Creosote oil, acenaphthene fraction

Endpoint summary

Description of key information

Wash oil PAH are absorbed rapidly through the pulmonary tract, the gastrointestinal tract and to a lesser extent through skin. Permeation through rat skin seems to be much more pronounced than through human skin.
The wash-oil relevant PAH are well metabolised mainly in the liver and effectively excreted into the urine and to a minor part into the faeces. The major metabolic pathway for typical PAH is epoxidation at an aromatic ring (P450 monooxygenases) in a first step, followed by ring cleavage/rearrangement resulting in a phenol or as alternative by epoxide hydroxylation to a dihydro-diol derivative, which may undergo secondary conversion by conjugation with glutathione, glucuronic acid or sulphate. 
The second prominent metabolic pathway is hydroxylation of aliphatic methyl substituents (e.g. in methylnaphthalenes) or ring-associated methylene groups (e.g. in fluorene and acenaphthene), followed by further oxidative conversion (via the aldehyde) to finally the carboxylic acid and/or by secondary conjugation as outlined above.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - dermal (%):

2

Additional information

Toxicokinetics

Creosote oil, acenaphthene fraction (wash oil) is composed of two and three ring PAH. Constituents with typical concentration above ca. 2 % w/w are naphthalene (11 – 13 % w/w), 1-methylnaphthalene (7 – 9 % w/w), 2 -methylnaphthalene (17 – 20 % w/w), biphenyl (5 – 6 % w/w), acenaphthene (13 – 15 % w/w), fluorene (4 – 5 % w/w), dibenzofuran (7 % w/w), quinoline (3 % w/w), and phenanthrene (2 % w/w). The carbocyclic PAH among them amount to ca. 60 % of total wash oil. Toxicokinetics of wash oil will strongly correlate to the respective properties of these substances.

In contrast to intensively investigated larger PAH of major interest (e.g. benzo[a]pyrene), wash oil constituents are of smaller molecular size with better water solubility, higher vapour pressures and lower log Pow values than four and more ring PAH. Nevertheless, they exhibit basic toxicokinetic characteristics of PAH. Wash oil toxicokinetics can largely be characterised based on information determined for its PAH constituents even if there are some differences depending on their individual properties (molecular structure, log Pow, water solubility, vapour pressure).

Absorption

In general, wash oil PAH constituents will be absorbed rapidly through the pulmonary tract, the gastrointestinal tract, and the skin. (EU 2003, US EPA 2003, Grimmer 1991). Degree of absorption may be different for individual substances. Gastrointestinal absorption in rodents has been reported to be 80 to over 90 % (US EPA 2003, Grimmer 1991). Effective absorption by the different routes is also evidenced by observation of systemic toxicity following exposure by the different routes.

Distribution

Experimental data on distribution of wash oil components are rare. For 2-methylnaphthalene (³H label), it was found that it is widely distributed among tissues reaching peak concentration in less than 6 hours. Major part of the label was present in gastrointestinal contents and urine after 2 and 6 hours (combined ca. 50 and 60 % respectively). Internal organs contained 1.4 and 2.1 % of the label distributed in gallbladder (ca 68 and 55 % of internal organs label), kidney (29 and 26%), liver (5.7 and 9.5%), blood (2.7 and 2.8%), and lung (2.4 and 2.8%) (US EPA 203). It is assumed that other small size PAH will be distributed similarly.

Metabolism

Some PAH constituents in wash oil have special structural features with regard to their aromatic nature. Methylnaphthalenes, acenaphthene, and fluorene possess besides aromatic carbon atoms also aliphatic carbon atoms. These are the methyl side group in methylnaphthalenes and the methylene groups bridging the two phenyl rings in acenaphthene and fluorene. Both structural elements are metabolised differently. In general, wash oil constituents are metabolised extensively particularly in the liver but also in other tissues (e.g. lung). Aim is to increase water solubility to enable excretion of the substance.

Major metabolic pathway for typical PAH is oxidation at an aromatic ring (P450 mono oxygenases) forming a cyclic epoxide in a first step followed by ring cleavage/rearrangement resulting in a phenol or by epoxide hydroxylation to a dihydro-diol derivative. In following steps conjugation by glutathione, sulphate or glucuronic acid may occur. Alternatively or in addition a second oxidation at another position of the aromatic system is possible also followed by conjugation.

Second metabolic pathway is hydroxylation of the aliphatic methyl or methylene groups. Methyl substituents are oxidised to the hydroxymethyl derivative followed by further oxidative conversion (via the aldehyde) to finally the carboxylic acid. The acid may be conjugated with glycine or glucuronic acid (US EPA 2003). In acenaphthene, oxidation of the two methylene groups results in the 1-,8-dicarboxylic acid identified as the anhydride of the acid (Chang 1943).

Metabolites of naphthalene in humans are 1- and 2-naphthol, and 1-,2- and 1-,4-naphthoquinones being formed from 1-,2-dihydro-diol or from successive oxidation at the same benzene ring. In rats, the metabolites identified were: mercapturic acid conjugate (38 % of administered radioactivity), 1-,2-dihydro-diol glucuronide (22 %), naphthol and naphthol glucuronides (ca. 5 %), and 1,2-dihydro-1-hydroxy-2-methylthionaphthalene glucuronide (ca. 5 %) (EU 2003). For phenanthrene only approx. 3.8 % of the excreted dose were detected as hydroxy-phenanthrenes (1-, 2-position ca. 60 % of total OH-derivatives, 3-, 4-, and 9-position minor). Dihydro-diols were not detected and may have escaped determination (Grimmer et al.1991). In an experiment with liver microsomes from untreated rats (Jacob et al. 1982), trans 9-10- dihydro-diol was identified (K-region oxidation) indicating that other hydroxy-derivatives of phenanthrene can be formed as recovered in the study of Grimmer et al.

For methylnaphthalenes, the oxidation of the methyl side chains is the predominant pathway (2-methylnaphthalene 50 - 80 %). Dihydro-diols can be formed at different sites of the molecule (for 2-methylnaphthalene at the 3,4-, 5,6- and 7,8 position, 15 - 20% together).

Excretion

Excretion of wash oil constituents comprised of two aromatic rings is rapid primarily through the urinary route. With increasing size (increased lipophilicity) increasing parts may be excreted via faeces. For naphthalene, 83 % of the radioactivity administered was recovered in urine and 6% in faeces after 72 hours (Bakke 1985). About 85 % of the administered dose of 2-methylnaphthalene was eliminated within 48 hours (guinea pigs), approx. 72 % in urine and 11 - 14 % in faeces. was excreted to about 70 - 80 % within 48 hours in guinea pigs and to 55 % in rats. Total recovery of phenanthrene including hydroxyl derivatives was only 10.5 % within three days with 4.1 % in the urine and 6.4 % in faeces (ratio ca. 4 : 6). About 90 % of the dose could not be accounted for indicating that probably other water soluble metabolites are formed that were not recorded under the experimental conditions of the study (Grimmer 1991).

Dermal absorption

For creosote, there is evidence that only 2 % of a dermal dose will be absorbed through human skin within and after 8 hours of exposure (Fasano 2007 a, b). The conversion factor human vs. rat skin was found to be 0.12, which means that the dermal dose absorbable within 8 hours is about 8-fold higher in rat than in human skin.

Data for creosote cannot be transferred to wash oil without adaption. Studies of Van Rooij 1995 and Sartorelli 1999 show that lower molecular weight PAH are absorbed much faster than higher molecular weight PAH. For absorption through full thickness skin from the abdomen of monkeys (Ceropithecus aetops), differences in absorption rates from 129 ng/(h*cm²) (naphthalene) to 5.7 ng/(h*cm²) (phenanthrene) were observed when applied in artificial sweat. Calculated from this data, dermal absorption during a period of 8 hours ranges from about 6.4 % to 2.1 % of the dose applied.