Asphalt, oxidized

Carcinogenicity

Description of key information

One key animal inhalation carcinogenicity study (OECD 451) on fumes from air-rectified (partially oxidized) asphalt 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. It was concluded that the fumes from the test material were not carcinogenic to rats.

For dermal exposure, some of the studies are on oxidized asphalt itself whilst some are on a portion of the material represented by the fumes or fume condensate.  Studies on the substance itself indicate the substance is not carcinogenic.  The fume condensate collected from the headspace of storage tanks, indicate that oxidized asphalt fume condensate from Type III BURA, a specific subset of oxidized asphalt, has carcinogenic potential.  There are also additional studies that have used laboratory methods to prepare test samples that 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. 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 from the cohort study. 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.  In a supporting case control study, a dose-response relationship was not found with regard to exposure to asphalt fumes at levels reported for lung cancer and non-malignant respiratory disease, excluding influenza and pneumonia risk, in workers engaged in asphalt roofing manufacturing and asphalt production.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

103.9 mg/m³

Study duration:

chronic

Species:

rat

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

50

Study duration:

chronic

Species:

mouse

Justification for classification or non-classification

Based on the information presented above, oxidized asphalt is not considered to be a carcinogenic hazard and does not meet the criteria for classification as carcinogen under CLP EU Regulation 1272/2008.

Additional information

A number of carcinogenicity studies were identified. Animal cancer bioassays are available by inhalation and dermal routes of exposure. Two key epidemiological studies in European asphalt workers (2001, 2009) and one supporting epidemiological study (2002) are also available.

Inhalation Study

It is important to recognize that toxicity studies involving exposure to fumes represent only the volatile fraction of the whole material.

An inhalation study in rats on fumes from oxidized (air rectified) asphalt is available.

With regard to the inhalation study, a two-year bioassay with fumes from an oxidized asphalt (air-rectified) asphalt was conducted in Wistar rats (Crl: WI(WU) BR) (Fraunhofer, 2006; Fuhst et al., 2007). The animals, 50 males and 50 females per dose group, were exposed nose-only to fumes regenerated from the fume condensate at target concentrations of 0 (clean air), 4, 20 and 100 mg/m³ total 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 from bitumen 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 [Fraunhofer, 2006; Fuhst et al., 2007]). 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 BAL 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 phagocytic 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 to bitumen 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 inhalation of fumes from oxidized asphalt (air rectified) did not result in treatment related carcinogenic lesions in the rats.

Dermal Studies

A relatively large number of mouse skin-painting studies have been performed. Most of these involve dermal application of dilutions of bitumen (either oxidized asphalt or straight run bitumen), using a variety of solvents. In addition, a limited number of skin painting experiments have been performed using condensates of fumes derived from heated material. Although there is evidence to suggest that some bitumens or bitumen 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. It is important to recognize that toxicity studies involving exposure to fumes or fume condensates represent only the volatile fraction of the whole material.

One key dermal carcinogenicity study using fume condensate of oxidized asphalt was identified and summarized below. 

The carcinogenic potential of fume condensate from Built Up Roofing Asphalt (BURA) Type III, an oxidized asphalt, was evaluated using two different fume condensates (MPI Research, 2010; published in Clark et al., 2011). One was collected from the head space of a heated storage tank [Tank Roofing asphalt fume sample A (TR-A)], whilst the other was a laboratory fume condensate, generated using the same BURA in a laboratory fume generator [Laboratory Roofing bitumen fume sample A (LR-A) under identical conditions to those employed by Niemeir et al 1988]. LR-A was used as a test material in order to compare results from earlier studies that had utilised a laboratory fume condensate collected under incongruous operating conditions, which subsequently was suspected of affecting the composition of the material generated (Sivak et al, 1989; Sivak et al. 1997; Niemeir et al. 1988). A side by side comparison of TR-A and LR-A was conducted to evaluate the carcinogenic potential of a field representative sample, and a laboratory generated sample. In a mouse skin painting study, 37.5ml of BURA Type III oxidized asphalt fume condensate, diluted in mineral oil, was applied two times per week to the shorn dorsal area of C3H/HeNCrL mice for 2 years, resulting in a total weekly dose of 50 mg fume condensate /animal.

The TR-A treated group had survival rates that were similar to mineral oil control animals for the duration of the study. Dermal irritation in TR-A animals was not remarkable, and comparable to mineral oil control animals, until approximately week 53. After this the irritation levels gradually increased for the remainder of the study although did not reach marked levels. Body weights in all groups followed an expected pattern, which included some increase in bodyweight consistent with skin tumour production.

During the treatment period, the mortality incidence in the LR-A treated group was broadly similar to controls until Week 60. After this point mortality increased in LR-A treated animals, although a sufficient proportion of the animals survived to study termination. Body weights in all groups followed an expected pattern including increase weights consistent with skin tumour production. Dermal irritation in LR-A treated animals was not remarkable, and comparable to controls, until approximately week 46. After this, the incidence and level of dermal irritation increased rapidly, reaching near marked levels by week 57, and affecting the majority of animals. Dermal irritation remained at this level for the remainder of the study.

