Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP status unknown, near-guideline study, published in peer reviewed literature, restrictions in design and/or reporting but otherwise adequate for assessment

Data source

Reference
Reference Type:
publication
Title:
Evaluation of the systemic toxicity of coal liquefaction-derived materials following repeated dermal exposure in the rabbit
Author:
McKee RH, Kapp RW and Ward DP
Year:
1985
Bibliographic source:
Journal of Applied Toxicology, Vol. 5, No. 6, pp 345-351

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
fuel oil was not removed after each dose, but allowed to accumulate during the exposure period, therefore there may have been greater total absorption
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test materials (as cited in study report): Fuel oil (204-538°C)
- Substance type: liquid fuel from coal
- Physical state: liquid
- Composition of test material, percentage of components: 70/30 (w/w) blend of recycle solvent and vacuum gas oil (nominal boiling range 427-449°C), composition as follows: carbon 88%, hydrogen 10%, oxygen 1.5%, nitrogen 0.24%, sulphur 0.34%; saturates 37%, aromatics 63%; polycyclic aromatic hydrocarbons 3153 µg/g
- Distillation curve: 5 wt% 181°C, 50 wt% 299°C, 95 wt% 657°C
- Specific gravity: 11.6°API
- Flash point: 107°C

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Somerset Breeding Laboratories, Somerset, NJ
- Age at study initiation: not reported
- Weight at study initiation: 3-5 kg
- Fasting period before study: no
- Housing: individually in stainless steel cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 18-22°C
- Humidity: 40-70%
- Air changes (per hr): no data
- Photoperiod: 12hrs dark / 12hrs light

IN-LIFE DATES: not reported

Administration / exposure

Type of coverage:
not specified
Vehicle:
other: Primol 185 (white oil)
Details on exposure:
TEST SITE
- Area of exposure: unabraded skin of dorsal surface, between the shoulders and lumbar region
- % coverage: no data; approximately 200 cm2 of hair was removed from the application site
- Type of wrap if used: no data
- Time intervals for shavings or clipplings: prior to dosing and then twice weekly

REMOVAL OF TEST SUBSTANCE
- Washing (if done): residual fuel oil was not removed between doses

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 25 mg/L and 100 mg/L
- Constant volume or concentration used: yes 2 mL/kg
- Fuel oil was applied as a suspension

VEHICLE
- Justification for use and choice of vehicle (if other than water): not reported

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50 and 200 mg/kg
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on the findings of preliminary studies

Examinations

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

DETAILED CLINICAL OBSERVATIONS: No data

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

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal: Yes, weekly

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

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to dosing and at study termination
- Anaesthetic used for blood collection: No data
- Animals fasted: 24 hrs prior to necropsy
- How many animals: 5/sex/group
- Parameters examined: not reported

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to dosing and at study termination
- Animals fasted: 24 hrs prior to necropsy
- How many animals: 5/sex/group
- Parameters examined: SGOT, SGPT, cholesterol, albumin, alkaline phosphatase, blood urea nitrogen, glucose, globulin, creatinine, chloride, potassium, sodium and calcium

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes; adrenal, brain, bone marrow, epididymis, heart, kidneys, lungs, liver, ovary, pancreas, prostate, skin, spleen, seminal vesicle, testis, thymus and urinary bladder.
Other examinations:
Organ weights: liver, kidneys, epididymides and testes
Statistics:
Group mean and standard deviations were calculated and values compared to control by Dunnett's test

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
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
Details on results:
DERMAL IRRITATION
The low dose and control animals showed a low incidence of desquamation. High dose animals showed desquamation, blanching, atonia and fissuring.

BODY WEIGHT AND WEIGHT GAIN
Reduced in both groups, achieving statistical significance in high dose females during the last 3 weeks of the study.

FOOD CONSUMPTION
Reduced in both groups but the difference did not achieve statistical significance compared to control.

CLINICAL CHEMISTRY
Cholesterol levels showed a dose related increase with effects at 200 mg/kg statistically significant in males and females.

ORGAN WEIGHTS
Increased liver weight was seen in both sexes at each dose level. Organ to bodyweight ratios of kidney were raised in males and females in the high dose.

GROSS PATHOLOGY
Atrophy was seen in the testes, epididymides and seminal vesicles of one male in the high dose. Enlarged livers were seen in all treated animals.

HISTOPATHOLOGY: NON-NEOPLASTIC
Diffuse hepatocytomegaly was seen in the livers of 9 of the high dose and 4 of the low dose animals, ranging from slight to severe in severity. Cytoplasmic degeneration and vacuolated hepatocytes were noted occasionally in the high dose group. No similar findings were seen in control animals.
Thymic atrophy was seen in 6 of 8 high dose animals, ranging from slight to severe severity. No cases of thymic atrophy were seen in low dose animals or controls. In the kidneys, a few mild inflammatory changes were seen, but similar lesions were also seen in the control animals.

Effect levels

Dose descriptor:
LOAEL
Effect level:
50 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: reduced bodyweight, increased liver weight and higher serum cholesterol at lowest dose tested

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Fuel oil (nominal boiling range 204-538°C) produced evidence of systemic toxicity and dermal irritation at 50 mg/kg/day.
Executive summary:

Fuel oil (nominal boiling range 204 -538°C) was investigated for dermal irritation and systemic toxicity in New Zealand White rabbits. Animals were dosed 0, 50 or 200 mg/kg 5 days/week for 4 weeks.

Dermal irritation and body weight loss were observed. A NOAEL for dermal irritation and systemic toxicity was not achieved. A LOAEL of 50 mg/kg/day was estimated, based on body weight reduction, liver weight increase and serum cholesterol increase.