unchanged hydrocarbon, whereas about 14% of ingested pristane was excreted in urine as pristane metabolites and tritiated water. After one week, 8.3% of the ingested 3H still was stored in the carcass and the radioactive distribution in tissues and organs showed a preferential incorporation into adipose tissue and liver. Over 75% of the radioactivity stored in the carcass was associated with pristane metabolites and tritiated water. Tissue metabolites were characterized by thin layer chromatography, gas chromatography, and mass spectrometric analyses. Four metabolites were identified: pristan-1-ol, pristane-2-ol, pristanic acid and 4, 8, 12-trimethyltridecanoic acid. These results demonstrated that pristane undergoes subterminal hydroxylation or terminal oxidation followed by the classical beta-oxidation process.

 

Labeled paraffins with 8-18 C atoms prepared from unsaturated hydrocarbons by addition of deuterium have been added in oily solution to normal rats¿ food. After six days an increase of deuterium content in the body fluid of all the rats was observed indicating that the labeled compounds had been metabolized. Deuterium was found in the fatty acids of the body fats and the liver lipids especially after feeding octadecane and hexadecane. Isolating oleic, stearic, and palmitic acids containing deuterium, indicated that methyl- and beta-oxidation of these hydrocarbons has occurred. Fatty acids resulting from the metabolism of hydrocarbons with shorter chains were not deposited but in these cases the urine contained fatty acids with higher deutrium content than after administration of octadecane and hexadecane. According to the deuterium content of the neutral fractions from the liver and body lipids all the hydrocarbons tested were deposited only to a small extent, the largest depots occurring mainly after feeding with octadecane and hexadecane.

 

Discussion on absorption rate:

There have not been any in vivo dermal absorption studies of C14 ¿ C20 aliphatic, <2% aromatic hydrocarbon fluids, but there have been in vitro studies of similar constituents, particularly hexadecane.   

 

The percutaneous absorption and cutaneous disposition of topically applied neat Jet-A, JP-8, and JP-8(100) jet fuels (25 µL/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 A), the highest percutaneous absorption value was 2 µg/cm²/hr for pentane. Lower values (< ~ 1 µg/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 µg/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 µg/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; Kim et al., 2006) are less than 2 µg/cm²/day. The only exceptions are the values for naphthalene from Mohammad et al. (2005) which range from 4.2-6.6 µg/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 µg/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 µg/cm²/hr will be used as a common percutaneous absorption rate for all hydrocarbon solvents for which dermal exposure estimates are provided.

 

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

 

Constituent	Molecular Weight	nmol/min/cm^2	nmol/hr/cm^2	µg/cm^2/hr	Reference
Aliphatic Constituents
Pentane	72	0.52	31.2	2.2	Tsuruta 1982
2-methyl pentane	86	0.02	1.2	0.1	Tsuruta, 1982
n-hexane	86	0.02	0.6	0.5	Tsuruta, 1982
n-heptane	100	0.02	1.2	0.1	Tsuruta, 1982
n-octane	114	0.08 x 10-3	0.005	0.0005	Tsuruta, 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 B. 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., Nylander-French, L.A. (2006). Dermal absorption and penetration of jet fuel components in humans.Toxicology Letters165: 11-21.

 

McDougal, J., Pollard, D., Weisman, W., Garrett, C., Miller, T. (2000). Assessment of skin absorption and penetration of JP-8 jet fuel and its components.Toxicological Sciences25: 247-255.

 

Muhammad, F., Monteiro-Riviere, N., Baynes, R., J. Riviere (2005). Effect of in vivo jet fuel exposure on subsequentin vitrodermal absorption of individual aromatic and aliphatic hydrocarbon fuel constituents.Journal of Toxicology and Environmental Health Part A68: 719-737.

 

Riviere, J., Brooks, J., Monteiro-Riviere, N., Budsaba, K., Smith, C. (1999). Dermal absorption and distribution of topically dosed jet fuels jet A, JP-8 andJP-8(100).Toxicology and Applied Pharmacology160: 60-75.

 

Singh, S. 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 Pharmacology14: 77-85.

 

Singh S., Zhao K., Singh J. (2002).In vitropermeability and binding of hydrocarbons in pig ear and human abdominal skin.Drug and Chemical Toxicology25(1): 83-92.

 

Singh, S., Zhao, K., Singh, J. (2003).In vivopercutaneous absorption, skin barrier perturbation and irritation from JP-8 jet fuel components.Drug and Chemical Toxicology26: 135-146.

 

Tsuruta, H. (1982). Percutaneous absorption of organic solvents III. On the penetration rates of hydrophobic solvents through the excised rat skin.Industrial Health20: 335-345.