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Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Distillates (Petroleum), steam-cracked, dimerised (C5-12, C10-rich) was formerly a member of the LOA Category L (Resin Oils and Cyclic Dienes), and the following Category L streams, with which these studies were conducted, resemble Distillates (Petroleum), steam-cracked, dimerised (C5-12, C10-rich) from a compositional standpoint, only containing much lower levels of benzene.

Other data included are for key constituents of Distillates (Petroleum), steam-cracked, dimerised (C5-12, C10-rich), including benzene, toluene and DCPD.

 

3a,4,7,7a-tetrahydro-4,7-methanoindene (DCPD, dicyclopentadiene; does not warrant classification under GHS/CLP):

DCPD key studies are considered to be a bacterial mutation assay (NOTOX, 2000), a mammalian cell cytogenetic assay (JETOC, 1998b), and a mammalian gene mutation assay (Harlan, 2014). The data from these assays show that DCPD is not mutagenic in vitro.

 

Benzene (classification under GHS/CLP: cat 1B H340: May cause genetic defects):

Benzene has been extensively examined for the core endpoints of gene mutation in bacteria, gene mutation in mammalian cells and chromosomal damage in mammalian cells in a number of laboratories. The results have been conflicting, with predominantly negative results being reported from earlier studies, especially with bacterial systems. However, positive results have been reported for bacterial mutation (Glatt et al, 1989), mammalian cell gene mutation (Tsutsui et al, 1997) and mammalian cell chromosomal damage (Ishidate and Sofuni, 1985). It is considered that containment of the material in contact with the target cells, together with an appropriate source of metabolism is required to allow the identification of a mutagenic response.

 

 

Toluene (does not warrant classification under GHS/CLP):

Toluene has been examined for mutagenicity in gene mutation in bacterial cells as well as gene mutation in mammalian cells and has shown negative results in these core assay types (Haworth 1983, Litton 1978 and McGregor 1988).

 

In addition to data presented above on constituents of Distillates (Petroleum), steam-cracked, dimerised (C5-12, C10-rich), data are available for UVCBs with similar compositions – these are also produced via similar manufacturing processes and are rich in DCPD and other cyclic olefins, as well as aromatic compounds. In vitro genotoxicity data are available for the following UVCBs: CAS 68477-54-3 (Low Dicyclopentadiene Resin Oil), CAS 68478-10-4 (Dicyclopentadiene/Codimer Concentrate), CAS 64742-94-5 (Solvent naphtha (petroleum), heavy arom.), CAS 101316 -62 -5 (Extract residues (coal), light oil alk., acid ext., indene fraction), CAS 68516-20-1 (Naphtha (petroleum), steam-cracked middle arom.), CAS 68526-56-7 (Alkenes, C9-11, C10-rich), and CAS 65996-79-4 (Solvent naphtha (coal)). These studies show negative results and do not warrant classification under GHS/CLP.

Genetic toxicity in vivo

Description of key information

3a,4,7,7a-tetrahydro-4,7-methanoindene (DCPD, dicyclopentadiene; does not warrant classification under GHS/CLP):

There are no available in vivo studies on DCPD, however there is an important supporting bone marrow micronucleus study in the mouse available on DCPD / codimer concentrate, containing 29.175% dicyclopentadiene (DuPont, 2004). This is a recognised core assay type for investigating mutation in vivo which showed a negative result for DCPD/codimer concentrate mutagenicity in vivo.

 

Benzene (classification under GHS/CLP: cat 1B H340: May cause genetic defects):

The key benzene studies in in vivo systems are considered to be cytogenetic studies in the bone marrow and germ cells (Ciranni et al, 1991; Farris et al, 1996). A gene mutation study in somatic cells by Mullin et al. (1995) has been reported but this and other similar studies have been observed to have limitations.

The available data in animals and humans indicate that benzene and/or its metabolites are indirect genotoxicants rather than direct mutagens (Schnatter et al. 2020). The Mode of Action of benzene and benzene metabolites aligns with a number of threshold mechanisms described by North et al. (2020a), which are initiated by the reactive oxygen species, protein cross-linking, and protein adduct formation.

In a review by Schnatter et al. 2020, seventy seven repeat dose studies addressing genotoxic and cytogenetic effects of benzene in exposed human worker populations, focusing on micronuclei formation and chromosomal aberrations were analysed. Genotoxicity endpoint (as well as haematotoxicity) was selected as one of most sensitive and relevant endpoints to the proposed mode of action (MOA) and protecting against it will protect against benzene carcinogenicity. Lowest and No- Adverse Effect Concentrations (LOAECs and NOAECs) were derived from the highest quality studies and further assessed as being “more certain” or “less certain”. The genotoxicity, studies showed effects near 2 ppm and showed no effects at about 0.69 ppm (the findings supported the haematotoxicity results). Several sensitivity analyses supported these observations. These data define a benzene LOAEC of 2 ppm (8 h TWA) and a NOAEC of 0.5 ppm (8 h TWA).

 

Toluene (does not warrant classification under GHS/CLP):

The key study is considered to be a cytogenetic study in the rat (Litton, 1978). This is a recognised core assay type for investigating mutation in vivo, which gave a negative response. A number of additional cytogenetic studies have been carried out in the rat and mouse, and their findings support the conclusion that toluene is non-genotoxic in somatic cells in vivo (EU RAR, 2003).

A number of studies have examined occupational settings where toluene has been in use, and reported changes in certain genotoxicity parameters. However, equivocal results have been obtained and the inability to control confounding factors such as possible co-exposure to other agents does not allow meaningful conclusions for toluene (EU RAR, 2003). Prolonged exposure to 50 ppm toluene did not induce increased frequencies of sister chromatid exchange in peripheral blood lymphocytes of human volunteers (EU RAR, 2003).

 

In addition to data presented above on constituents of the UVCB Distillates (Petroleum), steam-cracked, dimerised (C5-12, C10-rich), data are available for UVCB with similar compositions – these are also produced via similar manufacturing processes and are rich in DCPD and other cyclic olefins, as well as aromatic compounds. The UVCB Low Dicyclopentadiene Resin Oil (CAS 68477-54-3): No positive mutagenic response was observed in vivo. Not statistically significant increase in micronucleated polychromatic erythrocytes was seen in male or female mouse bone marrow when evaluated after two administrations, approximately 24 hours apart. The highest dose administrated on the study was 1750 mg/Kg (ACC, 2004o).

 

Since Distillates (Petroleum), steam-cracked, dimerised (C5-12, C10-rich) contains ≥ 0.1% benzene, it is considered to be mutagenic and will require classification for this end-point.

 

References:

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

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (positive)

Justification for classification or non-classification

Available data for Distillates (Petroleum), steam-cracked, dimerised (C5-12, C10-rich) indicate that it that contains ≥0.1% benzene and it should be classified as Cat 1B, H340 under GHS/CLP “May cause genetic defects”.