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Carcinogenicity

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Description of key information

Chronic (repeated and prolonged) skin contact with kerosine has the potential to result in tumour formation as a consequence of repeated cycles of irritation, skin damage and repair (similar to OECD 451). In the absence of skin irritation (see key study), no carcinogenic response was seen, indicating a non-genotoxic mechanism mediated by dermal irritation.

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 study available

Carcinogenicity: via dermal route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
Not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
This study is classified as reliable with restrictions because the use of secondary sources of data is acceptable when they are based on a critical evaluation of peer-reviewed data and a consequent selection of a reliable and representative value for the property under investigation. The introduction to the Overview of the CONCAWE Middle Distillate Programme states that the report reviewed the results from a three phase programme of work designed to investigate the factors influencing the skin carcinogenicity of middle distillates. Therefore, although the proprietary study report is not available, the values presented here are acceptable as they are from a reliable secondary source of mammalian toxicity data.
Justification for type of information:
Read across justification included in Section 13
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
yes
GLP compliance:
yes
Species:
mouse
Strain:
C3H
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Not reported
- Age at study initiation: Not reported
- Weight at study initiation: Not reported
- Housing: Individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Not reported


ENVIRONMENTAL CONDITIONS: details not provided, only stated as controlled environmental conditions.


IN-LIFE DATES: Not reported
Route of administration:
dermal
Vehicle:
other: high-dose undiluted, lower doses diluted with mineral oil
Details on exposure:
Groups of 50 male C3H mice were treated with the test material. Three dosing regimes were employed, each using a standard dose volume of 50 microlitres. These were designed to ensure that each group received the equal weekly dose of test material regardless of dilution. The three regimes were:    
100%, applied 2 times per week (expected to cause irritation)    
50%, applied 4 times per week (expected to cause slight irritation)    
28.5%, applied 7 times per week (expected to be non-irritating)
This was intended to clarify the role of skin irritation in skin tumour formation. The diluent used was a highly refined non-irritating mineral oil. Control groups consisted of a positive control, using heavy clarified oil known to be carcinogenic, and a vehicle control, using the highly refined mineral oil.
Skin irritation was assessed daily, using a numerical scoring system. Animals were examined weekly for evidence of dermal growths or other signs of toxicity. All animals were sacrificed, either when considered moribund, suspected of having a carcinoma, or after 104 weeks treatment, and were subject to detailed necropsy examination.

TEST SITE
- Area of exposure: Not reported
- % coverage: Not reported
- Type of wrap if used: Not reported
- Time intervals for shavings or clippings: Not reported

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Not reported
- Time after start of exposure: Not reported

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 50 microlitres
- Concentration (if solution): 28.5 or 50% solution in mineral oil
- Constant volume or concentration used: Yes

VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on results from phase 2 (subchronic toxicity)
- Concentration (if solution): 28.5 or 50% solution
- Purity: Not reported

USE OF RESTRAINERS FOR PREVENTING INGESTION: No
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Not applicable
Duration of treatment / exposure:
2 years
Frequency of treatment:
Low dose: 7 days a week, mid dose: 4 days a week, high dose: twice a week
Post exposure period:
No
Remarks:
Doses / Concentrations:
0, 28.5, 50, or 100%
Basis:
nominal conc.
No. of animals per sex per dose:
Fifty males
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on subchronic study
- Rationale for animal assignment (if not random): Not reported
Positive control:
Heavy clarified oil (HCO)
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: Throughout the study

BODY WEIGHT: No data

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes, apparently only on the gross skin lesions
Other examinations:
None detailed
Statistics:
None reported
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY: The pattern of mortality in animals from the 28.5% treatment groups was generally similar to that of the mineral oil (negative) control group, with slightly higher mortality in the 50% or 100% groups. Groups treated with undiluted kerosine or 50% kerosine had the lowest survival rate. Survival in the positive control group (median 300 days) was also significantly lower than the controls (median 582 days). Dermal irritation was observed in the positive- and negative control substances, and was generally greater after treatment with neat distillate twice per week compared with more frequent treatment with lower concentrations.

GROSS PATHOLOGY: There were no significant treatment-related gross findings at necropsy other than skin irritation and masses (tumours) at the treatment site.

