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Toxicological information

Carcinogenicity

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Description of key information

Kerosine is not carcinogenic when animals are exposed via the oral or inhalation route.  However, chronic skin contact with kerosines and jet fuel may lead to tumour formation as a consequence of repeated cycles of irritation, skin damage and repair (similar to OECD 451). 

Key value for chemical safety assessment

Carcinogenicity: via dermal route

Endpoint conclusion
Dose descriptor:
LOAEL
200 mg/kg bw/day

Additional information

In general, the potential of petroleum hydrocarbons to induce skin tumours is considered to be largely dependent on the presence of polycyclic aromatic compounds. However, middle distillates such as kerosine and jet fuels contain relatively low concentrations of polycyclic aromatic compounds and are non-genotoxic in both in vitro and in vivo tests systems. Nevertheless they elicited skin tumours in mouse epidermal carcinogenesis studies. This carcinogenic response is characterized by a long latency with only a small percentage of animals developing tumours compared to the response triggered by polycyclic aromatic compounds known to be skin carcinogens. Numerous studies have shown that chronic irritation and inflammation are required in the development of skin tumours, whilst prevention of chronic skin irritation precludes the formation of dermal tumours. The concentration of 200 mg/kg (~ 540 mg/200 cm2) which caused slight irritation in the rabbits was considered to be a LOAEL.

 

Kerosine is not carcinogenic when animals are exposed via the oral or inhalation route. Studies in animals do not show any evidence for a carcinogenic response following oral exposure to jet fuel. Dermal exposure to jet fuel and kerosine, however, resulted in skin tumour formation depending on the exposure conditions. Jet fuels and kerosines were not found to be mutagenic or genotoxic, and the observations from animal studies confirm the non-genotoxic nature of the skin tumour formation. Although dermal irritation alone seems not sufficient to cause dermal tumourigenicity, studies clearly show that dermal irritation and inflammation are prerequisites for dermal carcinogenicity. In studies where dermal irritation and/or inflammation were prevented but other factors, such as dermal uptake of polycyclic aromatic compounds were kept identical, no skin tumours were observed. Chronic irritation leading to tumour induction via an epigenetic (non-genotoxic) mechanism appears the basis of these findings since dilution with highly refined mineral oil greatly decreased skin irritancy and markedly reduced tumour yield despite the total dose applied per week remaining constant (Dally et al., 1996). The strong indications that skin tumours are caused by an epigenetic effect allows setting a threshold for carcinogenicity. Based on the fact that in the absence of dermal irritation dermal tumours do not develop, the NOAEL for dermal carcinogenicity can be considered equal to the NOAEL for dermal irritation. In conclusion, chronic skin contact with kerosines may lead to tumour formation as a consequence of repeated cycles of irritation, skin damage and repair.

 

In a key carcinogenicity study (Klimisch score=1; Freeman et al., 1993), 37.5μL of Jet fuel A was administered dermally to the shaved backs of 50 male C3H/HeNCrlBR mice per dose, twice a week for 2 years or intermittently so that application of the jet fuel was suspended when dermal irritation was noted in 20% of the group and was resumed when irritation resolved in all but 20% of the affected animals. Negative and positive controls responded as expected. Dermal irritation occurred at the test site with the incidence and severity lessened in the intermittent group. Skin irritation was minimal in the controls. Histopathology of the skin found the following non-neoplastic lesions: acanthosis (focal and diffuse), epidermal necrosis, necrotic cell debris on epidermal surface, erosion/ulceration, subepidermal inflammatory infiltrate, dermal fibrosis, and oedema. There was a significant increase in tumours at the application site with continuous treatment compared to the control (0% versus 44%), but not with intermittent treatment (0% versus 2%).  With continuous treatment, there was a treatment-related increase in dermal tumour incidence compared to controls. However, stopping treatment during dermal irritation nearly eliminated the carcinogenic effect.

