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EC number: 295-518-9
CAS number: 92062-05-0
A complex combination of hydrocarbons obtained from the vacuum distillation of the products from a thermal cracking process. It consists predominantly of hydrocarbons having carbon numbers predominantly greater than C34 and boiling above approximately 495°C (923°F).
A large number of published in-vitro and in-vivo genetic toxicity studies were identified. In-vitro studies included Ames, or modified Ames tests, chromosomal aberration studies, micronuclei and mouse lymphoma assays and Comet assays to investigate DNA damage. In-vivo studies included transgenic studies, cytogenicity investigations, micronucleus assays, Comet assays (for DNA damage) and investigation of DNA adduct formation and gene expression profiling.
In-vitro studies were undertaken on condensates of bitumen, or solutions of bitumen in solvent whereas in-vivo studies were carried out following inhalation exposure to bitumen fumes, dermal exposure to fume condensates/solvent solutions, oral exposure to bitumen solutions or intratracheal administration of condensate.
Two inhalation transgenic animal model studies (non-guideline) were identified as key in vivo studies. Both studies (one in mice and another in rats) produced negative results. Results of a key ‘read across’ micronucleus assay are available for a mixture of air-rectified bitumen and vacuum residue which was negative. Supporting oral cytogenetic assays were also negative. In vitro gene mutation studies in bacteria (OECD 471) were identified on bitumen and showed mixed results.
In conclusion, although the in-vitro and in-vivo studies identified showed some mixed results the large body of data did not show clear, consistent evidence of genotoxic activity.
Additional information from genetic toxicity in vivo:
It is important to recognize that
toxicity studies involving exposure to fume or fume condensates from
bitumens represent only the volatile fraction of the whole material.
One key gene
mutation study in bacteria (Klimisch score=2) was identified. In a
reverse gene mutation assay in bacteria, strains TA98, TA100, YG 1041
and YG 1042 of S. typhimurium were exposed to bitumen fume condensates
in DMSO at amounts not exceeding 10 µL and 0.1 mL of the overnight
culture in the presence and absence of mammalian metabolic activation
using pre-incubation method (De Meo et al., 1996). There was no evidence
of mutagenic activity in any samples without metabolic activation. All
samples and strains with metabolic activation showed varying degrees of
mutagenic activity from 268 (x 0.08) to 11748 rev/ µL. The
positive controls induced the appropriate responses in the corresponding
In three supporting studies, 3 bitumen and 2
RAE samples were examined for mutagenic activity in one histidine
dependent auxotroph of Salmonella typhimurium, strain TA98, using a
modification of the pour-plate assay designed to detect mutagenicity
mediated by polynuclear aromatic compounds derived from petroleum, based
upon the principles of the ASTM Standard Test Method E 1687. A clear
indication of mutagenic activity is indicated by an MI value >/=1. The
results showed, that the test substance, CAS 8052-42-4 had a
Mutagenicity Index (MI) of 2.63, test substance, CAS 64741-56-6 had a
Mutagenicity Index (MI) of 0.84, and the test substance, CAS 92062-05-0
had a Mutagenicity Index (MI) of 2.84.
In a key gene
mutation study (Kriech et al., 2007, Klimisch score = 2), four samples
of fume condensate originating from paving bitumen were tested in a
modified Ames assay. The
four samples were collected from bitumen storage tanks (indicated by
TR). Three of the four samples were negative whilst one
showed a marginally positive response.
In a mammalian
micronucleus assay, Chinese hamster cell V79 cultures were exposed to
Type I and Type III roofing (oxidized) asphalt fume condensates (generated
at temperatures similar to actual roofing operation (316 ±
DMSO at concentrations of 0, 62.5, 125, 187.5, and 250 μg/mL for 24
hours (Qian et al., 1996). The results were expressed as the mean number
of cells with micronucleus per 1000 cells. Fume condensates of both
types I and III oxidized asphalt were found capable of causing
micronucleus formation in mammalian cells in vitro. The genotoxic
potential appears to be similar for both types of oxidized asphalt
condensate. Both condensates caused a similar dose-related increase in
the frequency of micronucleated cells. The increase was statistically
significant for all four concentrations tested. These findings indicate
that both Type I and Type III roofing oxidized asphalt fumes are capable
of causing cytogenetic damage, principally to the spindle apparatus in
cultured mammalian cells.
With regard to in
vivo studies, the genotoxic effects of fumes from bitumen were studied
in transgenic (Big Blue) mice (Micillino, 2002) and rats (Bottin et al.,
2006). Animals were exposed, nose only, to 100 mg/m3 (TPM)
bitumen fumes for 6 hours a day for
five consecutive days. Mutation
properties of bitumen were evaluated by analyzing the mutation frequency
and spectrum of neutral receptor gene cII inserted into the rodent
genome. For the
mouse study, DNA adducts and cII mutant frequencies in the isolated lung
DNA were not different in the exposed mice compared to controls. The
mutation spectra were also very similar in the exposed and control
animals and indicated that exposure to about 100 mg/m3 (TPM) of fumes
from bitumen similar to those produced during road paving did not induce
any genotoxic effect. Contrasting
those results found in mice, rat DNA adducts could be detected using 32P-postlabelling
in the transgenic rats and there was a clear increase in excretion of
1-hydroxypyrene in the exposed animals. However,
like in the mice, the cII mutant frequencies were not changed but a
small, albeit statistically not significant, change in incidence of
transversions was observed. Consequently, it was concluded that, despite
the presence of DNA adducts, there was no mutagenic potential from fumes
generated from bitumens heated to temperatures used during road paving
studies, it is clearly shown that bitumen-induced DNA adducts are not
necessarily linked to mutagenic effects. Overall, there is no convincing
evidence from studies in animals that exposure to fumes from bitumen
causes mutagenic or clastogenic effects.
supports that bitumen is not mutagenic including API, 1984a, b; Gate et
al., 2006; Ma et al., 2002; Machado et al., 1993; Robinson et al., 1984,
Halter 2007, Booth 1998).This
information is presented in the dossier.
Justification for selection of genetic toxicity endpoint
An in-vivo transgenic study was selected but other studies eg in-vivo micronucleus studies would also be valid.
oil products containing relatively high concentrations of polycyclic
aromatic compounds (PAC) are considered genotoxic carcinogens. The EU
legislation aims primarily to classify substances as mutagenic if there
is evidence of producing heritable genetic damage, i.e. evidence of
producing mutations that are transmitted to the progeny or evidence of
producing somatic mutations in combination with evidence of the
substance or relevant metabolite reaching the germ line cells in the
reproductive organs. The PAC in oil products are poorly bioavailable due
to their physico-chemical properties (low water solubility and high
molecular weight), making it unlikely that the genotoxic constituents
can reach and cause damage to germ cells
2007; Potter, 1999).
Considering their poor bioavailability, oil products do not need to be
classified as mutagenic unless there is clear evidence that germ cells
are affected by exposure, consistent with DSD.
A large number of
in-vitro and in-vivo genotoxicity studies are available for bitumens or
air-rectified bitumen. Although the database provides some mixed results,
overall the data do not provide clear consistent evidence of genotoxic
activity. Chronic inhalation studies with oxidized (air-rectified)
asphalt, together with comparative fume composition information,
indicate that read across to the bitumen category, is appropriate. Based
on these in vivo animal studies, it clearly is shown that
bitumen-induced DNA adducts are not necessarily linked to mutagenic
effects. Consequently, bitumens are unlikely to be mutagenic and do not
meet the criteria for classification and labelling under CLP
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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