In mice treated with oxidized asphalt fume condensate (TR-A), 8 mice developed squamous cell carcinomas, 1 mouse developed a keratoacanthoma, and 4 mice developed squamous cell papillomas. In the mice treated with laboratory generated fume condensate (LR-A), 35 mice developed squamous cell carcinomas, 2 mice developed a keratoacanthoma, and 3 mice developed squamous cell papillomas The first onset of skin tumors in TR-A treated animals was observed in week 62 and in week 50 for LR-A treated animals.

In the 0.05% BaP positive control group (diluted in toluene) 34 mice developed squamous cell carcinomas, 3 mice keratoacanthomas, 2 mice squamous cell papillomas, 2 mice fibrosarcomas, 4 mice undifferentiated sarcomas, and 3 mice developed schwannomas. The first dermal tumour in the BaP group was found in week 28. In the negative control groups (mineral oil and toluene vehicle control), no skin tumors were observed.

It was concluded that both TR-A and LR-A were carcinogenic to mouse skin. Although the materials produced markedly different responses, both produced tumours following the onset of dermal irritation. The tumour response observed with LR-A was comparable with that reported by Sivak (Sivak, 1997).

Additionally the following supporting studies have been identified: Sivak et al, 1989; Sivak et al. 1997; Niemeier et al. 1988; Wallcave et al., 1971; Hueper and Paine, 1969; Simmers, 1965; Emmett et al., 1981; Robinson et al., 1984. 

In addition to the carcinogenicity studies presented above, one six-month mouse skin tumour initiation and promotion study (Freeman et al., 2011) was identified in which oxidized asphalt fume condensate (ACF) was dermally administered to 30 Crl:CD1male mice per group at dose levels of 50 mg/week (doses were applied twice daily at 25 mg). For the study, the initiation phase was defined as weeks one and two of the study, and the promotion phase of the study was defined as weeks three through study termination. Mineral oil (MO) served as the vehicle control. 7,12-Dimethylbenzanthracene (DMBA) served as a positive control initiating agent and was administered once only on day one at a dose of 50 µg; 12-0-tetradecanoyl-13-acetate (TPA) was the positive control promoting agent and was administered twice weekly at a dose of 5 µg (0.01% in acetone) during the promotion phase starting on week three and ending at study termination.

There was no apparent relationship between skin irritation and tumour development in this study. A statistically significant number of tumour-bearing animals (eight) was observed in the group initiated with the oxidized asphalt fume condensate and promoted with TPA compared to the MO/MO control group. Five of the 8 tumour-bearing animals in this group exhibited benign squamous cell papillomas; two of these animals had multiple papillomas. In the group initiated with DMBA and promoted with the asphalt fume condensate sample, only two mice developed tumors. In the positive control group initiated with DMBA and promoted with TPA, a positive response was observed with 29 of the 30 animals exhibiting tumors, which were multiple in many of the animals. Tumours observed in the positive group included malignant squamous cell carcinomas, benign squamous cell papillomas and benign keratoacanthomas.

Based on the results, the authors concluded that there was no apparent relationship between skin irritation and tumour development. There was a statistically significant tumour response in mice initiated with field-matched asphalt fume condensate and promoted with TPA. Consequently, the results suggest that oxidized asphalt fume condensate is more indicative of genotoxicity rather than a non-genotoxic mode of action.

Epidemiology Studies

In a retrospective cohort study (IARC, 2001) 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 resultsdid not allow to conclude on the presence or absence of a causal linkbetween exposure to bitumen and cancer risk, a follow-up case-control study was recommended.

A case-control study (IARC, 2009) was conducted as a follow-up to the previous cohort study. In the cohort study there was an association between lung cancer mortality and increasing average exposure to bitumen fume, but a similar association was not observed with increasing duration of exposure or with cumulative exposure. This case-control study of lung cancer was conducted 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, who 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 condensate 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.

Two case control studies were conducted for workers engaged in asphalt roofing manufacturing and asphalt production to determine whether there was an increased risk associated with exposure to asphalt fumes or respirable crystalline silica in these industries (Watkins et al., 2002). Cases included 31 white male lung cancer deaths and 8 black male lung cancer deaths, and 27 white male non-malignant respiratory disease (NMRD) deaths and one black male NMRD death. Three of the white male deaths attributed to influenza were excluded from the NMRD analysis. Control groups (133 controls for lung cancer; 80 controls for NMRD) were comprised of decedents or retirees from the roofing and asphalt facilities who were not cases. An attempt was made to match up to a maximum of four controls per case on gender, race, and year of birth (±2 years). Industrial hygiene data was mined to obtain exposure information for 1 of the 14 process categories in the roofing facilities or 1 of the 10 process categories in the asphalt production facilities based on task or job title associated with the personal. Pre-1977 exposure scenarios were constructed to estimate historic exposures for asphalt fumes and respirable crystalline silica since this data was not collected. The only statistically significant elevated ORs were for cigarette smoking in both the lung cancer and the non-malignant disease analyses. A dose-response relationship was not found with regard to exposure to asphalt fumes at levels reported for lung cancer and non-malignant respiratory disease, excluding influenza and pneumonia risk.

There was no consistent evidence of an association between indicators of inhalation or dermal exposure to bitumen and lung cancer risk.

Justification for selection of carcinogenicity via inhalation route endpoint:

well conducted 2 yr inhalation study in rats

Justification for selection of carcinogenicity via dermal route endpoint:

Good quality dermal cancer study in mice

Carcinogenicity: via dermal route (target organ): other: skin