Registration Dossier

Toxicological information

Repeated dose toxicity: dermal

Currently viewing:

Administrative data

Endpoint:
chronic toxicity: dermal
Remarks:
combined repeated dose and carcinogenicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report. GLP.
Justification for type of information:
Concawe believes that dermal is the most relevant exposure route, and is sufficiently robust, to identify any potential hazards from repeated exposures to petroleum products to be able to adequately manage the potentially associated risks. However, the primary objective of the testing required for REACH is the identification of hazard, for which the default exposure route under the regulation is oral as this is considered to maximise systemic exposure. To address the regulatory exposure route issue, Concawe will review the current data base for evidence of systemic toxicity after dermal exposure and will also conduct a number of oral OECD 422 studies on prioritized substances in each relevant petroleum category. The document attached provides a concise overview of the information to further support the dermal route of exposure and proposed additional work, as part of a larger testing strategy (the strategy document can be found in Annex 13).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1983
Report Date:
1983

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Test material form:
other: low viscosity liquid hydrocarbon

Test animals

Species:
mouse
Strain:
Swiss Webster
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Eppley Colony
- Age at study initiation: 5 weeks
- Housing: Each group in separate rooms
- Diet (e.g. ad libitum): Wayne Lab Blox Pellets ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 3 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72 ± 2
- Humidity (%): 55 ± 5
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Duration of treatment / exposure:
Lifetime of the mice
Frequency of treatment:
3 times per week
Doses / concentrations
Remarks:
Doses / Concentrations:
0.05 ml
Basis:
nominal per unit body weight
No. of animals per sex per dose:
50 mice per dose
Control animals:
yes
Details on study design:
Negative control: 122 mice used
Positive control:
Positive control animals were treated according to the same protocol as test animals. Two positive control groups of 50 male mice were painted three times weekly with 0.05% and 0.15% BP, respectively. The designated doses were delivered in 0.05 ml aliquots to a shaved 1 square centimeter area of skin in the interscapular region.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: 3 times per week

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: 3 times per week

BODY WEIGHT: Yes
- Time schedule for examinations: twice per month
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes. All applications sites were examined. All tumors and suspect lesions were diagnosed microscopically. All tumors and other pathological lesions were examined histologically. Sections of skin, lung, liver, kidney, urinary bladder, and other gross pathology were preserved in 10% phosphate buffered formalin, stained with hematoxylin and eosin, and examined microscopically.
Statistics:
Where appropriate, statistical analyses using Fisher's Exact Test and the reference Biometrika Tables for Statisticians vol I (Cambridge Univ. Press, 1966, pp 73-80) were applied. In addition the Chi-square distribution was calculated according to Colton (Statistics in Medicine, Theodor Colton, Little, Brown and Co., Boston, 1974, pp 176-7, 348). For possible rare tumors designated in the text probabilities were also calculated using the Poisson distribution . Unless designated otherwise, the Chi-square calculation was applied.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: The mean survival of the four treated groups was 14/50 (28%) compared to 112/122 (92%) in the untreated control.
BODY WEIGHT AND WEIGHT GAIN: Decreased body weight gain was observed in the treated groups when compared to the untreated control.

GROSS PATHOLOGY: Multiple pathological disorders of kidney,lung, liver, lymph node, and spleen were observed in differing frequencies in treated groups compared with the untreated control.

HISTOPATHOLOGY: NON-NEOPLASTIC: Primarily inflammatory and degenerative lesions.

HISTOPATHOLOGY: NEOPLASTIC: There were few apparent neoplastic responses.

Effect levels

Dose descriptor:
NOAEL
Effect level:
0.5 other: ml
Sex:
male
Basis for effect level:
other: Chronic treatment with PS-6 did not significantly change the incidence of liver hemangiomas, lung adenomas, or of malignant lymphomas compared to negative and historical controls.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The incidence of skin carcinomas, liver hemangiomas, lung adenomas, and malignant lymphomas was no greater with the test substance than for the negative control group. Unleaded gasoline did not display chronic dermal toxicant propoerties in this study. This finding does not warrant the classification of unleaded gasoline as a chronic dermal toxicant under Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP) or under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
Executive summary:

Unleaded gasoline was examined for its chronic dermal toxicity potential. Unleaded gasoline was administered via dermal application to the skin of 50 Swiss mice three times per week for two years. A negative control group was not treated while the two positive control groups were administered 0.05 ml of 0.05% BaP and 0.05 ml of 0.15% BaP in acetone. The test substance caused hyperkeratosis, fibrosis of the dermis, extoabscess and skin ulceration in the treatment areas. The incidence of skin carcinomas, liver hemangiomas, lung adenomas, and malignant lymphomas was no greater with the test substance than for the negative control group. Unleaded gasoline did not display chronic dermal toxicant properties in this study. This finding does not warrant the classification of unleaded gasoline as a chronic dermal toxicant under Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP) or under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.