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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1966
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1967
Report Date:
1967

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 452 (Chronic Toxicity Studies)
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: no data
- Expiration date of the lot/batch: no data
- Purity test date: no data

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: no data
- Stability under test conditions: no data
- Solubility and stability of the test substance in the solvent/vehicle: no solvent/ vehicle was used

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: no data

Test animals

Species:
rat
Strain:
Osborne-Mendel
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: no data
- Females (if applicable) nulliparous and non-pregnant: no data
- Age at study initiation: weaning or young adult
- Weight at study initiation: no data
- Fasting period before study: no fasting period
- Housing: individually in wire cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: no data

DETAILS OF FOOD AND WATER QUALITY: Fresh diet was made and distributed weekly

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

Administration / exposure

Route of administration:
oral: feed
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: no data

DIET PREPARATION
- Rate of preparation of diet (frequency): Fresh diet was made and distributed weekly
- Mixing appropriate amounts with (Type of food): no data
- Storage temperature of food: no data

Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Experiment I: 15 weeks
Experiment II: 1 year
Frequency of treatment:
7 days a week
Doses / concentrationsopen allclose all
Dose / conc.:
10 000 ppm
Remarks:
Experiment I
Dose / conc.:
2 500 ppm
Remarks:
Experiment II
No. of animals per sex per dose:
Experiment I: 10 males and 10 females
Experiment II: 5 males and 5 females
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: not specified
- Rationale for selecting satellite groups: no satellite groups used

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: one a week
- Cage side observations checked: general condition

DETAILED CLINICAL OBSERVATIONS: No


BODY WEIGHT: Yes
- Time schedule for examinations: once a week

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at three and six months (1-year study) and prior to termination of the study (15-week and 1-year study)
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: Not specified
- Parameters checked: white cell counts, red cell counts, haemoglobins and haematocrits

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No


Sacrifice and pathology:
GROSS PATHOLOGY: Yes (See table 1)

HISTOPATHOLOGY: Yes (See table 1)

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 examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
15-week study: microscopic to slight hydropic changes of hepatic cells in males only.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
15-week study
Effect level:
> 10 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Dose descriptor:
NOAEL
Remarks:
1-year study
Effect level:
> 2 500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
In a sub-chronic repeated dose toxicity study via oral route, similar to OECD Test Guideline 408 microscopic to slight hydropic changes of hepatic cells were reported in males only. This effect is not considered adverse because of the lack of consistency among treatment groups. Thus, these changes in the hepatic cells were likely to be adaptive. No NOAEL value was reported, however according to the study reviewer and the reported data the NOAEL is concluded to be greater than 10000 ppm.
In a chronic (1-year) repeated dose oral toxicity study in rats, similar to OECD Test Gudeline 452 (Chronic Toxicity Studies), no effects were reported during the conditions of the study. It is concluded that the NOAEL of trans-anethole is greater than the highest dose tested, 2500 ppm.