Hydrocarbons, C10, aromatics, <1% naphthalene

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result:
C10-C12 Aromatic hydrocarbon fluids can be absorbed when inhaled or ingested. C10-C12 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, C10-C12 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. Due to the rapid excretion, bioaccumulation of the test substance in the tissues is not likely to occur.

Short description of key information on absorption rate:
C10-C12 Aromatic fluids are poorly absorbed dermally with an estimated overall percutaneous absorption rate of approximately 2ug/cm2/hr or 1% of the total fluid applied. When dermally absorbed, C10-C12 Aromatics are rapidly eliminated.

Additional information

C10-C12 Aromatic fluids are readily absorbed when inhaled or ingested.  C10-C12 Aromatic fluids are poorly absorbed dermally with an estimated overall percutaneous absorption rate of approximately 2ug/cm2/hr or 1% of the total fluid volume. Bioaccumulation of C10-C12 Aromatic fluids is not expected.

Discussion on bioaccumulation potential result:

There have not been any toxicokinetic studies of C10-C12 Aromatics, but there have been studies of some of the constituents, particularly naphthalene and methyl naphthalenes. Due to the structural similarity of these molecules to other constituents of the C10-C12 Aromatics, it seems reasonable to assume that the solvents would have toxicokinetic properties similar to those of these constituents.

Biotransformation of 1,4-diethenylbenzene in rat was studied. Nine urinary metabolites, namely, N-acetyl-S-[2-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine, N-acetyl-S-[1-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine, N-acetyl-S-[1-(4-formylphenyl)-2-hydroxyethyl]-L-cysteine, 1-(4-ethenylphenyl)ethane-1,2-diol, 4-ethenylbenzoic acid, 4-ethenylbenzoyl-glycine, 1-ethenyl-4-(1-hydroxyethyl)benzene, 4-(1,2-dihydroxyethyl)benzoic acid, (4-carboxymethylphenyl)acetylglycine, N-acetyl-S-[2-carboxy-1-(4-ethenylphenyl)ethyl]-L-cysteine, and two isomeric beta-D-glucosiduronates derived from 1-(4-ethenylphenyl)ethane-1,2-diol, were isolated and identified by n.m.r. and mass spectrometry.  GC-mass spectral analysis of the methylated urine extract allowed the identification of four other metabolites, as 4-ethenylphenylacetic acid, 4-ethenylphenylacetylglycine, 4-ethenylmandelic acid, and 4-ethenylphenylglyoxylic acid. The structures of the identified metabolites indicate that the main reactive intermediate in the metabolism of 1,4-diethenylbenzene is 4-ethenylphenyloxirane. The first step in the biotransformation of 1,4-diethenylbenzene is the formation of an oxirane. Subsequent steps lead to oxidation of the second ethenyl group leading to the aldehyde N-acetyl-S-[1-(4-formylphenyl)-2-hydroxyethyl]-L-cysteine metabolite. Rats dosed with a single i.p. dose excreted nearly 5.6% of the dose as the glycine conjugate 12, irrespective of the dose. In contrast, the total thioether fraction decreased significantly with increasing dose, being 23 +/- 3, 17 +/- 5 and 12 +/- 1% of dose at 100, 200 and 300 mg/kg, respectively (mean +/- SD).

 

The metabolism of p-tert-butyltoluene (TBT) was studied in the rat and guinea pig. Both the methyl and the tert.-butyl group were oxidized to alcohol and carboxylic acid derivatives in these species. The major urinary metabolites in rats were p-tert-butylbenzoic acid and its alcohol derivative 2-(p-carboxyphenyl)-2-methylpropan-1-ol whereas p-tert-butylbenzoylglycine was the most prominent metabolite in guinea pig urine. No significant differences in metabolism were found when TBT was given intragastrically or by inhalation. The intragastric administration of 14C-TBT to rats showed that the bulk of the excretion of radioactivity occurred within three days. A recovery of 83% was achieved and the ratio of urinary/faecal radioactivity was roughly 3.5:1. 