HISTOPATHOLOGY: NEOPLASTIC : Benign and/or malignant skin tumours were diagnosed at the application site in several of the groups, and were frequent in the positive control group where a total of 164 tumours (88 benign, 73 malignant) developed in 47 mice with 217 days to first tumour. This contrasts with the negative control group which was tumour free. Tumours were observed only in the high dose group of mice. No mice had tumours in the middle and low dose groups.
Relevance of carcinogenic effects / potential:
An undiluted hydrotreated straight-run kerosine appeared to produce tumours by a non-genotoxic mechanism involving skin irritation.

Table 1. Skin tumour incidence

Treatment

%
Test Oil

Days to first tumour

Number of histologically confirmed tumours

squamous cell carcinoma

papilloma

kerato-acanthoma

basal cell carcinoma

fibro-
sarcoma

melanoma

Mineral oil

100

-

-

-

-

-

-

-

HCO

5

217

73

88

3

-

-

-

MD3

28.5

-

-

-

-

-

-

-

 

50

-

-

-

-

-

-

-

 

100

441

7

6

-

1

3/5*

-

 * number of animals with specified tumour / total number of tumours per group.

Conclusions:
An undiluted hydrotreated straight-run kerosine was considered to produce skin tumours by a non-genotoxic mechanism involving skin irritation.
Executive summary:

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.

Of the 3 groups treated with hydrotreated kerosine, only the group treated with undiluted material developed skin tumours. Twelve animals developed a total of 20 tumours (6 benign,14 malignant).

There were no significant treatment-related gross findings at necropsy other than skin irritation and masses (tumours) at the treatment site. Benign and/or malignant skin tumours were diagnosed at the application site in several of the groups, and were frequent in the positive control group where a total of 164 tumours (88 benign, 73 malignant) developed in 47 mice with 217 days to first tumour. This contrasts with the negative control group which was tumour free. Tumours occurred only in the high dose group treated with MD3 (441 days until the first tumour).

For the hydrotreated straight run 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 promoters but not initiators and furthermore that skin irritation plays an important role in skin tumour development.

This study received a Klimisch score of 2 and is classified as reliable with restrictions because the use of secondary sources of data is acceptable when they are based on a critical evaluation of peer-reviewed data and a consequent selection of a reliable and representative value for the property under investigation. The introduction to the Overview of the CONCAWE Middle Distillate Programme states that the report reviewed the results from a three phase programme of work designed to investigate the factors influencing the skin carcinogenicity of middle distillates. Therefore, although the proprietary study report is not available, the values presented here are acceptable as they are from a reliable secondary source of mammalian toxicity data.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

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).

.

Additional information

Data on related substances have been used to 'read-across' and predict the hazard properties. A 'read-across' justification document can be found in section 13.

The potential of petroleum hydrocarbons to induce skin tumours is generally considered to be largely dependent on the presence of polycyclic aromatic compounds. Middle distillate fractions such as kerosine however contain relatively low concentrations of polycyclic aromatic compounds and are non-genotoxic in both in vitro and in vivo test systems. Nevertheless in some mouse epidermal carcinogenesis studies they do give rise to skin tumours. 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 which are known to be skin carcinogens. Numerous studies have shown that chronic irritation and inflammation promote the development of skin tumours, whilst prevention of chronic skin irritation precludes the formation of dermal tumours.   

Hydrodesulfurised kerosine (CAS # 64742-81-0) was tested in a standard 2-year bioassay in C3H/HeJ mice (API, 1989). The animals, 50 per group, were treated twice weekly with 50 μl of neat 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 varying degrees of dermal irritation; 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 hydrodesulfurised kerosine treated group was 76 weeks, significantly longer than the 47 weeks observed in the 0.05% benz(a)pyrene treated group. The number of tumours, 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(44 mice surviving). It was concluded that under the conditions of the test, hydrodesulfurised kerosine was a skin carcinogen.

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 (Dally et al 1996, Nessel 1999, Exxon 1996). 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 material it was 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 (Skisak 1991) 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.

Justification for selection of carcinogenicity via dermal route endpoint:

Part of a well conducted research programme to investigate the role of skin irritation in the development of skin tumours following repeated application of petroleum middle distillate fractions to the skin of mice

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