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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:
experimental study
Remarks:
Test substance represents a main component (stereoisomer) of the registered substance
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, limited documentation

Data source

Reference
Reference Type:
publication
Title:
Pharmakologische Untersuchungen von Kamillen-Inhaltsstoffen
Author:
Habersang S., Leuschner F., Isaac O. & Thiemer K.
Year:
1979
Bibliographic source:
Planta medica, 37(2):115-123.

Materials and methods

Principles of method if other than guideline:
no data
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Levomenol
EC Number:
245-423-3
EC Name:
Levomenol
Cas Number:
23089-26-1
Molecular formula:
C15H26O
IUPAC Name:
(2S)-6-methyl-2-[(1S)-4-methylcyclohex-3-en-1-yl]hept-5-en-2-ol
Test material form:
other: oily liquid
Details on test material:
- Name of test material: (-)-alpha-Bisabolol, 6-methyl-2-(4-methylcyclohex-3-en-1-yl)hept-5-en-2-ol

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: S. Ivanovas, 7967 Kißlegg/Allgäu, Germany
- Weight at study initiation: 98 - 106 g (main study); 128 - 146 g (orientation study)
- Housing: test animals housed singly in a Makrolon cage Type II or in groups of two oder three in Makrolon cages type III
- Diet: Altromin® standard diet; ad libitum
- Water: ad libitum

Administration / exposure

Route of administration:
oral: gavage
Duration of treatment / exposure:
6 weeks (orientation study), 4 weeks (main study)
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
Preliminary study: 1 mL/kg bw/d (approx. 930 mg/kg bw/d) for 6 weeks; Main study: 2, 3 mL/kg bw/d (approx. 1860, 2790 mg/kg bw/d) for 4 weeks
Basis:

No. of animals per sex per dose:
Preliminary study: two groups of 20 rats (10 per sex per dose)
Main study: three groups of 40 rats (20 per sex per dose)
Control animals:
yes
Details on study design:
Post-exposure period: none
Positive control:
not applicable

Examinations

Observations and examinations performed and frequency:
Observations/examinations included general state, behaviour, signs of intoxication, food consumption, body weight.

Hematological  examination:
- Hemoglobin
- Erythrocyte, Leucocyte, Reticuocyte, Thrombocyte counts
- Differential blood count
- Hematokrit
- protombin time

Clinical chemical examination:
- SGPT
- SGOT
- alkaline phosphatase
- glucose
- uric acid / urea nitrogen
- creatinine
- total bilirubin
- total protein
- CO2
- sodium
- potassium
- chloride

Urinalysis:
- color
- specific gravity
- pH
- glucose
- hemoglobin
- bilirubin
- ketones
- sediment

Ophthalmoscopy, audition ability, dentition examination
Sacrifice and pathology:
gross pathology

organ weights:
- heart
- liver
- lung
- spleen
- kidneys
- adrenals
- thymus
- hypophysis
- gonads
- thyroid
- brain

histology:
- heart
- liver
- lung
- spleen
- kidneys
- adrenals
- thymus
- hypophysis
- gonads
- thyroid
- brain
- prostate /uterus
- stomach / duodenum / jejunum / ileum / colon / rectum
- salival gland
- eye with optic nerve
- urinary blatter
- bone marrow
- trachea
- aorta
- pancreas
- mesenterial lymph nodes
- peripheral nerve
- skeletal muscle

Results and discussion

Effect levels

Dose descriptor:
NOAEL
Effect level:
ca. 1 other: ml/ kg bw/d
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: (approx. 930 mg/kg bw/d) based on the absence of effects observed in the orientation study

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

1) Orientating study:

There was no evidence of intolerance.

2) Main study:

Reduced body weights and motor restlessness was observed in the tested groups, the high dose animals being more affected than the low dose animals. The high dose level was lethal, mortality was 20% in this dose group. Urinalysis revealed a positive keton body reaction; however, since no clincochemical parameters indicated any impairment of the lipid metabolism, the presence of a test substance metabolite is suggested.

Clinical-chemical examination showed increases in SGOT and alkaline phosphatase (slightly increased in males and significantly increased in females). No other changes in urine and clinical chemical parameters were noted; hematological parameters were unaffected. The final examination revealed serve inflammatory effects in the liver, kidney, trachea, thymus, spleen and stomach, according the reduction of body weight. At the low dose level, these changes were only minimal. According to the authors, these inflammatory reactions were considered to be caused by reduced body weights leading to an impaired immune defense.

Applicant's summary and conclusion

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