 

In another key carcinogenicity study (Klimisch score=1; Clark et al., 1988), 25 mg of petroleum-derived Jet A was administered dermally to the shaved backs of 25 C3H/HeJ mice/sex/dose, three times a week for 105 weeks. Due to high mortality, Jet A application was discontinued during week 62, but surviving animals were observed until study termination. Negative and positive controls responded as expected. Dermal irritation first appeared at the test site after 10 to 15 days. Inflammation at the test site, characterized by reddening and swelling, progressed from the dermal irritation, generally after 6 months of treatment. Jet A females had inflammation occurring as early as 2 months. Necrosis (occurring by the end of the first year) at the test site was characterized by loss of skin integrity with visible cracking, separation and sloughing of skin, in many cases revealing the underlying mesenchymal tissue. Treated animals had a higher incidence of mortality with less than 10% of the treated mice surviving to study termination (even though treatment was discontinued in the Jet A mice during week 62) compared to approximately 45% in the shaved controls. There was a significant increase in tumours at the application site (0%, 26%, and 26% in the controls, JP-4, and Jet A groups). The majority of the tumours were squamous cell carcinomas or fibrosarcomas. At the doses tested, there was a treatment-related increase in dermal tumour incidence when compared to controls.

 

Straight-run kerosine (CAS # 8008-20-6) and hydrodesulfurised kerosine (CAS # 64742-81-0) were tested in standard 2-year bioassays in C3H/HeJ mice (API, 1989a; API, 1989b). The animals, 50 per group, were treated twice weekly with 50 μl straight-run kerosine or with hydrodesulfurised kerosine. As positive controls, two groups of 50 mice were exposed twice weekly to 50 μl of 0.01% or 0.05% benzo(a)pyrene in toluene, respectively. Two negative control groups received either 50 μl toluene or no treatment. Animals in all groups but the negative control group with no treatment at all showed dermal irritation, but the dermal lesions in the toluene control group were less than in the test group. In all test groups dermal tumours developed. The mean latency time for tumour formation in the straight-run kerosine as well as the hydrodesulfurised kerosine treated group was with 77 and 76 weeks, respectively, significantly longer than the 47 weeks observed in the 0.05% benz(a)pyrene treated group. The number of tumours, 1 benign and 29 malignant, in the 45 surviving animal in the straight-run kerosine treated mice and 1 benign and 19 malignant, in the 41 surviving mice was also significantly less than in the benzo(a)pyrene treated groups (11 benign and 13 malignant tumours in the 0.01% benzo(a)pyrene group and 2 benign and 44 malignant in the 0.05% benzo(a)pyrene group) whilst the toluene group showed no dermal tumours at all (44 mice surviving). It was concluded that both straight-run and hydrodesulfurised kerosine were moderate skin carcinogens.

 

In the key carcinogenicity study from NTP (Klimisch score=1; NTP, 1986), JP-5 navy fuel in acetone was administered to 50 B6C3F1 mice/sex/dose dermally at dose levels of 0 (vehicle control), 250, or 500 mg/kg bw/day for up to 103 weeks. There was a significant decrease in survival in females at both treatment doses. Remaining high-dose females were sacrificed at week 90. There was no treatment-related effect on survival in male mice. Body weight was reduced in high-dose males and females beginning in week 32. Body weight was reduced by 13 to 25% in females and 14 to 22% in males after week 60. Specifics of the gross pathology were not provided. However, there was an increase in the incidence and severity of chronic dermatitis at the application site. There was an increase in ulcers at both the application site and inguinal sites for both treatments in males and females. There was an increase in the following non-neoplastic lesions in the high-dose males and females: amyloid in the liver, kidney, adrenal cortex (males only), spleen, and multiple organs; granulocytic hyperplasia in the bone marrow; and hyperplasia of the axillary lymph nodes (females only). There was a significant negative trend in the incidence of malignant lymphomas in males (8/50, 3/50, and 1/49 in control, low, and high dose groups). The LOAEL is 250 mg/kg/day, based on dermatitis and decreased survival in females. No NOAEL can be determined. At the doses tested, there was not a treatment-related increase in tumour incidence when compared to controls.

