Registration Dossier

Toxicological information

Repeated dose toxicity: dermal

Currently viewing:

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:
1988-03-22 to 1988-06-24
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable with restrictions because it is an acceptable and a 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:
1989
Report date:
1989

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
64741-49-7
Cas Number:
64741-49-7
IUPAC Name:
64741-49-7
Constituent 2
Reference substance name:
Vacuum tower overheads
IUPAC Name:
Vacuum tower overheads
Test material form:
other: liquid
Details on test material:
- Name of test material (as cited in study report): Vacuum Tower Overheads (CAS# 64741-49-7)
No other test material information was provided.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Taconic, Germantown, New York
- Age at study initiation: approximately 29 days of age
- Weight at study initiation: not reported
- Fasting period before study:
- Housing: individually housed in suspended, stainless steel cages with wire mesh bottoms and fronts.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 12 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 22 degrees Celsius
- Humidity (%): relative humidity
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 hours dark/ 12 hours light

Administration / exposure

Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: dorsal trunk
- % coverage: not reported
- Type of wrap if used: test site remained open
- Time intervals for shavings or clippings: 24 hours prior to dosing then once per week


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


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): dependent on body weight of the animal
- Concentration (if solution):
- Constant volume or concentration used: within 10% accuracy


VEHICLE - no vehicle was used.


USE OF RESTRAINERS FOR PREVENTING INGESTION: yes - Elizabethan collars
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
Exposure for 13 weeks
Frequency of treatment:
Five days per week for 13 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
30, 125, and 500 mg/kg/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
10 male and 10 female per dose
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Dose level chosen based on data obtained in studies with other similar substances such as Heavy Vacuum Gas Oil, Heavy Coker Gas Oil and Coker Light Gas Oil.
- Rationale for animal assignment (if not random): Random
Positive control:
no positive controls were used.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once daily


DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: scored weekly.


BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed one week prior to dosing, immediately before dosing and weekly thereafter.


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


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: Yes
- Time schedule for collection of blood: during week 5 and 13.
- Anaesthetic used for blood collection: yes, with diethyl ether.
- Animals fasted: Yes
- How many animals: all surviving animals at week 5 and week 13
- Parameters checked in table [No.?] were examined. - red blood count, white blood cell differentials, mean corpuscular volume, mean corpuscular hemaglobin and mean corpuscular haemoglobin concentration.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: during weeks 5 and week 13
- Animals fasted: No data
- How many animals: all surviving animals at week 5 and week 13.
- Parameters checked in table [No.?] were examined. - sorbitol dehydrogenase, alanin aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, inorganic phosphorus, creatinine, calcium, chloride, triglycerides, albumin, potassium, sodium, total protein, uric acid, urea nitrogen, glucose, cholesterol.


URINALYSIS: Yes
- Time schedule for collection of urine:during weeks 5 and week 13
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. Check for appearance, bilirubin, blood, glucose, specific gravity, ketone, pH, protein, and urobilinogen.


OTHER: MORBIDITY and MORTALITY - twice daily at least six hours apart.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
Spermatozoa/spermatid evaluations were made on male rats. Body and organ weights were also obtained.
Statistics:
ANOVA F-tests were performed on quantitative data followed by Dunnett's test or Tukey's multiple range test. Differences were found to be statistically significant if p< 0.05.

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):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY - No animals died before scheduled sacrifice and necropsy. Slight erythema, flaking of the skin were observed in the treated groups during the dosing phase.


BODY WEIGHT AND WEIGHT GAIN - High-dose males weighed significantly less than control males during weeks 8 through week 13. High-dose females weighed significantly less than control females during week 11.

HAEMATOLOGY - adverse affects were seen in decrease of red blood counts, haemoglobin and hematocrit in high-dose animals.


CLINICAL CHEMISTRY - A linear relationship was found between dose and serum level for urea nitrogen, alanin aminotransferase, and cholesterol in males and cholesterol, albumin and calcium in females.


ORGAN WEIGHTS - Liver weights increased in males and females dosed at 125 and 500 mg/kg/day. A decrease in thymus weights was seen in males and females dosed at 500 mg/kg/day.

Effect levels

Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: clinical signs; body weight; haematology; clinical chemistry; organ weights

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The dermal application of Vacuum Tower Overheads was found to affect both haematology and serum parameters as well as the body, thymus and liver weights of exposed animals. The adverse effects on the thymus had been reported in other studies referenced in this study report.
The NOAEL has been reported as 30 mg/kg/day
Executive summary:

In a 90 -day dermal toxicity study, Vacuum Tower Overheads were applied to the shaved skin of 30 young adult male and female Sprague-Dawley rats at dose levels 0, 30, 125, and 500 mg/kg/day for 5 days/week during a 90 -day period.

The dermal application of Vacuum Tower Overheads was found to affect both haematology and serum parameters as well as the body, thymus and liver weights of exposed animals. The adverse effects on the thymus had been reported in other studies referenced in this study report. No treatment-related effects were noted in examination of the weight of epididymides, ovaries, prostate, testes or uterus nor in the histopathology of the ovaries and testes nor in the number of epididymal sperm, sperm/g cauda epididymis, number of abnormal and normal sperm, number of testicular spermatids, and sperm/g testis.

The NOAEL has been reported as 30 mg/kg/day.

This study is classified as reliable with restrictions because it is an acceptable and a well-documented study report.