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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
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other: GLP compliant, near guideline study, available as unpublished report, fully adequate for assessment
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

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:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Principles of method if other than guideline:
not applicable
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
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 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.