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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1985-07-03
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable with restriction because it is an acceptable and well documented study report.
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:
1985
Report Date:
1985

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: low viscosity hydrocarbon liquid
Details on test material:
- Name of test material (as cited in study report): Light cycle oil (CAS# 64741-59-9)

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Not reported
- Age at study initiation: not reported
- Weight at study initiation: not reported
- Fasting period before study: not reported
- Housing: not reported
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

Administration / exposure

Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: back of animals
- % coverage: no reported
- Time intervals for shavings or clippings: weekly


USE OF RESTRAINERS FOR PREVENTING INGESTION: yes. Cardboard Elizabethan collars were fitted to the rats to minimize ingestion of Light Cycle Oil.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
substance remained on the skin throughout the study.
Frequency of treatment:
The rats were treated 5 days a week for 13 consecutive weeks.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 8, 25, 125, and 500 and 1,250 mg/kg/day
Basis:
no data
No. of animals per sex per dose:
10 male and 10 female rat were exposed per dose.
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: no data
- Rational for animal assignment [if not random]: Toxicity studies by other routes of administration are most frequently conducted in rats because of their predictive value for human risk assessment; therefore rats were chosen as the experimental model for this study. Additionally, since rats have a much shorter lifespan than humans, this study, which covers approximately 1/10 the lifespan of rats, is intended to elicit the toxic phenomena that might occur during occupationl exposure for a similar fraction of the human lifespan.
- Rationale for selecting satellite groups: no data
- Post-exposure recovery period in satellite groups: no data
- Section schedule rationale (if not random):no data
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical observations were made daily


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

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were taken daily.

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 data


WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood samples were collected from control animals and those dosed at 500 mg/kg/day during weeks 4 and 13.
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data

NEUROBEHAVIOURAL EXAMINATION: No data

CAGE SIDE OBSERVATIONS: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
none reported

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 examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
effects observed, treatment-related
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY -
Animals dosed at 1250 mg/kg/day were terminated after two weeks due to lack of body weight and thymus weight gain and dermal effects. Observed effects at the site of application were severe erythema, edema, stiff cracking skin (500 mg/kg/day and 1250 mg/kg/day) occurred within one week of exposure. The epidermis began to slough off for those exposed to 1250 mg/kg/day. Rats dosed at 500 /mg/kg/day were reported to experience ulceration, with a moderate degree of chronic inflammation of the skin and hair follicles.

BODY WEIGHT AND WEIGHT GAIN - Body weight effects were reported to be dose-related.
Male and female animals treated at dose level 1250 mg/kg/day and males treated at 500 mg/kg/day gained less weight than the controls. Animals dosed as 1250 mg/kg/day were sacrificed at the end of the second week of treatment, due to their poor appearance. Females dosed at 500 mg/kg/day and males dosed as 125 mg/kg/day had slightly lower body weights than the respective control rats.


FOOD CONSUMPTION - no data


FOOD EFFICIENCY - no data


WATER CONSUMPTION - no data


OPHTHALMOSCOPIC EXAMINATION - no data


HAEMATOLOGY - no data


CLINICAL CHEMISTRY - no data


URINALYSIS - no data


NEUROBEHAVIOUR - no data


ORGAN WEIGHTS -The thymus of male and females animals dosed at 500 mg/kg/day was reported to be smaller than normal, based on visual inspection and weight. The slight reduction in thymus weight in males treated at 125 mg/kg/day was attributed to be a minimal effect of Light Cycle Oil. Compared to the livers of the control animals, the size of the liver in both male and female animals dosed at 500 mg/kg/day was slightly increased.

HISTOPATHOLOGY: NON-NEOPLASTIC: Microscopic examination of the thymus was greater in males than in females. Examination of the thymus of rats treated at 500 mg/kg/day revealed a depletion of lymphocytes and a slight increase in the amount of connective tissue in the thymus; this was most more prevalent in the males than in the females. The reduced thymus size was judged to have resulted from the depletion of lymphocytes within the thymus. Slight decreases in lymphocytes are not easily detected during microscopic examination; therefore, the thymus weight was considered to be the most sensitive indicator of the effect of Light Cycle Oil on the thymus. For males treated at 125 mg/kg/day, there was slight reduction in thymus weight; this was judged to represent a minimal effect of Light Cycle Oil on the thymus.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
25 mg/kg bw/day
Sex:
male
Basis for effect level:
other: overall effects clinical signs;body weight; haematology; gross pathology; organ weights;
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day
Sex:
female
Basis for effect level:
other: overall effects clinical signs; mortality; body weight; haematology; gross pathology; organ weights (liver and thymus)

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The dermal administration of Light Catalytically Cracked Distillate at doses of 125, 500 and/or 1,250 mg/kg/day resulted in reduction in body weight, reduction in thymus weights and an increase in liver weight. Severe erythema and edema was also reported. Histopathologic evaluation was limited to control animals and those dosed at 500 mg/kg/day. A NOEL was calculated as 25 mg/kg/day for males and 125 mg/kg/day for females.
Executive summary:

In an 90 -day dermal toxicity study, Light Catalytically Cracked Distillate was applied to the shaved skin of 10 males and 10 females per dose at dose levels of 8, 25, 125, and 500 and 1,250 mg/kg/day, for 5 days/week during a 90 -day period.

Dermal treatment with Light Catalytically Cracked Distillate at doses of 125, 500 and/or 1,250 mg/kg/day resulted in reductions in body weight,thymus weight and an increase in liver weight. Severe erythema and edema was also reported. Histopathologic evaluation was limited to control animals and those dosed at 500 mg/kg/day. A NOEL was calculated as 25 mg/kg/day for males and 125 mg/kg/day for females.

This study received a Klimisch score of 2 and is classified as reliable with restrictions because it is an acceptable and well documented study report.