Distillates (petroleum), cracked, ethylene manuf. by-product, C9-10 fraction

Endpoint summary

Additional information

Toxicokinetic behaviour of some pure substances present in these streams has been extensively studied and reported. In many circumstances the body burden of the substance and/or metabolites is dependent upon several factors such as the rate and extent of uptake, distribution, metabolism and excretion. In complex mixtures, however, the toxicokinetics of even well-studied pure substances may vary depending upon interaction with other chemical species available within the mixture. For example, the substances present may compete for the uptake, metabolism, and/or elimination of the complex mixture. This situation, already complicated, is further exacerbated when the composition of the mixture is uncertain and variable.

For this ‘Resin Oils and Cyclic Dienes (DCDP rich)’ category the marker substances, in their pure form, have well-defined toxicokinetic parameters that have been taken into account during the derivation of their respective DNEL’s. The overall DNEL of this category is driven by the DNELs for benzene and dicyclopentadiene.

The toxicokinetics of dicyclopentadiene has been evaluated in rats, mice and dogs (Litton Bionetics, 1976). Elimination from plasma was biphasic in all three species; terminal half lives were 18 to 27 hours. Radioactivity was rapidly and widely distributed into tissues in all three species; the highest concentrations were found in the body fat, adrenal glands and urinary bladder in the rat; in the urinary bladder, gall bladder and body fat in the mouse; and in the bile, gall bladder and bladder in the dog. In all three species, the majority of the radioactivity was excreted in the urine. Urinary radioactivity was present as 6 -7 constituents; conjugates but no unchanged dicyclopentadiene were present. A further studywascarried out in a lactating Jersey cow (Ivie, 1980). On the basis of this study it was concluded that exposure of livestock to small quantities of dicyclopentadiene would not result in perceptible contamination of the milk or meat.

ATSDR have also reviewed the toxicokinetics of naphthalene (ATSDR, 2005) and report that naphthalene is readily absorbed into the systemic circulation following inhalation or ingestion. Systemic absorption of naphthalene can also occur following dermal contact however, the rate and extent of naphthalene absorption for all routes is unknown in many instances. Naphthalene is initially metabolised into a number of reactive epoxide and quinone metabolites by cytochrome P450 oxidation. Metabolites of naphthalene are excreted in the urine as mercapturic acids, methylthio derivatives and glucuronide conjugates. Glutathione and cysteine conjugates are excreted in the bile. Following ingestion the urinary excretion of naphthalene metabolites is prolonged due to delayed absorption from the gastrointestinal tract.

Styrene toxicokinetics were reviewed by ATSDR in 2007. It can be concluded that styrene is well absorbed by the inhalation and oral routes and poorly absorbed through the skin. Once absorbed, styrene is widely distributed throughout the body, with the highest levels detected in fat. There are several metabolic pathways for styrene; the primary pathway is oxidation of the side chain by cytochrome P450 to form styrene 7,8-oxide. The styrene oxide is further metabolized to ultimately form mandelic acid or phenylglyoxylic acid or can be conjugated with glutathione. Styrene is rapidly eliminated primarily in the urine as mandelic acid and phenylglyoxylic acid.

Toluene toxicokinetics were reviewed by the EU (EU, 2003a). In summary, the major uptake of toluene vapour is through the respiratory system. It is absorbed rapidly via inhalation and the amount absorbed (approximately 50%) depends on pulmonary ventilation. Toluene is almost completely absorbed from the gastrointestinal tract. Liquid toluene can be absorbed through the skin but dermal absorption from toluene vapours is not likely to be an important route of exposure. Dermal absorption of liquid toluene was predicted using a model which considers absorption as a two stage process, permeation of the stratum corneum followed by transfer from the stratum corneum to the epidermis. The model predicted a maximum flux of 0.0000581 mg/cm²/min giving a dermal absorption value of approximately 3.6% of the amount applied as liquid toluene. Toluene is distributed to various tissues, the amount depending on the tissue/blood partition coefficient, the duration and level of exposure, and the rate of elimination. Biotransformation of toluene occurs mainly by oxidation. The endoplasmic reticulum of liver parenchymal cells is the principal site of oxidation which involves the P450 system. Analysis of blood and urine samples from workers and volunteers exposed to toluene via inhalation in concentrations ranging from 100 to 600 ppm (377-2,261 mg/m³) indicate that of the biotransformed toluene, ~ 99% is oxidised via benzyl alcohol and benzaldehyde to benzoic acid. The remaining 1% is oxidised in the aromatic ring, forming ortho-, meta- and para-cresol. In the rat, elimination of toluene is rapid with most toluene eliminated from fat after 12 hours. Within a few hours after termination of exposure the blood and alveolar air contains very little toluene. A proportion (around 20%) of the absorbed toluene is eliminated in the expired air. The remaining 80% of the absorbed toluene is metabolised in the liver by the P450 system, mainly via benzyl alcohol and benzaldehyde to benzoic acid. Benzoic acid is conjugated with glycine and excreted in the urine as hippuric acid.

The metabolism and kinetics of xylene isomers has been reviewed extensively by ATSDR (2007c). All the xylene isomers are well absorbed via the oral route. They are rapidly distributed through the body and any unmetabolised compound quickly eliminated in exhaled air. In gavage dosing experiments in animals, 90% absorption has been estimated. In humans, inhalation absorption has been estimated at about 60-65% based on human data. The major pathway of xylene metabolism in humans involves mixed function oxidases in the liver, with minor metabolism occurring in the lung and kidneys. Xylenes are transformed primarily to methylbenzoic acid followed by conjugation with glycine to form the main metabolites, the corresponding methylhippuric acid isomers, which are eliminated in the urine. 

References

ATSDR (2005). Toxicological profile for naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene. U.S. Department of Health and Human Services Public Health Service Agency for Toxic Substances and Disease Registry.

ATSDR (2007b). Draft toxicological profile for styrene. U. S. Department of Health and Human Services Public Health Service Agency for Toxic Substances and Disease Registry.

ATSDR (2007c). Toxicological profile for xylene. U. S. Department of Health and Human Services Public Health Service Agency for Toxic Substances and Disease Registry.

EU (2003a). European Union Risk Assessment Report for Toluene. EC Joint Research Centre http: //ecb. jrc. ec. europa. eu/DOCUMENTS/Existing- Chemicals/RISK_ASSESSMENT/REPORT/toluenereport032. pdf

Ivie GW and Oehler DD (1980). Fate of dicyclopentadiene in a lactating cow. Bull. Environm. Contam. Toxicol. 24, 662-670.

Litton Bionetics (1976). Mammalian toxicological evaluation of DIMP and DCPD. Testing laboratory: Litton Bionetics Inc.5516 Nicholson Ave. Report no.: DAMD 17. 75-C-5068. Owner company: U. S. Army Med. Res. and Dev. Command,, D. C. 20314,. Report date: 1976-06-25.