As summarized in the ATSDR toxicological profile, naphthalene (NAP), 1-methylnaphthalene (1-MN) and 2-methylnaphthalene (2-MN) are well absorbed if ingested.  As one example, at least 80% of an oral dose of 2-MN was absorbed within 24 hours of oral administration to guinea pigs (Teshima et al., 1983).  Conversely, it is believed that only limited absorption occurs following dermal contact. Riviere et al. (1999) for example, reported that 1.17 + 0.07% of the naphthalene content of a sample of jet fuel A (Jet-A) was percutaneously absorbed in a porcine skin flap model.  Further studies by the same group (Baynes, et al., 2000) reported flux values ranging from approximately 1-2 ug/cm2/hr.  Subsequent work by Singh and Singh (2003) reported a value of approximately 1 nmol/cm2/hr or approximately 0.1 ug/cm2/hr.  Kim et al. (2006) reported values of approximately 300-500 ng/cm2/hr for NAP, 1-MN and 2-MN from a study utilizing human volunteers.  Of these, the report by Kim et al. (2006) is probably the most reliable as it came from direct human measurements; reassurance is provided by the similar estimates obtained by other experimental techniques.  The potential for systemic doses from inhalation exposures is unknown.   

 

Once absorbed, naphthalenes are distributed to the principal organs. 

 

Naphthalene is metabolized by side chain oxidation, leading to the formation of mono- or di-alcohols.  These can be glucuronidated and excreted in the urine or further metabolized to quinones which are then further metabolized before being excreted. The methyl naphthalenes are preferentially metabolized by side chain oxidation to form naphthoic acids although ring oxidation can also occur.  As with naphthalene, these species or their subsequent metabolites are generally glucuronidated and excreted in the urine. The majority of administered material is excreted within about 24 hours, principally as urinary metabolites. 

 

Teshima R, Nagamatsu K, Ikebuchi H, et al. 1983. In vivo and in vitro metabolism of 2-methylnaphthalene in the guinea pig. Drug Metab Dispos 11(2):152-157.

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

Baynes, R., Brooks, J., and Riviere, J. (2000).  Membrane transport of naphthalene and dodecane in jet fuel mixtures.  Toxicology and Industrial Health 16:225-238.

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 and JP-8(100).  Toxicology and Applied Pharmacology 160:60-75.

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.

Discussion on absorption rate:

There have not been any dermal absorption studies of C10-C12 Aromatics, but there have been studies of some of the constituents, particularly naphthalene and methyl naphthalenes.  Due to the structural similarity of these molecules to other constituents of the C10-C12 Aromatics, it seems reasonable to assume that the solvents would have toxicokinetic properties similar to those of these constituents.  

 

ANIMAL DERMAL ABSORPTION DATA - IN VITRO DATA

 

Perfused porcine skin flaps were used to determine the absorption and disposition of naphthalene. Naphthalene absorption had a clear peak absorptive flux at less than 1h and the absorption was (mean +/- SEM; % dose) naphthalene (1.17 +/-0.07).  The area under the curve (AUC) was determined to be (mean +/- SEM; % dose-h/mL): naphthalene (0.0199 +/- 0.0020). In contrast, deposition within dosed skin showed the reverse pattern.

 

HUMAN DERMAL ABSORPTION DATA

 

SKIN PENETRATION:  

The slopes of the curves for aromatic compounds began to decrease at 120 min but did not reach zero. The apparent Kp was calculated for each volunteer and component of JP-8, assuming the absorbed compounds were restricted to the blood compartment in the body. The mean apparent Kp in decreasing order is naphthalene > 1-methyl naphthalene = 2-methyl naphthalene. A Student's t- test for comparison of the apparent Kp estimates for 1-methyl naphthalene and 2-methyl naphthalene showed no statistically significant difference (p > 0.05).  The apparent permeability coefficients (cm/h) of aromatic hydrocarbons were determined to be: Naphthalene 5.3E-05; 1-Methyl naphthalene 2.9E-05; 2-Methyl naphthalene 3.2 E-05.

COMPARISON TO IN VITRO STUDIES:

This study, conducted with human subjects, indicates that permeability coefficients estimated in vitro may overestimate the internal dose of various components of JP-8. To illustrate, the Kp values determined from rat skin, pig skin, and this study to estimate the internal dose of naphthalene: Mrat = 1.29 mg, Mpig = 0.53 mg, and Mhuman = 0.13 mg.  The Kp from rat skin overestimates human internal dose by a factor of 10, and the Kp from pig skin by a factor of 4.

 

MODEL:

A mathematical model was developed to describe the diffusion coefficients (Dsc) of aromatic hydrocarbons. The diffusion coefficients (Dsc, cm2/min x 10^-8) of aromatic hydrocarbons were determined to be: Naphthalene 4.2+/-1.4; 1-Methyl naphthalene 4.6 +/-2.7; 2-Methyl naphthalene 4.5+/-2.6.

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

 

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

 

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.

 

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.

 

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.

 

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.