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EC number: 265-057-8 | CAS number: 64741-56-6 A complex residuum from the vacuum distillation of the residuum from atmospheric distillation of crude oil. It consists of hydrocarbons having carbon numbers predominantly greater than C34 and boiling above approximately 495°C (923°F).
One key ‘read across’ animal inhalation carcinogenicity study (OECD 451) on fumes from a commercial paving bitumen (mixture of 70% air-rectified and 30% vacuum residue) was identified. For this study, no increases in the number of tumour-bearing animals were observed among the groups, nor were any statistically-significant increases in organ-related tumour incidences found in exposed animals compared to the controls. Since read across is considered valid it was concluded that the fumes from bitumen were not carcinogenic to the rats.
In a key dermal cancer study (Clark et al 2011), there was no evidence of a carcinogenic effect following daily skin application of a paving bitumen fume condensate in mice for 2 years.
A number of other animal supporting skin painting studies are available. Some studies report weak activity but the presence of solvents clearly increases bioavailability and/or dermal absorption. In addition, the conditions and method of sample preparation can influence the composition of fume condensates, rendering them unrepresentative of material to which workers may be exposed.
Two key epidemiological studies examining European asphalt workers were identified. Based on the results of the cohort study, no conclusion could be reached on the presence or absence of a causal link between exposure to bitumen fume and the risk of lung and oral / pharyngeal cancer. In the follow-up ‘nested’ case control study, there was no evidence of an association between indicators of inhalation or dermal exposure to bitumen and lung cancer risk.
Based on an overall evaluation of the results of the key and supporting animal studies, and two key epidemiology studies, it is concluded there no evidence to support that dermal or inhalation exposure to bitumen presents a carcinogenic hazard under normal condition of use.
Based on the information presented above, bitumen is not considered to be a carcinogenic hazard and does not meet the criteria for classification as a carcinogen under CLP Regulation, (EC)1272/2008.
A number of carcinogenicity studies using either bitumen or condensed bitumen fume were identified. Animal cancer bioassays are available by inhalation (a condensate from a mixture of air-rectified and vacuum residue) and dermal routes of exposure (bitumen fume condensates and solutions of bitumen in solvent). Two key epidemiological studies in European asphalt workers (2001, 2009) are also available.
It is important to recognize that toxicity studies involving exposure to bitumen fumes represent only the volatile fraction of the whole material.
No chronic cancer inhalation study on bitumen has been performed. Results of studies performed on fume condensate collected from a mixture of air-rectified and vacuum residue have been used for ‘read across’. The read across was based on the fact that the fumes of this material have been assessed and compared with fumes from straight-run paving bitumen and found to be comparable in composition and physical properties.
With regard to the read-across inhalation study, a two-year bioassay with fumes from a mixture of air-rectified bitumen and vacuum residue was conducted in Wistar rats (Crl: WI(WU) BR) (Fuhst 2006). The animals, 50 males and 50 females per dose group, were exposed nose-only to fumes regenerated from the bitumen fume condensate at target concentrations of 0 (clean air), 4, 20 and 100 mg/m3total hydrocarbon concentration for 6 hours a day, 5 days/week for 104 weeks. These concentrations were chosen based on a series of range-finding experiments in which the animals at the highest dose showed signs of slight respiratory irritation. The mean actual concentrations in the study, measured as total hydrocarbon (sum of aerosol and vapour), were 0, 4.1±0.3, 20.7±1.8, and 103.9±9.7 mg/m3using the methodology described by BIA. (Note: taking into account the conversion factor of 1.66 between the absolute concentration of fumes and the concentration measured with this method, the concentrations were 0, 6.8 mg/m3, 34.4 mg/m3, and 172.5 mg/m3, respectively [Fuhst 2006].) Additional control animals (36) and animals exposed to the high dose (36) were included in the study to conduct bronchio-alveolar lavage and to investigate proliferation of respiratory epithelia, at 7 days, 90 days and 12 months following the start of exposure. In the main study, no statistically significant differences in mortality incidence were observed among the various groups: the mortality prior to final sacrifice was 10, 18, 16 and 14% in the males and 28, 12, 16 and 22% in the females for the control, low-, medium- and high-dose groups, respectively. A statistically-significant reduction in body weight gain was observed in the medium-dose groups from day 119 (males and females) and in the high-dose groups as of day 21 (males) or day 28 (females). The difference at sacrifice averaged –3% (males) and –8% (females) of the medium-dose group and –7% (males) and –8% (females) in the high-dose group.
