3,7,11,15-tetramethylhexadec-1-en-3-ol

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Peer-reviewed data, available as short summary from secondary source, reliability according to HPV/ICCA SIDS.

Data source

Reference

Reference Type:

secondary source

Title:

Unnamed

Year:

1998

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

14 day recovery group

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3,7,11,15-tetramethylhexadec-1-en-3-ol

EC Number:

208-008-8

EC Name:

3,7,11,15-tetramethylhexadec-1-en-3-ol

Cas Number:

505-32-8

Molecular formula:

C20H40O

IUPAC Name:

3,7,11,15-tetramethylhexadec-1-en-3-ol

Details on test material:

no data

Test animals

Species:

rat

Strain:

other: Cr1:CD(SD)BR (VAF plus)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River UK, Margate, UK
- Age at study initiation: approximately 28 days old at arrival
- Weight at study initiation: males 154-186 g and females 122-164 g
- Housing: groups of six per sex in grid-bottomed stainless-steel cages (TR18, Modular Systems, Kent, UK), suspended over cardboard-lined litter trays.
- Diet (e.g. ad libitum): SQC Rat and Mouse Maintenance Diet No. 1, Expanded (Special Diets Services, Whitham, UK) ad libidum
- Water (e.g. ad libitum): tap water ad libidum
- Acclimation period: 13 days prior to the start of dosing


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-24
- Humidity (%): 36 to 49%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
Separate formulations were prepared daily for each dose level.

VEHICLE
- Amount of vehicle (if gavage): 50 ml solution/kg bw

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

As a confirmation of concentrations, samples of each formulation including the vehicle only control prepared on day 1 of weeks 1 and 4 of dosing were sent to the sponsor and analysed.

Duration of treatment / exposure:

28 consecutive days

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 250, 500, 1000
Basis:
actual ingested

No. of animals per sex per dose:

12 (control, 1000 mg/kg bw/day group)
6 (250, 500 mg/kg bw/day group)

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for mortality and morbidity.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: All visible signs (including behavioural) of reaction to treatment were recorded daily.

BODY WEIGHT: Yes
- Time schedule for examinations: start of the study and then twice weekly up to the day of necropsy.

FOOD CONSUMPTION:
The amount of food consumed by each cage of animals was recorded weekly throughout the treatment and treatment-free periods

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 data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: from the first 6 males and females in each group during week 4 of treatment. Further samples were taken from the remaining animals towards the end of week 2 of the treatment-free period.
- Anaesthetic used for blood collection: No data
- Animals fasted: No data

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: from the first 6 males and females in each group during week 4 of treatment. Further samples were taken from the remaining animals towards the end of week 2 of the treatment-free period.
- Animals fasted: No data

URINALYSIS: Yes
- Time schedule for collection of urine:from the first 6 males and females in each group during week 4 of treatment. Further samples were taken from the remaining animals towards the end of week 2 of the treatment-free period.
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data

NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

At the end of the treatment and treatment-free period, the respective animals were killed by CO2 asphyxiation. Dissections were completed in two days respectively one day for the remaining treatment-free animals. All animals were weighed, examined externally, the abdominal cavity opened, exsanguinated, macroscopically examined and the following selected organs excised and weighed: adrenals, brain, epididymides, heart, kidneys, liver, ovaries, spleen, testes, thymus. Tissue samples were taken and fixed for histology from 22 organs and sites, including all gross lesions.

Statistics:

Sexes were analysed separately. Observations included bodyweights, bodyweight gains over the treatment period, food consumption, absolute and relative organ weights as well as clinical pathology data. The data were subjected to ANOVA. If between-group differences in variance were detected, pairwise tests versus controls were performed using Williams' test. Statistical significance was declared at two-sided 5% level and also noted at 1% and 0.1% levels. Haematological, biochemical and urinalytical results were analysed non-parametrically.

Results and discussion

Results of examinations

Details on results:

CLINICAL SIGNS AND MORTALITY
There were no mortalities during this study. Fur-staining was recorded in a number of females given 1000 mg/kg bw/d. One female from this group also showed hypoactivity, hunched posture, weight loss and pallor. These signs were considered related to the treatment. All other signs noted were considered not to be related to the treatment.

BODY WEIGHT AND WEIGHT GAIN
Both bodyweights and bodyweight gains were normal for rats of this age and strain in all four groups.

FOOD CONSUMPTION
There were no obvious treatment-related effects on food consumption.

HAEMATOLOGY
At the end of the 4-week treatment, increased white blood cell (WBC) count was noted for the high-dose females. In the high-dose males the group mean prothrombin time was slightly reduced. At the end of the treatment-free period, the WBC count in females remained marginally higher than in controls but fell within the quoted background ranges and was considered to have recovered. The prothrombin time in males was comparable with controls.

CLINICAL CHEMISTRY
Small but statistically significant increases in alanine aminotransferase (ALT) were observed in mid-dose males and in both sexes at high dosage. Groups mean cholesterol levels in females demonstrated an apparent dose-related increase. Calcium levels were also elevated in low-dose females and in both sexes at mid and high dose. At the end of the treatment-free period there were no significant differences from controls regarding those parameters reexamined.

URINALYSIS
After 4 weeks of treatment urine volumes were increased, with a corresponding decrease in specific gravity, in mid-dose males and in both sexes at high dosage. At the end of the treatment-free period the group mean urine volume in both sexes at high dosage was higher than in associated controls, again with a corresponding decrease in specific gravity.

ORGAN WEIGHTS
Absolute and relative liver weights were increased in both sexes at a dose of 1000 mg/kg bw/d. Absolute kidney weights were increased in females at all dose levels, although when related to bodyweight this increase was only significant at the high dose. Absolute spleen weights were increased in both sexes in all dose groups; when related to bodyweight, spleen mass showed an increase for females only at the high dose. The dead bodyweights of males from treated groups were significantly higher than controls, which was considered to be the reason for the apparent increased absolute spleen weights and also a reduction in bodyweight-related brain weights seen in both sexes at high dose. At the end of the treatment-free period the liver weights of females had dropped to significantly below the comparable control levels. The liver weights of males from the high-dose group had regained levels similar to controls. Other, minor changes noted were considered not to be related to treatment.

GROSS PATHOLOGY
No obvious treatment-related abnormalities were observed at dissection.

HISTOPATHOLOGY
No treatment-related effects were recorded during histopathology. A small number of findings were within the normal range of background alterations for untreated rats of this strain and age and were considered not to be related to treatment.

Effect levels

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (actual dose received)

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified