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Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
calculation (if not (Q)SAR)
Remarks:
Migrated phrase: estimated by calculation
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The toxicokinetic behaviour of the substance was estimated based on the results of physicochemical and toxicological assessments and testing on the substance.

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2014
Report date:
2014

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The toxicokinetic behaviour of the substance was estimated based on the results of physicochemical and toxicological assessments and testing on the substance.
GLP compliance:
no

Test material

Constituent 1
Reference substance name:
Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped
EC Number:
941-627-8
Molecular formula:
Not Applicable
IUPAC Name:
Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped
Constituent 2
Reference substance name:
Not assigned
IUPAC Name:
Not assigned
Test material form:
other: Liquid
Details on test material:
Name: Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped
Structure: A complex combination of hydrocarbons produced by thermal cracking of range of hydrocarbon feedstocks at a temperature of 450-500°C. It consists of hydrocarbons having carbon numbers predominantly in the range C7-C31 and boiling in the range of approximately 180-500°C. It contains a relatively large proportion of substituted aromatic hydrocarbons, particularly 1-ring aromatic hydrocarbons.
Radiolabelling:
no

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
- Aromatic hydrocarbons in the range C5 to C8:
o Inhalation Exposure: Studies with humans and animals are available for benzene, ethylbenzene, toluene, and xylenes; these studies indicate that these compounds are rapidly and efficiently absorbed following inhalation exposure. Published retention percentages for these compounds after inspiration in human studies range from approximately 30% to 70-80% (1).
o Oral Exposure: Animal studies are available for benzene, ethylbenzene, toluene, and xylenes, indicating that these compounds are rapidly and efficiently absorbed following oral exposure. Published absorption percentages for oral doses of benzene, ethylbenzene, toluene, and xylenes in animal studies range from about 80% to 97% (1).
o Dermal Exposure: Studies with animals indicate that benzene, ethylbenzene, toluene, and xylenes are dermally absorbed, but to a lesser extent than absorption via inhalation or oral exposure (1).
− Aromatic hydrocarbons in the range C9 to C16:
o Inhalation Exposure: Studies measuring the rate and extent of absorption in humans or animals following inhalation exposure to naphthalene or the monomethyl naphthalenes were not available, but observations of systemic health effects in humans and animals provide qualitative evidence of absorption of these indicator compounds (1).
o Oral Exposure: No data regarding the extent or rate of absorption of ingested naphthalene or monomethyl naphthalenes were available, except for a report that 80% of an oral dose of 2-methyl naphthalene was recovered as metabolites in the urine of rats within 24 hours (1).
o Dermal Exposure: Data regarding the rate and extent of dermally administered naphthalene or monomethyl naphthalenes were restricted to observations of systemic effects in humans and animals following dermal exposure to these compounds (1).
− Low olefinic hydrocarbons:
o Inhalation Exposure: Data are available for limonene, indicating that the compound is rapidly absorbed (2).
o Oral Exposure: Studies measuring the extent of absorption of ingested limonene show that orally administered limonene is rapidly and almost completely taken up from the gastrointestinal tract in humans as well as in animals (2).
o Dermal Exposure: A study on shaved mice shows that the dermal absorption of limonene from bathing water was rapid, reaching the maximum level in 10 min. Another study indicates that the dermal uptake of limonene in humans is low compared with that by inhalation (2). Studies performed with different sensitisation assay on limonene showed that the substance was a skin sensitizer, proving that limonene is absorbed after dermal exposure (3).
− Caprolactam:
o Inhalation Exposure: No data available.
o Oral Exposure: Studies on rats indicate that caprolactam is rapidly absorbed through the stomach (4).
o Dermal Exposure: No data available.
− Discussion:
o According to the above data, Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped might be expected to be well absorbed after oral, inhalation, or dermal exposure. However, the results of the acute oral toxicity study on Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped, showing no effect in rats after an ingestion of 2000 mg/kg appears to indicate otherwise. The results could either mean that the substance was not absorbed, or that the substance was absorbed but did not prove to be harmful to rats.