Lactic dehydrogenase activity in fluid, indicating an increased permeability of cell membranes, was slightly elevated in the exposed females (but not males). However, the absolute values were low and below the values of historical controls and were considered of minor relevance by the investigators. Gamma-glutamyltransferase levels in fluid, indicative of increased phagocytitic activity of macrophages, were slightly increased in both males and females. Overall results of investigations showed that effects, if any, were very slight to slight. The authors conclude that the broncheoalveolar region of the respiratory tract is not significantly impacted by exposure oxidized (air-rectified) asphalt fume. Unit Length Labelling Index was comparable in lung parenchyma of treated and control animals. No consistent effects on cell proliferation were seen for level 1 respiratory epithelium, level 1 non-ciliated epithelium and level 3 olfactory epithelium. The only consistent increase in proliferation was seen in the transitional zone of respiratory to olfactory epithelium in the exposed males, but not females. At the mid-dose level (20.7 mg/m3) the full histopathology at the termination of the study after 2 years of exposure showed some slight effects in the nasal passages. In particular hyperplasia of mucous cells (goblet cells) and eosinophilic cytoplasmic inclusions in the olfactory epithelium were observed. In addition, a statistically-significant increased incidence of mononuclear cell infiltrates was seen in the epithelium of the nasal and para-nasal cavities in animals of the mid- and high-dose groups. These effects were also seen at a lower incidence in the animals of the control and low-dose groups and are probably adaptive in nature.
No increases in the number of tumour-bearing animals were observed among the groups, nor were any statistically-significant increases in organ-related tumour incidences found in exposed animals compared to the controls. It was concluded that the fumes from a sample of mixed air-rectified asphalt and vacuum residue were not carcinogenic to rats.
A relatively large number of mouse skin-painting studies have been performed. Most of these involve dermal application of dilutions of bitumen, using a variety of solvents. In addition, a limited number of skin painting experiments have been performed using condensates of fumes derived from heating bitumens or (condensates of) fumes collected from the headspace of heated storage tanks. Although there is evidence to suggest that some bitumens or fume condensates are weakly carcinogenic, the data indicate that activity is heavily dependent on the type of solvent diluent used and / or the conditions under which the fume condensates were prepared.
In a key carcinogenicity dermal skin painting study (Clark et al., 2011),the carcinogenic potential of fume condensate from a tank paving grade asphalt (TP-D), collected from the head space of an asphalt storage tank, was tested in a mouse skin painting study. Aliquots (37.5 μl) of the tank paving asphalt fume condensate dissolved in mineral oil were painted daily on the shaved back of 80 male C3H/HeNCrL mice for 2 years. The total weekly dose of fume condensate was 50 mg. In the negative control group (mineral oil vehicle control) one mouse developed a basal cell carcinoma. In the mice treated with paving asphalt fume condensate, a single animal with a squamous cell papilloma was found at terminal sacrifice (week 104). In addition, tumours observed in other organs were within the incidence range of historical controls for this strain and not considered significant. The positive control (benzo[a]pyrene (BaP), 0.05% in toluene) exhibited the expected skin tumour response; 37 squamous cell carcinomas, 3 keratoacanthomas, 1 squamous cell papilloma, 1 fibrosarcoma, 1 melanoma, 2 undifferentiated sarcomas, and 2 developed schwannomas.
Five supporting dermal cancer studies on bitumen were identified.
In a dermal carcinogenicity study (Goyak et al., 2011),asphalt Cement 20 (CAS # 8052-4204) or Coastal Residuum (CAS # 64741-56-6), were applied as 30% or 75% w/v solutions in mineral oil, twice weekly (at 37.5 μL per dose totalling a weekly dose of 75 μL) to the clipped backs of 50 male C3H/HeNCrlBR mice for a period of 24 months. Benzo[a]pyrene ([BaP] (0.05% (w/v) dilution in toluene) was used as the positive control. Survivorship was unaffected by treatment.Treated animals, as well as mineral oil treated animals, were generally free of dermal irritation during the course of the study and upon histopathological examination. Animals treated with BaP and its vehicle, toluene, exhibited slight-to-moderate dermal irritation throughout the study. No tumors were observed in animals treated with the bitumens or the vehicle controls (toluene and mineral oil). The positive control, BaP, produced histopathologically confirmed tumors in 92% of the animals. Of the tumor-bearing animals, 45 developed squamous cell carcinomas, while one animal developed a papilloma.
