Registration Dossier

Administrative data

Description of key information

The following key studies were identified: a read across combined repeated dose/ reproductive/developmental toxicity screening test (OECD 422); two 28-day dermal studies (OECD 410); and a read across chronic inhalation study (OECD 451). For the dermal studies performed on rabbits, the NOAEL topical effects for both samples of vacuum residue was 200 mg/kg/day and the NOAEL for systemic effects was 2000 mg/kg; both endpoints were based on absence of significant histopathological findings. For the chronic inhalation study, the NOAEL for systemic effects in the rat following inhalation was 103.9 mg/m3 (172.5 mg/m3 adjusted) based on the absence of any histopathological changes or alterations in clinical chemistry or haematology. The LOEC for local effects was 20.7 mg/m³ (34.4 mg/m³ adjusted), based on irritant effects on the nasal passages. The NOAEC was set at half the LOAEC, that is 10.4 mg/m³ total hydrocarbon concentration (17.2 mg/m³ adjusted) based on the minimal effects and the facts that in the 90-day study and the reproductive toxicity screening studies NOAECs of 20.1 mg/m³ (30.4 mg/m³ adjusted) and 30 mg/m3 were found, respectively.

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
103.9 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subacute
Species:
rabbit

Additional information

No repeat-dose oral studies on bitumens have been identified. Two key studies involving repeated dermal exposure are available. Read across, repeat dose inhalation studies are available for fumes from condensates of oxidized and air-rectified asphalts.

Read across for the key inhalation studies is justified because fumes of air-rectified asphalt have been shown to be comparable with fumes of paving bitumen. In a comparative analytical study, fumes from a straight-run and air-rectified grades were closely similar in terms of composition and physical properties.

A combined repeated dose/ reproductive/developmental toxicity screening test (Fraunhofer, 2009; Klimisch score=1), two 28 -day dermal studies (API, 1983c, d; Klimisch score=1), and a chronic inhalation study (Fraunhofer, 2006; Klimisch score=1) were identified as key studies. Results of these are presented below.It is important to recognize that toxicity studies involving exposure to fumes represent only the volatile fraction of the whole material.

In a read across combined repeat dose/ reproductive/developmental screening study rats were exposed to roofing (oxidised) asphalt fume condensate at target concentrations of 30, 100, and 300 mg/m³ total hydrocarbons, respectively, or clean air by nose only inhalation, 6 hours per day, 7 days per week (Klimisch score=1). The average concentrations measured continuously during the whole exposure period by aerosol photometers were 30.0 mg/m³, 100.1 mg/m³ and 297.3 mg/m³ total hydrocarbon concentration for the low-, mid- and high-dose group. In the subchronic subgroup, males and females were exposed for 28 days. Breeding females were exposed daily for 2 weeks before mating and during the mating period (up to 2 weeks). After successful mating, females were exposed daily from gestational day 0 through 20 (Fraunhofer 2009, Parker et al., 2011).

 

There were no treatment-related effects on clinical signs, mortality or neurological tests. Results of the study indicated that body weight gain and food consumption were significantly reduced in male rats in the 300 mg/m³ group. Results in females could not be assessed due to randomization errors. The absolute and relative lung weight was statistically-significantly increased in the high-dose males. Relative lung weight was statistically-significantly increased in the female 100 and 300 mg/m³ groups as well as in the 300 mg/m³ group of the breeding females. There were no treatment-related effects observed in haematology and clinical chemistry. Treatment-related findings were observed in the nasal cavity and in the lungs. In the nasal cavity, a statistically significant decrease of inflammatory cell infiltration was observed in the high-dose group as compared to the control group. 

In summary, the low dose 30 mg/m3 was determined as the systemic NOAEC for the study, with clear (mild) effects in the high dose, and significantly increased mean relative lung weight in mid-dose sub-chronic females although, in the absence of any histopathological correlates.

In two 28 -day dermal studies, petroleum vacuum residues (CAS# 64741-56-6) were tested on rabbits (API, 1983c, d). For both studies, four groups of 5 male and 5 female rabbits were exposed to two different samples of vacuum residue once per day, three days/week for 4 weeks (12 applications in total). Doses applied were 0 (sham-exposed), 200, 1000 or 2000 mg/kg body weight. The neat material was slightly heated just prior to application to decrease its viscosity, put on a 4 x 4 inch patch and subsequently applied to shaved dorsal skin under occlusion. After 6 hours the patch was removed and any remaining test material was wiped off using gauze; however, the test material was not completely removed. Body weight was recorded prior to the first application and from then on weekly. Each day, the treatment site was examined and scored for erythema and oedema (Draize scores). Scoring for erythema proved difficult due to residual material on the skin that prevented observance of the colour of the skin. At the end of the study, all animals were sacrificed for clinical chemistry, haematology and histopathology investigations.

