Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity oral: key study: results from a publication leading to the conclusion that NOEL is 15 mg/kg bw/day for rats. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: According to OECD guideline. No data on GLP.
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: CFE
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Bush Boake Allen Ltd., London
- Weight at study initiation: 100-120 g (male) and 90-105 g (female)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 1ºC
- Humidity (%): 50-60%
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 5 mL total dose/kg/day
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
13 weeks ( 0, 15, 90 or 270 mg/kg bw/day)
2 to 6 weeks (0, 90 or 270 mg/kg bw/day)
Frequency of treatment:
Daily
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
13 weeks exposure
Dose / conc.:
15 mg/kg bw/day (actual dose received)
Remarks:
13 weeks exposure
Dose / conc.:
90 mg/kg bw/day (actual dose received)
Remarks:
13 weeks exposure
Dose / conc.:
270 mg/kg bw/day (actual dose received)
Remarks:
13 weeks exposure
No. of animals per sex per dose:
15 male and 15 female: 0, 15, 90 or 270 mg/kg bw/day
5 male and 5 female: 0, 90 or 270 mg/kg bw/day
Control animals:
yes
Observations and examinations performed and frequency:
BODY WEIGHT: Yes
- Time schedule for examinations: weekly

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after sacrifice

URINALYSIS: Yes
- Time schedule for collection of urine: collected during the final week and week 6

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Clinical signs:
no effects observed
Description (incidence and severity):
No deaths and no abnormalities in behaviour or appearance occurred during the study
Mortality:
no mortality observed
Description (incidence):
No deaths and no abnormalities in behaviour or appearance occurred during the study
Body weight and weight changes:
no effects observed
Description (incidence and severity):
no significant differences between test and control animals
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
no significant differences between test and control animals
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
no significant differences between test and control animals
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Only in males treated with the highers dose increase of mean water consumption was observed
Haematological findings:
no effects observed
Description (incidence and severity):
no differences between the test and control groups
Urinalysis findings:
no effects observed
Description (incidence and severity):
The females treated with IBA gave results similar to those of female controls throughout. In males there were no differences between control and IBA-treated rats at week 2 but at week 6 cell excretion was increased in rats receiving 270 mg/kg bw/day
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
there was increase of weight of some organs.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histological changes associated with IBA treatment were confined to treatment at the 270 mg/kg bw/day level.
Key result
Dose descriptor:
NOEL
Effect level:
15 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
organ weights and organ / body weight ratios
Critical effects observed:
not specified
Conclusions:
The NOEL for Isobornyl acetate (13 weeks) was 15 mg/kg bw/day.
Executive summary:

Repeated dose toxicity study (oral route) of Isobornyl acetate was performed according to OECD guideline 408. The substance was dissolved in corn oil and administered daily to rats by stomach tube in doses: 0 (control), 15, 90 or 270 mg/kg body weight/day during 13 weeks. There were no differences between treated and control animals in the rate of body-weight gain, the food intake or the results of haematological investigations. In male rats given 270 mg/kg bw/day there was a decrease in renal concentrating ability, an increase in water intake, exfoliation of renal tubular cells, increased kidney weight and vacuolation of the renal tubular cells. Signs of nephrotoxicity were also seen with daily doses of 90 mg/kg bw/day.

Vacuolation of the epithelium of the intrahepatic bile-duct and increase in liver weights were found at 270 mg/kg bw/day. The caecum were also enlarged at this dosage level.

The no-effect level found was at 15 mg/kg bw/day.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
15 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
reliable
Organ:
kidney
liver

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available (further information necessary)

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose toxicity study (oral route) of Isobornyl acetate was performed according to OECD guideline 408. The substance was dissolved in corn oil and administered daily to rats by stomach tube in doses: 0 (control), 15, 90 or 270 mg/kg body weight/day during 13 weeks. There were no differences between treated and control animals in the rate of body-weight gain, the food intake or the results of haematological investigations. In male rats given 270 mg/kg bw/day there was a decrease in renal concentrating ability, an increase in water intake, exfoliation of renal tubular cells, increased kidney weight and vacuolation of the renal tubular cells. Signs of nephrotoxicity were also seen with daily doses of 90 mg/kg bw/day. Vacuolation of the epithelium of the intrahepatic bile-duct and increase in liver weights were found at 270 mg/kg bw/day. The caecum were also enlarged at this dosage level. The no (adverse) effect level found was at 15 mg/kg bw/day.

Justification for classification or non-classification

According to CLP Regulation and the available data, the substance under study does not meet the criteria to be classified.