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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Data is from peer-reviewed journal.

Data source

Reference
Reference Type:
publication
Title:
Repeated dose oral toxicity study of the test chemical
Author:
Hagan et al
Year:
1967
Bibliographic source:
Fd Cosmet. Toxicol

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
The chronic repeated dose toxicity study of the test chemical in rat was conducted to evaluate adverse effects by oral route.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: Reaction mass of 4-(2,6,6-trimethylcyclohex-2-ene-1-yl)-but-3-ene-2-one and 4-(2,6,6-trimethylcyclohex-1-ene-1-yl)-but-3-ene-2-one
- IUPAC name: Reaction mass of 4-(2,6,6-trimethylcyclohex-2-ene-1-yl)-but-3-ene-2-one and 4-(2,6,6-trimethylcyclohex-1-ene-1-yl)-but-3-ene-2-one
- Molecular formula: C13H20O
- Molecular weight: 192.3 g/mole
- Smiles : C1([C@@H](C(=CCC1)C)\C=C\C(C)=O)(C)C
- Inchl: 1S/C13H20O/c1-10-6-5-9-13(3,4)12(10)8-7-11(2)14/h6-8,12H,5,9H2,1-4H3/b8-7+
- Substance type: Organic
- Physical state: Solid (yellow)
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Substance tested: Reaction mass of 4-(2,6,6-trimethylcyclohex-2-ene-1-yl)-but-3-ene-2-one and -(2,6,6-trimethylcyclohex-1-ene-1-yl)-but-3-ene-2-one Standard (60% alpha-ionone and 40% ß-ionone)

Test animals

Species:
rat
Strain:
Osborne-Mendel
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: No data available
- Females (if applicable) nulliparous and non-pregnant: No data available
- Age at study initiation: Weanling rats used in the study.
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: The animals were housed individually in wire cages.
- Diet (e.g. ad libitum): Food, ad libitum
- Water (e.g. ad libitum): Water, ad libitum
- Acclimation period: No data available

DETAILS OF FOOD AND WATER QUALITY: No data available

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

IN-LIFE DATES: From: To: No data available

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: Diet
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: No data available

DIET PREPARATION
- Rate of preparation of diet (frequency): Fresh diets were made and distributed weekly.
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): Diet
- Concentration in vehicle: 0, 50, 125, 500 mg/kg bw
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
17 weeks
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm
Remarks:
(approximately equivalent to 0 mg/kg body weight)
Dose / conc.:
1 000 ppm
Remarks:
(approximately equivalent to 50 mg/kg body weight)
Dose / conc.:
2 500 ppm
Remarks:
(approximately equivalent to 125 mg/kg body weight)
Dose / conc.:
10 000 ppm
Remarks:
(approximately equivalent to 500 mg/kg body weight)
No. of animals per sex per dose:
0 ppm (approximately equivalent to 0 mg/kg body weight) : 10 male and 10 female
1000 ppm (approximately equivalent to 50 mg/kg body weight) : 10 male and 10 female
2500 ppm (approximately equivalent to 125 mg/kg body weight) : 10 male and 10 female
10,000 ppm (approximately equivalent to 500 mg/kg body weight) : 10 male and 10 female
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Not specified
- Time schedule: Not specified
- Cage side observations checked in table [No.?] were included. Not specified

DETAILED CLINICAL OBSERVATIONS: Not specified
- Time schedule: Not specified

BODY WEIGHT: Yes
- Time schedule for examinations: Recorded every week.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Not specified
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified
- The rat's food intake were recorded every week.

FOOD EFFICIENCY:Not specified
- 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: Not specified

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not specified
- Time schedule for examinations: Not specified

OPHTHALMOSCOPIC EXAMINATION: Not specified
- Time schedule for examinations: Not specified
- Dose groups that were examined: Not specified

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Not specified
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: Not specified
- Parameters checked in table [No.?] were examined: These examinations included white cell counts, red cell counts, haemoglobins and haematocrits.

CLINICAL CHEMISTRY: Not specified
- Time schedule for collection of blood: Not specified
- Animals fasted: Not specified
- How many animals:Not specified
- Parameters checked in table [No.?] were examined. Not specified

URINALYSIS: Not specified
- Time schedule for collection of urine:Not specified
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Not specified
- Parameters checked in table [No.?] were examined. Not specified

NEUROBEHAVIOURAL EXAMINATION: Not specified
- Time schedule for examinations: Not specified
- Dose groups that were examined: Not specified
- Battery of functions tested: sensory activity / grip strength / motor activity / other: Not specified

IMMUNOLOGY: Not specified
- Time schedule for examinations: Not specified
- How many animals: Not specified
- Dose groups that were examined: Not specified
- Parameters checked in table [No.?] were examined: Not specified

OTHER: General condition of rats were recorded every week.
Sacrifice and pathology:
At the termination of the experiment the rats were sacrificed and exsanguinated.

GROSS PATHOLOGY: Yes
The tissues of all the rats were examined macroscopically at the time of sacrifice. The viscera were removed and the liver, kidneys, spleen, heart, and testes were weighed.

HISTOPATHOLOGY: Yes
These organs, the remaining abdominal and thoracic viscera, and one hind leg, for bone, bone marrow, and muscle, were preserved in 10 % buffered formalin-saline solution for histopathological examination.
Other examinations:
No data available
Statistics:
No data available

Results and discussion

Results of examinations

Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No adverse effects were observed on final body weight of rats on all levels of the test chemical in the diet.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No adverse effects were observed on food intake of rats on all levels ofthe test chemical in the diet.
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 adverse effects were observed on haematology of rats on all levels of the test chemical in the diet.
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No adverse effects were observed on growth and appearance of rats on all levels of the test chemical in the diet.
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No adverse effects were observed on organ weights of rats on all levels of the test chemical in the diet.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No adverse effects were observed on macroscopic appearance of organs of rats on all levels of the test chemical in the diet.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
A dose-dependent slight to moderate swelling of liver parenchyma was noted which occurred to a very slight degree at the lowest level.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Effect levels

Dose descriptor:
NOAEL
Effect level:
125 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
haematology
behaviour (functional findings)
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
other: No adverse effects were seen.

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
It was concluded that the no-observed adverse effect level (NOAEL) of the test chemical in this chronic study was considered to be 125.0 mg/kg bw.

Executive summary:

The chronic repeated dose toxicity study of the test chemical in rat was conducted to evaluate adverse effects by oral route. Groups of 10 male and 10 female rats were maintained for 17 weeks on diets containing the test chemical at levels of 0, 1000, 2500, and 10.000 ppm (approximately equivalent to 50, 125, and 500 mg/kg body weight). No adverse effects were observed on growth, appearance, food intake, haematology, final body weight, organ weights or macroscopic appearance of organs of rats on all levels of the test chemical in the diet. However, microscopic examination revealed swelling of the hepatic parenchymal cells at all dietary levels. This "swelling of parenchymal cells" was dose-dependent, being "slight to moderate" at the highest dietary level (500 mg/kg bw/day), "slight" at the intermediate level (125 mg/kg bw/day), and "very slight" at the lowest level (50 mg/kg bw/day). Thus, it was concluded that the no-observed adverse effect level (NOAEL) of the test chemical in this chronic study was considered to be 125.0 mg/kg bw.