Hydrocarbons, C4, steam-cracker distillate

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP compliant, near guideline study, available as unpublished report, fully adequate for assessment

Justification for type of information:

Read-across discussed in Category Justification Document (CJD)

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Cross-reference 3

Reason / purpose for cross-reference:

read-across: supporting information

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1986

Report date:

1986

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Principles of method if other than guideline:

not applicable

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-methylpropene

EC Number:

204-066-3

EC Name:

2-methylpropene

Cas Number:

115-11-7

Molecular formula:

C4H8

IUPAC Name:

2-methylprop-1-ene

Constituent 2

Reference substance name:

isobutylene

IUPAC Name:

isobutylene

Details on test material:

- Name of test material (as cited in study report): isobutylene
- Lot/batch No.: T101/OH
- Storage condition of test material: in a freezer in a pressurized cylinder

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals (CR1:CD SD (BR) supplied by Charles River UK, Margate, Kent, UK. They were obtained as weanlings (about 28d old) and acclimatised for 2 weeks before start of treatment.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
VEHICLE: corn oil
- Concentration in vehicle: 0, 0.05, 0.50 and 5.00 % v/v for dose levels of 0, 1.49, 14.86 and 148.55 mg/kg/day respectively
- Amount of vehicle (if gavage): constant volume of 5 mL/kg bodyweight was dosed.
- All preparation was carried out in a freezer then the formulation was slowly allowed to come to room temperature.
- Dosing solutions were prepared fresh each day.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples taken from all dosing formulations prepared in weeks 1 and 4 and analysed in duplicate for achieved concentration. The preparations were in the range 71-134% of nominal and were considered to be acceptable.

Duration of treatment / exposure:

28 days

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 1.49, 14.86, 148.55 mg/kg
Basis:
other: nominal

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Based on a range-finding study

Positive control:

none

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: First day , at weekly intervals thereafter and at termination.

FOOD CONSUMPTION: Yes
- Time schedule: weekly

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: During week 4
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: All
- Parameters examined: Haemoglobin, mean cell volume, red blood cell count, mean cell haemoglobin, packed cell volume, mean cell haemoglobin concentration, total and differential white cell count, platelet count.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: During week 4
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: All
- Parameters examined: glutamate oxaloacetic transaminase, glutamate pyruvate transaminase, alkaline phosphatase, blood urea nitrogen, glucose, sodium, potassium, calcium, inorganic phosphorus, chloride, creatinine, total protein, albumin, albumin/globulin ratio, bilirubin

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes

ORGAN WEIGHTS: YES (adrenals, liver, kidneys, testes form all animals)

HISTOPATHOLOGY: Yes (All of the following from the controls and 148.55 mg/kg groups): adrenals, colon, caecum, duodenum, heart, ileum, jejunum, kidneys, liver, oesophagus, rectum, spleen, stomach, gross lesions

Other examinations:

none

Statistics:

group mean values and standard deviations where appropriate

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

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:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY: No mortalities or treatment-related effects

BODY WEIGHT AND WEIGHT GAIN: No treatment-related effects

FOOD CONSUMPTION: No treatment-related effects

HAEMATOLOGY: Stat sig treatment-related decrease in white blood cell counts of females dosed with 148.55 mg/kg/day compared to controls. However, values were within the background range.

CLINICAL CHEMISTRY: Slight treatment-related increases in blood urea nitrogen in males and in glucose levels in females compared to controls. However, values were within the background range.

ORGAN WEIGHTS: Relative liver and kidney weights were increased by approximately 5% in females dosed at 148.55 mg/kg/day. However, values were within the background range.

GROSS PATHOLOGY: No treatment-related effects

HISTOPATHOLOGY: No treatment-related effects

Effect levels

Dose descriptor:

NOAEL

Effect level:

148.6 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: there were no mortalities or adverse treatment-related effects

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

none

Applicant's summary and conclusion

Conclusions:

No toxicologically significant changes were observed at dose levels up to 148.6 mg isobutylene/kg/day administered orally to rats over 28 days. Oral administration is an unusual route for a gaseous substance but the analytical results indicate that the gas remained dissolved and the target concentration was achieved.

Executive summary:

No toxicologically significant changes were observed at dose levels up to 148.6 mg isobutylene/kg/day administered orally to rats over 28 days. There were no treatment-related changes in viability, clinical condition, body weight, food consumption and gross pathology or histopathology. Slight changes in haematology and clinical chemistry and organ weights were observed, but the values remained within what was considered the normal range. A NOAEL of 148.55 mg/kg/day was established.