In another dermal skin painting study (Hueper et al., 1960), various bitumens were dissolved in an acetone dilution (concentration not specified) and applied twice weekly for 2 years to the skin of groups of 25 or 50 male and 25 or 50 female mice. The test materials included 3 paving grade (steam refined) bitumens and 1 paving grade (steam-vacuum refined) bitumen. The study showed a low average skin tumour incidence rate of 2% (range 0-4%: paving grade (steam refined) tumour incidence: 0/100 (0%), 2/50 (4%), and 0/50 (0%); paving grade (steam-vacuum refined). In the 200 mice of the negative control group no tumours were found but in mice painted under identical conditions with coal tar solutions (positive control) the tumour incident rate was 52% (26/50).
The carcinogenic potential of 8 bitumens was investigated in a skin painting study in Swiss mice (Wallcave et al., 1971). All materials were analysed for PAH content. The substances were dissolved at 10% in benzene and this solution was applied onto the shaved back of 15 male and 15 female mice in a volume of 25 µl twice per week. In addition, 15 male and 15 female mice were painted with benzene only to serve as controls. The mean survival time of the bitumen painted mice was 81 weeks and the controls 82 weeks. With 4 of the 8 bitumens no skin tumours were found (0/24, 0/28, 0/32, 0/27; 0%). One bitumen sample induced a single carcinoma (1/27; 3.7%), and the three other samples induced 1, 2 and 2 papillomas (1/25, 2/28, 2/27; 4%, 7.1%, 7.4% respectively). The average incidence of tumours in the test groups was 2.8%. In the control group 1 papilloma was found (1/26, 3.8%). While bitumens induced tumours in this study, the incidence was found to be lower than that of the negative control groups.
The following supporting study (Robinson et al., 1984) is also included in the dossier.
Some older skin painting studies dissolved the bitumen in benzene or acetone and are less relevant because of bioavailability issues (Potter et al., 1999). In addition, the studies by Simmers and co-workers (1959, 1965a, b) suffer from a large number of experimental problems and cannot easily be interpreted. These studies were repeated by Hueper & Payne (1960) under identical conditions and then showed skin tumour incidences in mice painted with bitumen dilutions equal to, or lower than, control animals (average 2%) whilst the animals painted with coal tar dilutions (positive controls) showed a high incidence of skin tumours (52%). In the studies by Wallcave et al. (1971) animals were painted with bitumen dissolved in benzene. Some of the solutions produced tumours (a single carcinoma and some papilloma's), however, the tumour incidence was not elevated when the incidence in the solvent controls (3.8%) was subtracted from the tumour incidence observed in the animals treated with dissolved bitumens, and was well within the normal background of tumours observed in animals painted with neutral oils. More recent studies with bitumen dilutions were all negative ( Robinson et al., 1984). Skin painting studies using condensates of fumes from bitumen, are more relevant than bitumen dilutions. However, the results of the Niemeyer et al. (1988) and the Sivak et al. (1989, 1997) studies with oxidised bitumen should be interpreted with caution because in these studies fumes generated in the laboratory at high temperatures were used which are not representative for fumes generated under normal conditions (Kriech et al., 2007).
In a retrospective cohort study (2001; Klimisch score=1) of male workers exposed to fumes from bitumen, in the European asphalt industry, 29,820 workers were selected for analysis from companies in Denmark, Finland, France, Germany, Israel, Netherlands, Norway, and a national health survey in Sweden (mortality follow-up 1953 to 2000). A Road Construction Workers’ Exposure Matrix (ROCEM) was used to estimate exposure to bitumen fume. Other compounds included for exposure analysis were coal tar, 4-6 ring polycyclic aromatic hydrocarbons, organic vapour, diesel exhaust, asbestos, and silica dust. Standardized mortality ratios (SMRs) and their associated 95% confidence intervals were calculated for overall mortality and lung cancer as compared to national mortality rates. Comparisons between various job categories within the cohort were also determined.
Overall standardized mortality ratio for the whole cohort (SMR 0.92, 95% CI, 0.91 to 0.94) which included asphalt, ground workers, and building workers was similar to the value for workers exposed to bitumen fume (SMR 0.96, 95% CI, 0.93 to 0.99). Both values were below expected. The SMR for lung cancer in bitumen workers was 1.17 (95% CI, 1.04 to 1.30) compared to an SMR of 1.07 (95% CI, 1.00-1.15) for the overall cohort and an SMR of 1.01 (95% CI, 0.89 to 1.15) for building and ground construction workers. The relative risk (adjusted for age, seasonal variation in work, country, and employment duration) for lung cancer among workers exposed to bitumen fume compared to ground and building construction workers was 1.09 (95% CI, 0.89 to 1.34). In an analysis restricted to exposed workers, average exposure to bitumen fume (but not duration of exposure or cumulative exposure) was found to be statistically significantly related to lung cancer mortality. Excess numbers of death in bitumen workers from non neoplastic causes included bronchitis, emphysema, and asthma (SMR 1.21, 95% CI, 1.02-1.43).