With vacuum residue sample 81-13 (API, 1983d), one male from the high-dose group and one female from the control group died on days 9 and 3, respectively. These early decedents had no antemortem signs and hence deaths were considered non-treatment related. One male from the control group and one female from the intermediate-dose group were found moribund and sacrificed on days 6 and 10, respectively. Both animals showed paralysis of the hind limbs the day prior to the sacrifice. These deaths were also not considered treatment-related, but rather as the result of trauma during dosing and wrapping. Treatment-related findings were flaking skin, wheezing and a decreased food-intake (qualitative observation) resulting in less body weight gain in the exposed groups compared to controls. The lesser body weight gain was statistically significant in the high-dose males as compared to the control group. No treatment-related trends were observed in either clinical chemistry or haematology investigations. No treatment-related effects on reproductive organs were noted. Treatment related effects were observed in the skin of most high-dose males and females with very slight to slight oedema observed after the first treatment and consistent in all animals as of day 16 until the last day (day 28). In the intermediate-dose groups (1000 mg/kg) some animals showed slight oedema until day 10; as of day 11 almost all animals showed very slight to slight oedema until the end of the study. In the low-dose group (200 mg/kg) most males showed slight oedema in the last two weeks and most females in the last week of treatment. Gross pathology findings of reddened or thickened skin, were consistent with the microscopic observations of skin effects: minimal to moderate subacute, acanthotic dermatitis and minimal to moderate hyperkeratosis.

With the other sample of vacuum residue 81 -14 (API, 1983c), one male from the low-dose group and one female from the high-dose group were found dead on days 13 and 5, respectively. These early decedents had no antemortem signs and deaths were considered non-treatment related. Treatment-related findings were decreased food-intake (qualitative observation), wheezing, flaking skin and some other skin changes such as wart-like lesions and white discharge at the treated sites. No decrease in body weight gain was found in any of the treated groups as compared to the control group. Neither was there any treatment-related trends observed in clinical chemistry or haematology parameters. No treatment-related effects on reproductive organs were noted. Treatment-related dermal effects were observed in most animals from the high-dose group with very slight to slight oedema observed as of the first treatment and consistently observed in all animals from day 17 until the last day (day 28). In the intermediate-dose groups (1000 mg/kg), 3 of the 5 males and 3 of the 5 females showed slight to moderate oedema as of the first day of treatment and continued until the termination of the study (day 28) for 4 of the 5 males and 1 of the 5 females. In the low-dose group (200 mg/kg), 3 of the 5 males showed very slight oedema on some days whilst all females showed very slight to slight oedema on some days. Again, the gross pathology findings (thickened skin) were consistent with the microscopic observations that showed minimal to moderate subacute, acanthotic dermatitis and minimal to moderate hyperkeratosis which is considered to be adaptive in nature.

The NOAEL for both samples of vacuum residuum of 200 mg/kg/day was based on skin irritation, in the absence of significant histopathological findings. The NOAEL for systemic effects was 1000 mg/kg, based on body weight effects. However, as there were no clinical or histopathological findings, the decreased body weight was considered to be secondary to the reduced food intake and the value of 2000 mg/kg/day was taken forward to calculate the DNEL for dermal systemic effects.

With regard to the chronic inhalation study, a read across two-year bioassay with fumes from an oxidized (air-rectified) asphalt was conducted in Wistar rats (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 h/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 (THC, sum of aerosol and vapour), were 0, 4.1±0.3, 20.7±1.8, and 103.9±9.7 mg/m3 using the methodology described by BIA (Berufsgenossenschaftliches Institut fuer Arbeitssicherheit,). (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.) Additional control animals (36) and animals exposed to the high dose (36) were included in the study to conduct bronchio-alveolar lavage (BAL) 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 of 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. g-Glutamyltransferase levels in BAL fluid, indicative of increased phagocytitic activity of macrophages, were slightly increased in both males and females. Overall results of BAL 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 was 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. 

 

The NOAEC for systemic effects following inhalation was 103.9 mg/m3 (172.5 mg/m3 adjusted) based on the absence of any histopathological changes or alterations in clinical chemistry or haematology. The LOEC for local effects was 20.7 mg/m³ (34.4 mg/m³ adjusted), based on the irritation effects on the nasal passages. The NOAEC was set at half the LOAEC, that is 10.4 mg/m³ total hydrocarbon concentration (17.2 mg/m³ adjusted) based on the minimal effects and the facts that in the 90-day study and the reproductive toxicity screening studies NOAECs of 20.1 mg/m³ (30.4 mg/m³ adjusted) and 30 mg/m3were found, respectively.

Additional data supports that bitumen is not toxic or harmful after prolonged inhalation exposure (Fraunhofer, 2001, 2000). This information is presented in the dossier.


Repeated dose toxicity: dermal - systemic effects (target organ) other: skin

Justification for classification or non-classification

Data from repeated dose dermal or inhalation toxicity studies, showed no significant systemic toxicity. Therefore, bitumen is not classified for repeat dose toxicity underCLP Regulation, (EC)1272/2008.