 

To validate the modified Ames assay, Blackburn and co-workers compared the results of the assay with the results of a series of dermal carcinogenicity assays for a variety of undiluted, un-cracked distillates including straight-run kerosine (CAS # 8008-20-6, two samples tested) and hydrotreated kerosine (CAS # 64742-46-3) (Blackburnet al., 1986). In these studies groups of 50 C3H/HeJ mice, aged 6-8 weeks, were dosed twice weekly by application of 50 mg oil product on to the scapular region of the back that was shaven prior to the application. Negative control groups received sham treatment (shaving only) or 50 mg of toluene alone and positive control groups received 50 mg of 0.05% solution of benzo(a)pyrene in toluene. Dosing was continued until a papilloma larger than 1 mm3 appeared. Mice were shaven bi-weekly and the tumour incidence was reported every 4 to 6 weeks to study termination. The two straight-run kerosine samples showed an average latency period (i.e. the time to appearance of the first tumour) of 70 and 62 weeks and 9 and 4 animals with papillomas out of a total of 30 and 27 surviving animals, respectively. The hydrotreated kerosine showed a latency time of 79 weeks and 24 out of 38 surviving mice with papillomas (Blackburn et al., 1986). Although these studies did not report sufficient details to allow a comprehensive assessment, they clearly show that these middle distillates are able to produce papillomas in mice following repeated dermal application under experimental conditions.

 

The potential influence of skin irritation on tumour development in long-term mouse skin painting studies was investigated as part of the CONCAWE middle distillates programme. The study included straight run hydrotreated kerosine (MD3). This was tested alongside a negative control (highly refined, non-irritating mineral oil) and a positive control treatment (heavy clarified oil (HCO), 5% in mineral oil). Groups of 50 male C3H/HeNCrlBR VAF/Plus® mice were individually housed in stainless steel cages, and the various test (28.5%, 50%, or 100%) or control materials applied regularly to clipped dorsal skin. The treatment regime was designed to deliver a constant total weekly dose of each distillate while varying the extent of any local skin irritation by manipulating test material concentration and frequency of application. For the straight run hydrotreated kerosine, skin tumours only developed in the group of animals in which substantial skin irritation occurred during the study. Since no PACs were detected in the straight run kerosine it is concluded that the occurrence of tumours is likely to have been caused by a non-genotoxic mechanism. This conclusion is consistent with reports by others that lighter middle distillates are tumour promotors but not initiators and furthermore that skin irritation plays an important role in skin tumour development. These tumours are probably the consequence of a continuous cycle of cell damage and repair caused by chronic skin irritation. The conclusions gained from this study can be applied to other carcinogenicity studies on kerosines, and they show that tumours are noted in the presence of repeated dermal irritation, and that kerosines lack a genotoxic mechanism of carcinogenicity.

 

Additional data support that kerosines are not carcinogens (API, 1987b; Marino et al., 1990; Skisak, 1991; CONCAWE, 1991; CONCAWE, 1996; Exxon, 1996; Nessel, 1999). This information is presented in the dossier.


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

Justification for classification or non-classification

Jet fuels and kerosines were not found to be mutagenic or genotoxic, and the observations from animal studies confirm the non-genotoxic nature of the skin tumour formation. Although dermal irritation alone seems not sufficient to cause dermal tumourigenicity, studies clearly show that dermal irritation and inflammation are prerequisites for dermal carcinogenicity. In studies where dermal irritation and/or inflammation were prevented but other factors, such as dermal uptake of polycyclic aromatic compounds were kept identical, no skin tumours were observed. Based on this data, kerosines are classified as non-carcinogenic according to the EU CLP Regulation (EC No. 1272/2008).

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