Confounding factors in the analysis included exposure to other agents in the asphalt industry that may cause increased lung cancer risk (e. g., coal tar, asbestos, PAHs) and worker lifestyle factors such as tobacco smoking. Based on the results of the cohort study, the authors concluded (Boffetta et al 2003) that there was a slightly elevated risk of lung cancer, and possibly oral and pharyngeal cancers, in asphalt workers; the conclusion was more uncertain for the latter, since the number of cases was much smaller. There was no suggestion of an association between employment in the asphalt industry and other cancers. As the study results did not allow to conclude on the presence or absence of a causal link between exposure to bitumen fume and cancer risk, a follow-up case-control study was recommended.
A case-control study was conducted, as a follow-up to the previous cohort study, which investigated lung cancer nested within the original cohort to disentangle the contribution of bitumen from other agents occurring in the asphalt industry, other occupational exposures, and tobacco smoking. Cases were selected from the original cohort study and included male workers aged less than 75 years from Denmark, Finland, France, Germany, the Netherlands, Norway, and Israel, had been employed at least two full seasons in the asphalt industry, and died from (or were diagnosed with) lung cancer between 1980 and the end of follow-up (2002-2005). Controls were cohort members who were alive at the date of the death or diagnosis of the case, who were matched to cases (3:1 ratio) on year of birth (± 3 years) and country. Living workers (2% of cases, 66% of controls) or their next-of-kin (98% of cases, 34% of controls) were interviewed with respect to tobacco smoking and complete occupational history; living subjects or fellow workers were interviewed with respect to detailed working conditions within the asphalt industry. Estimates of exposure were derived for bitumen fume, organic vapour, bitumen derived polycyclic aromatic hydrocarbons (PAH) (inhalation exposures) and bitumen condensate (dermal exposure – this route of exposure was not included in the cohort phase of the study), as well as for asbestos, silica, diesel exhaust and coal tar (combined exposure within and outside the original asphalt companies for the latter four agents), based on company-level information gathered during the cohort phase of the study and individual-level information gathered during the case-control study. Odds ratios (OR) of lung cancer were estimated for ever exposure, duration of exposure, cumulative exposure and average exposure to bitumen and the other agents, after adjusting for tobacco smoking and coal tar. Additional sensitivity analyses were conducted to assess the robustness of the results.
A total of 433 cases and 1253 controls were included in the analysis (response rate 65% among cases and 58% among controls). Next of kin interviews were used for 96% of cases and 31% of controls. The OR for ever exposure to bitumen fume was 1.12 (95% confidence interval 0.84 -1.49), and there was no association between lung cancer risk and duration of exposure, cumulative exposure or average exposure. Results for exposure to organic vapour and PAH were similar to those for exposure to bitumen fume. The OR for ever exposure to bitumen condensate was 1.17 (95% CI 0.88 -1.56). There was no association with duration of exposure, cumulative exposure or average exposure to bitumen fume and lung cancer. The results were robust to sensitivity analyses (exclusion of one country at a time, restriction to good-quality interviews, to subjects with next of kin interviews, to workers employed for more than 5 years in the asphalt industry, and to complete case-control sets). The analysis on exposure to asbestos, silica and diesel exhaust did not reveal any association with lung cancer risk. Coal tar, on the other hand, was associated with lung cancer and cumulative exposure and, to a lesser extent, duration of exposure. A comparison of prevalence of smoking between living controls and individuals included in national surveys resulted in confounding OR in the range 1.07 – 1.28. OR for tobacco smoking were consistent with data from the literature. Sensitivity analyses did not suggest a bias from the use of interviews for most cases and a proportion of controls.
There was no consistent evidence of an association between indicators of inhalation or dermal exposure to bitumen and lung cancer risk.
Additional data supports that bitumen is not carcinogenic (CONCAWE, 1992; Fuhst, 2007). This information is presented in the dossier.
Justification for selection of carcinogenicity via inhalation route endpoint:
well-conducted, 2 year inhalation cancer study available (Fuhst et al 2006)
Justification for selection of carcinogenicity via dermal route endpoint:
Key study is Clark et al 2011 with a number of other supporting studies.
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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