o According to the Lower Olefins and Aromatics REACH Consortium (5), the absorption of Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped might be expected to be high considering its constituents; however, because the levels of the most hazardous components, naphthalene and ethylbenzene are low (8500 ppm and 6000 ppm respectively), the substance is not expected to be acutely toxic if it is absorbed.
o According to the American Petroleum Institute Petroleum HPV Testing Group, Gas Oil streams and fuels induce minimal acute toxicity by the oral, dermal and inhalation routes (6). Considering that Gas Oil streams - including CAS 64741-59-9, CAS 64741-44-2, and CAS 64741-82-8 - have analogous aromatic hydrocarbons fractions, their properties might be expected to be similar to Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped. This could either mean that these substances are not absorbed, or that if they are absorbed, they are not acutely toxic, which is consistent with the acute oral toxicity study on Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped.
o A toxicity to reproduction study performed on Distillates (petroleum), light thermal cracked administrated by dermal route at 125 mg/kg bwt/d, 5 d/wk, for 13 weeks was without effect on reproductive organ weights and histology in male and female rats, or on sperm/spermatid parameters in males. Nevertheless, it was noticed that the relative weight of epididymal, prostate and testes was increased significantly (10%, 18%, 10%, respectively) versus controls. The relative adrenal, brain, kidney, liver, spleen and thymus weights were also increased by a similar amount. This is in line with a significant 11-12% increase in terminal body weight for the test animals. These results prove that dermal absorption actually occurred and that a hazardous effect took place following absorption. This study has been used for read-across to Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped.
o Data are available that demonstrate the toxicity effects following both oral and dermal administration. Although the respective studies were performed on different oils, the samples that were tested are similar in terms of their composition and physico-chemical properties. Dermal data are available from the toxicity to reproduction study on Distillates (petroleum), light thermal-cracked and oral data are available from an acute oral toxicity study performed on Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped. The results of these two studies suggest that the systemic toxicity of the oils is likely to be greater when administered by the dermal route.
o Considering these results, it might me expected than a dermal absorption will occurred with Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped, and that it is likely to be better than oral absorption.
Details on distribution in tissues:
− Aromatic hydrocarbons in the range C5 to C8 : Studies with humans and animals exposed predominately to vapours of benzene, ethylbenzene, toluene, and xylenes (there are fewer data for oral and dermal exposure) indicate that, following absorption, substances in this fraction are widely distributed, especially to lipid-rich and highly perfused tissues. Studies of rats exposed by inhalation to single hydrocarbons at 100 ppm, 12 hours/day, for 3 days found that C6-C10 aromatics (benzene, toluene, xylene, trimethylbenzene, ethylbenzene, and t-butylbenzene), compared with C6-C10, n-alkanes (n-hexane through n-decane) and C6-C10, naphthenes (cyclohexane, methylcyclohexane, dimethylcyclohexane, trimethylcyclohexane, and t-butylcyclohexane), showed higher concentrations (μmol/kg) in blood, lower concentrations in organs, and a lower potential for accumulation in fat and other organs presumably due to faster metabolic disposition (1).
− Aromatic hydrocarbons in the range C9 to C16: Studies of swine after oral exposure to naphthalene, rats after dermal exposure to naphthalene, and guinea pigs after oral exposure to 2-methyl naphthalene indicate that these compounds, and their metabolites, are distributed throughout tissues and organs following absorption (1).
− Low olefinic hydrocarbons: Limonene is rapidly distributed to different tissues in the body. The high oil/blood partition coefficient and long half-life suggest a high affinity to adipose tissues. In rats, the tissue distribution was initially high in the liver, kidneys, and blood after oral administration. Studies also show a sex-related variation: the concentration of limonene equivalents was approximately three times higher in male rats than in females, and about 40% was reversibly bound to the male specific protein, α2µ-globulin (2).
− Caprolactam: Studies on rats indicate that caprolactam will be readily transported in the blood. It shows a low affinity for adipose tissues but is well distributed in other tissues (4).
− Discussion :
o Considering the above data, Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped might be expected to be well distributed in the body; however, only constituents from the low olefinic hydrocarbons group are likely to accumulate considering their affinity to adipose tissues.
