Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Justification for type of information:
Experimental study made available by ECHA

Data source

Reference
Reference Type:
review article or handbook
Title:
ECHA robust summaries for 198404-98-7
Author:
ECHA
Year:
2019
Bibliographic source:
ECHA robust summaries for 98404-98-7, ECHA,2019

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Directive 96/54/CE, B.7
Principles of method if other than guideline:
Short term repeated dose oral toxicity study was performed to determine the mutagenic nature of (1-METHYL-2-(1,2,2-TRIMETHYLBICYCLO(3.1.0)-HEX-3-YLMETHYL)CYCLOPROPYL)METHANOL( MIXTURE OF DIASTEREOISOMERS )
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Details on test material:
- Name of test material (IUPAC name): (1-METHYL-2-(1,2,2-TRIMETHYLBICYCLO(3.1.0)-HEX-3-YLMETHYL)CYCLOPROPYL)METHANOL( MIXTURE OF DIASTEREOISOMERS )
- Common name: Lokanol
- Molecular formula: C15H26O
- Molecular weight: 222.3694 g/mol
- InChl: 1S/C15H26O/c1-13(2)10(6-12-8-15(12,13)4)5-11-7-14(11,3)9-16/h10-12,16H,5-9H2,1-4H3
- Substance type: Organic
Specific details on test material used for the study:
- Name of test material (IUPAC name): (1-METHYL-2-(1,2,2-TRIMETHYLBICYCLO(3.1.0)-HEX-3-YLMETHYL)CYCLOPROPYL)METHANOL( MIXTURE OF DIASTEREOISOMERS )
- Common name: Lokanol
- Molecular formula: C15H26O
- Molecular weight: 222.3694 g/mol
- InChl: 1S/C15H26O/c1-13(2)10(6-12-8-15(12,13)4)5-11-7-14(11,3)9-16/h10-12,16H,5-9H2,1-4H3
- Substance type: Organic

Test animals

Species:
rat
Strain:
Wistar
Details on species / strain selection:
No data
Sex:
male/female
Details on test animals and environmental conditions:
No data

Administration / exposure

Route of administration:
oral: gavage
Details on route of administration:
No data
Vehicle:
other: Bidistilled water
Details on oral exposure:
Method of administration:
gavage
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
7 days/week
Doses / concentrations
Remarks:
0,20,100,500 mg/kg bw/day
No. of animals per sex per dose:
No. of animals per sex per dose
Male: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 20 mg/kg bw/day
Male: 5 animals at 100 mg/kg bw/day
Male: 5 animals at 500 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 20 mg/kg bw/day
Female: 5 animals at 100 mg/kg bw/day
Female: 5 animals at 500 mg/kg bw/day
Control animals:
yes, concurrent no treatment
Details on study design:
No data
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
No data
Sacrifice and pathology:
No data
Other examinations:
No data
Statistics:
No data

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs were observed during the test.
Mortality:
no mortality observed
Description (incidence):
No mortality during the test.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No treatment-related changes were seen in all animals.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There was a temporary decrease in the consumption of food in the test group, in females from group 4.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
No treatment-related changes were seen in all animals.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
The clinical biochemistry findings related to the test substance consist of:
- decreased glucose levels in males at 100 mg / kg / day and in both sexes at 500 mg / kg / day,
- increase in total cholesterol, triglycerides and phospholipids in females at 500 mg / kg / day
- stronger activity of gamma-glutamyltransferase in both sexes at 500 mg / kg / day,
- increased calcium levels in males and at females of groups 4
- decrease in potassium levels in both sexes at the dose 500 mg / kg / day.
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
At 500 mg / kg / day, there was an increase in the weight of liver in both sexes, at 100 mg / kg / day this effect is no longer observed that in males.
In males of group 4 we also observe a increased kidney weight and decreased weight thymus. There were also lower thymus weights in males at 100 mg / kg / day.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Liver (bigger) size increased in a male at 500 mg / kg / day.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
There were microscopic changes on male kidneys at 100 mg / kg / day and 500 mg / kg / day. These changes consisted of tubular basophilia and tubular mineralization at the corticomedullary junction
accompanied by tubular hyaline calculus in a single male treated at 500 mg / kg / day.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
FUNCTIONAL OBSERVATION BATTERY:
There was no evidence of abnormal behavior or abnormalities in any animal from any group that this is.
FORCE OF AGGREGATION:
Gripping force of anterior and posterior limbs showed no difference attributable to the administration of the test substance.
LOCOMOTRICE ACTIVITY:
There were no treatment-related changes in the animals.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
20 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
body weight and weight gain
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
Dose descriptor:
NOEL
Effect level:
20 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The No Observed Adverse Effect Level (NOAEL) and No Observable Effect Level (NOEL) values for (1-METHYL-2-(1,2,2-TRIMETHYLBICYCLO(3.1.0)-HEX-3-YLMETHYL)CYCLOPROPYL)METHANOL( MIXTURE OF DIASTEREOISOMERS) is considered to be 20 mg/kg bw/day, when rats were repeatedly exposed to the test chemical for 28 days.
Executive summary:

Short term repeated dose oral toxicity study was performed to determine the toxic nature of the test chemical (1-METHYL-2-(1,2,2-TRIMETHYLBICYCLO(3.1.0)-HEX-3-YLMETHYL)CYCLOPROPYL)METHANOL( MIXTURE OF DIASTEREOISOMERS). The study was performed using rats at dose levels of 0, 20, 100 or 500 mg/Kg bw by the oral gavage route for 28 days. The animals were observed for clinical signs, mortality, changes in body weight, organ weight and histological examination was performed at necropsy.No clinical signs were observed during the test.No mortality were observed during the test.No treatment-related body weight changes were seen in all animals.There was a temporary decrease in the consumption of food in the test group, in females from group 4.

The clinical biochemistry findings related to the test substance consist of:

- decreased glucose levels in males at 100 mg / kg / day and in both sexes at 500 mg / kg / day,

- increase in total cholesterol, triglycerides and phospholipids in females at 500 mg / kg / day

- stronger activity of gamma-glutamyltransferase in both sexes at 500 mg / kg / day,

- increased calcium levels in males and at females of groups 4

- decrease in potassium levels in both sexes at the dose 500 mg / kg / day.

At 500 mg / kg / day, there was an increase in the weight of liver in both sexes, at 100 mg / kg / day this effect is no longer observed that in males.

In males of group 4 we also observe a increased kidney weight and decreased weight thymus. There were also lower thymus weights in males at 100 mg / kg / day.

Liver (bigger) size increased in a male at 500 mg / kg / day.There were microscopic changes on male kidneys at 100 mg / kg / day and 500 mg / kg / day. These changes consisted of tubular basophilia and tubular mineralization at the corticomedullary junction accompanied by tubular hyaline calculus in a single male treated at 500 mg / kg / day.The No Observed Adverse Effect Level (NOAEL) and No Observable Effect Level (NOEL) for (1-METHYL-2-(1,2,2-TRIMETHYLBICYCLO(3.1.0)-HEX-3-YLMETHYL)CYCLOPROPYL)METHANOL( MIXTURE OF DIASTEREOISOMERS) is considered to be 20 mg/kg bw/day when rats were repeatedly exposed to the test chemical for 28 days.