Registration Dossier

Administrative data

Key value for chemical safety assessment

Additional information

Genotoxicity data are available for a number of specific streams identified for this category:

CAS 64742 -83 -2 (C4 Crude Butadiene): Positive results were seen in the mouse bone marrow micronucleus test. The incidence of micronucleated polychromatic erythrocytes (MN-PCE) in the bone marrow of mice exposed by inhalation (0.5, 10 or 20 mg/L, 4 hours/day, for 2 consecutive days) was statistically significant increased (2.4 to 4.4-fold) in both sexes of all groups (Dow, 2001).

API 83-04 (CAS 64741-63-5) and API 83-05 (CAS 68955-35-1) are two petroleum based naphthas comprising up to 100% aromatics, including substituted mono and di-aromatics with approximately 2-5% benzene and are considered appropriate for read-across to high benzene naphthas.

API 83-04 [light catalytic reformed naphtha]: In vitro treatment of mouse lymphoma cell line, L5178Y, with API 83-04 induced no reliable increases in the mutation frequency at the thymidine kinase (TK) locus either with or without rat liver S9 metabolic activation (API, 1985c). Negative results were also seen in vivo. Male and female rats were dosed at 250, 830 or 2500 mg/kg as a single ip injection. Bone marrow cells, arrested in metaphase and collected 6, 24 and 48 hours after treatment, were examined microscopically for numerical and structural chromosome aberrations. There were no significant increases in the percentage of chromosomally aberrant cells and no effect on the mitotic index of the bone marrow in either sex (API, 1986e).

API 83-05 [catalytic reformed naphtha]): Positive results were seen in vitro following treatment of mouse lymphoma cell line, L5178Y, with API 83-05. Significant increases in the mutant frequency at the thymidine kinase (TK) locus were seen in presence of rat liver S9 metabolic activation (API, 1985d). In a rat bone marrow micronucleus test (male and female rats dosed with 250, 260, 820, 830, 2420 or 2500 mg/kg as a single ip injection) there were no significant increases in the percentage of chromosomally aberrant cells and no effect on the mitotic index of the bone marrow in either sex. Catalytic reformed naphtha (API 83-05) was, therefore considered negative in this in vivo genotoxicity assay (API, 1985e).

Specific components which have been identified as present in some streams and shown to be mutagenic in vivo are benzene, 1,3-butadiene, and isoprene:

Benzene (Classification: EU –Toxic T Mutagen Cat 2 R46; GHS/CLP - Category 1B, H340): Benzene has been extensively examined for mutagenicity both in vitro and in vivo in a range of recognised core assay types. It has shown mixed results for mutagenicity in vitro although in mammalian cells there is overall evidence for potential mutagenic activity (EU, 2008b). Benzene has been shown to be mutagenic in vivo in both somatic cells and germ cells (Ciranni et al, 1991; Farris et al, 1996; Mullin et al, 1995).

1,3-Butadiene (Classification: EU –Toxic T Mutagen Cat 2 R46; GHS/CLP - Category 1B, H340): In non-human studies, 1,3-buta-diene is genotoxic in vitro and is genotoxic in vivo in both somatic and germ cells in the mouse (Araki et al, 1994, Asakura et al, 2008, Adler et al, 1994). The available data on several groups of 1,3-butadiene-exposed workers did not show any association between 1,3-butadiene exposure and increased gene mutations, primarily HPRT mutations. No 1,3-butadiene-related chromosome aberrations have been demonstrated in humans (Albertini et al 2001, 2003, 2007).

Isoprene (Classification: EU – Harmful Xn Mutagen Cat 3 R68; GHS/CLP - Category 2, H341): Isoprene has been examined for mutagenicity both in vitro and in vivo in a range of recognised core assay types. It has shown negative results for mutagenicity in vitro in the core endpoints of bacterial mutation and cytogenetic damage, both with and without S9. However, isoprene induced DNA damage (strand breaks) at high concentrations in a mammalian cell line in vitro. These effects were only observed in the presence of S9. There are several reports of isoprene inducing micronuclei in the bone marrow of mice exposed for different times from 12 days through to 80 weeks. A single examination in the rat reported a negative result for micronucleus induction, although this was in lung fibroblasts and not in bone marrow cells. A direct comment on the relative sensitivity to genotoxic effects of isoprene in the mouse and rat is therefore not possible. Isoprene is considered to be genotoxic in vivo, having shown clear effects in the mouse (Huntingdon Life Sciences (UK), 2004; NTP, 1995).

References

EU (2008b). European Union Risk Assessment Report for Benzene. EC Joint Research Centre. http: //ecb. jrc. ec. europa. eu/documents/Existing-chemicals/RISK_ASSESSMENT/REPORT/benzenereport063. pdf.


Short description of key information:
In vitro and/or in vivo genotoxicity data are available for 1 stream within this category (CAS 64742-83-2 [C4 crude butadiene]) and 2 related streams (API 83-04 [light catalytic reformed naphtha] and API 83-05 [catalytic reformed naphtha]). These studies show both positive and negative results. However, there are substantial data on the genotoxicity of a number of specific components present in some streams. Of these, benzene, 1,3-butadiene and isoprene have been shown to be mutagenic in vivo. As benzene is a Category 2 mutagen and is present in all streams at a concentration of 0.1% or greater then High Benzene Naphtha streams are considered to be mutagenic.

Endpoint Conclusion: Adverse effect observed (positive)

Justification for classification or non-classification

High Benzene Naphtha streams contain ≥0.1% benzene and therefore are considered to be mutagenic. In addition they may contain up to 1% 1,3-butadiene and up to 6% isoprene.

It is proposed that High Benzene Naphtha streams are classified as Mutagenic Cat 2, R46 under Dir 1999/45/EC and Cat 1B, H340 under Reg (EC) 1272/2008.