o Results of the acute toxicity: oral study, showing no weight gain or loss could either mean that Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped was not absorbed, or that only a small fraction accumulated in the rats, which is consistent with this assessment.
Details on excretion:
−n Aromatic hydrocarbons in the range C5 to C8: Studies with humans and animals exposed by various routes to benzene, ethylbenzene, toluene, and xylenes, indicate that compounds in this fraction may be expected to be eliminated predominately by urinary excretion of metabolites and to lesser degree by exhalation of unchanged parent compounds or biliary excretion of metabolites (1).
− Aromatic hydrocarbons in the range C9 to C16: Data from studies with animals exposed by several routes to naphthalene and monomethyl naphthalenes indicate that urinary excretion of metabolites represents the predominant pathway of elimination for these compounds (1).
− Low olefinic hydrocarbons: Elimination of limonene occurs primarily through the urine (2).
− Caprolactam: Twenty-four hours after administration of an oral dose of 0.18 mg/kg of caprolactam to rats, 77.6 +/- 0.7% of the compound had been excreted in the urine, 3.5 +/- 1.1% in the faeces and 1.5 +/- 0.1% in the expired air of the animals. Elimination of caprolactam in the urine and expired air was most rapid during the initial 6 hours following dosing, after which excretion continued at a much-reduced rate. (4).
− Discussion:
o According to the above information, excretion of Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped might be expected to occur mostly in the urine, if the substance is absorbed.
o Results of the acute oral toxicity study, showing no effect in rats after ingestion of 2000 mg/kg of Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped, could either mean that the substance is not absorbed and therefore elimination in the urine is not relevant, or that the substance was absorbed but did not prove to be harmful to rats. In the latter case, it would most likely be eliminated in the urine.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
− Aromatic hydrocarbons in the range C5 to C8 : As indicated by studies with humans and animals exposed to benzene, ethylbenzene, toluene, and xylenes, compounds in this fraction may be expected to be metabolised via cytochrome P-450 oxidases, either at carbons in the aromatic ring or in alkyl side groups, to metabolic intermediates that can be conjugated with glucuronides, sulfates, glutathione, or amino acids (e.g., cysteine or glycine). The resultant oxidated metabolites or conjugated metabolites are more water-soluble than parent compounds and are subject to urinary or, in some cases, biliary excretion. Metabolism of benzene, ethylbenzene, toluene, and xylenes can represent both a detoxification process (e.g. enhancement of the formation and excretion of hippuric acid can counteract the acute neurotoxicity of toluene in animals) and a toxification process (e.g. cancer and hematopoietic effects from chronic exposure to benzene appear to be caused by reactive metabolic intermediates) (1).
− Aromatic hydrocarbons in the range C9 to C16 : Studies with animals following oral, intraperitoneal, or subcutaneous administration of naphthalene or 2-methyl naphthalene indicate that ring oxidation occurs via an initial epoxide intermediate that subsequently is converted to alcohol, dihydrodiol and quinone derivatives, some of which are conjugated to glutathione, glucuronic acid, or glycine, and that the presence of alkyl side groups presents another site for oxidation and conjugation. Naphthol and naphthoquinone derivatives have been detected in the urine of humans following exposure to naphthalene (1).
− Low olefinic hydrocarbons: The biotransformation of limonene has been studied in many species, with several possible pathways of metabolism. About 25-30% of an oral dose of limonene in humans was found in urine as limonene-8,9-diol and its glucuronide, about 7-11% was eliminated as perillic acid and its metabolites. Following the inhalation exposure of volunteers to limonene at 450 mg/m3 for 2 hours, about 1% was eliminated unchanged in exhaled air, whereas about 0.003% was eliminated unchanged in the urine (2).
− Caprolactam: Studies on rats show that caprolactam is mainly metabolised in one major metabolite called M I and a less important one called M II (4). In another study, M I was identified as 6-amino-gamma-caprolactone, and M II as 6-aminohexanoic acid (7)(7).
− Discussion:
o According to the above information, aromatic hydrocarbons in the range C5 to C16 (69%) and caprolactam (3.6%) contained in Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped might be expected to be rapidly metabolised. Low olefinic hydrocarbons (15%) will be metabolised to a lesser extent.
o The result of the in vitro genetic toxicity study on Gas oil (polymer derived) thermal-cracked, full range implies that a toxic effect could occur following metabolic activation. However, the acute oral toxicity study did not show any adverse effects. There are several possible explanations for this:

• The substance was not absorbed and thus could not be metabolised
• Absorption occurred but not the metabolism
• Absorption occurred but metabolism did not generate the expected harmful compound(s)
• Absorption occurred but there as insufficient material to induce any adverse effects
• Any adverse effect could not be observed in this study, since it is only a short-term test.

However, it should be noted that a positive in vitro genetic toxicity result was obtained on Gas oil (polymer derived) thermal-cracked, full range, and then used as a conservative approach for a read-across. Gas oil (polymer derived) thermal-cracked, full range contains more constituents expected to be genotoxic than Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
Based on the results of the absorption, distribution, metabolism and excretion of components of the UVCB substance it is expected that the aromatic hydrocarbons and low olefin hydrocarbons will be well distributed in the body, but aromatic hydrocarbons do not tend to concentrate and might be expected to be readily metabolised and excreted through the urine; however, low olefin hydrocarbons might be expected to remain longer in the body due to their lipophilic nature, whilst being metabolised and excreted predominately through the urine. According to the information available, the substance might be expected to be well absorbed after oral, dermal, or inhalation exposure.
Executive summary:

The toxicokinetic behaviour of the substance was estimated based on the results of physicochemical and toxicological assessments and testing on the substance. Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped is a UVCB and, for the purpose of this toxicokinetics assessment, it has been treated as a complex mixture. The components of the oil have been considered and representatives from each of the different chemical groups that are deemed to have the greatest toxicological significance have been selected for investigation in the assessment process. Component Groups investigated:

- Aliphatic hydrocarbons in the range C8 to C30 (5%): this group will not be considered in the assessment due to their low concentration and limited hazardous properties.

- Aromatic hydrocarbons in the range C5 to C8 (5%)

- Aromatic hydrocarbons in the range C9 to C16 (64%)

- Low olefinic hydrocarbons (15%)

The absence of specific toxicokinetic data from animal testing means that it is not possible to make firm conclusions concerning the absorption, distribution, metabolism or excretion. However, an assessment of the toxicokinetic behaviour of selected components has been performed in conjunction with an assessment of available toxicological data on Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped and its parent oil, Gas oil (polymer-derived), thermal cracked, full range.

According to the information available, the substance might be expected to be well absorbed after oral, dermal, or inhalation exposure. The results of the acute oral toxicity study on Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped, showing no effect in rats after an ingestion of 2000 mg/kg could indicate either that the substance was not absorbed, or that the substance was absorbed but did not prove to be harmful to rats, which is consistent with the information from the Lower Olefins and Aromatics REACH Consortium (5) and The American Petroleum Institute (API) Petroleum HPV Testing Group (6). However, it should be noted that dermal absorption might be expected to be better than oral absorption.

Aromatic hydrocarbons and low olefin hydrocarbons might be expected to be well distributed in the body, but aromatic hydrocarbons do not tend to concentrate and might be expected to be readily metabolised and excreted through the urine; however, low olefin hydrocarbons might be expected to remain longer in the body due to their lipophilic nature, whilst being metabolised and excreted predominately through the urine. Results of the acute toxicity: oral study, showing no weight gain or loss could either mean that Thermal cracking oil from blends of rubber, fuel oils and paraffin waxes, steam-stripped was not absorbed, or that only a small fraction accumulated in the rats while the other fraction was rapidly excreted, which is consistent with this assessment

It is not considered appropriate to perform further animal studies on this substance.