2,6-bis(4-ethylphenyl)perhydro-1,3,5,7-tetraoxanaphth-4-ylethane-1,2-diol

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

11 May 1981 - 05 October 1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study report makes no reference to an official test guideline, or claim of GLP compliance, however the study report is comprehensive and the methodology and observations are well documented. The study methodology was broadly consistent with modern test guidelines, and so the results are considered reliable with restrictions.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1981

Report date:

1981

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

not applicable

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2,6-bis(4-ethylphenyl)perhydro-1,3,5,7-tetraoxanaphth-4-ylethane-1,2-diol

EC Number:

406-176-9

EC Name:

2,6-bis(4-ethylphenyl)perhydro-1,3,5,7-tetraoxanaphth-4-ylethane-1,2-diol

Cas Number:

79072-96-1

Molecular formula:

Hill formula: C24 H30 O6

IUPAC Name:

1-[2,6-bis(4-ethylphenyl)-hexahydro-[1,3]dioxino[5,4-d][1,3]dioxin-4-yl]ethane-1,2-diol

Test animals

Species:

mouse

Strain:

other: Crj:CD-1 (ICR)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 4 Weeks
- Weight at study initiation: 28 to 33 g (Males); 20 to 25 g (Females)
- Housing: Stainless steel wire mesh cages (260 x 380 x 210 mm)
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 1 Week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±1°C
- Humidity (%): 55±5%
- Photoperiod (hrs dark / hrs light): 12 hours lighting.

IN-LIFE DATES: From: 18 May 1981 To: 19 August 1981

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: Added to powder diet

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

13 Weeks. Note that some animals (5 animals/20 for each dose group) were sacrificed after 5 weeks for interim examination.

Frequency of treatment:

Treated diet was made available ad libitum.

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 5000, 15000, and 50000 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

20

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: Random

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations checke:

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

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: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Recorded weekly

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Performed prior to sacrifice at 5 weeks for the animals in the 5-week treatment group, and at 13 weeks in the remainder of animals.
- Anaesthetic used for blood collection: Yes (identity)
- Animals fasted: Yes, 16 hours
- How many animals: 5 animals at week 5; 15 animals at week 13

CLINICAL CHEMISTRY: Yes
- Collection as per Haematology, above

URINALYSIS: Yes
- Time schedule for collection of urine: Performed prior to sacrifice at 5 weeks for the animals in the 5-week treatment group, and at 13 weeks in the remainder of animals.
- Metabolism cages used for collection of urine: No
- Animals fasted: Yes 16 hours

NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:

OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: No

Statistics:

Numerical data generated during the conduct of the study were subjected to the calculation of group mean values with standard deviation and statistical analysis using Student's "t" test.

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:

no effects observed

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
No deaths ocurred during the study. No abnormal symptoms were observed in all treated and control animals throughout the study.

BODY WEIGHT AND WEIGHT GAIN
over the course of the 13 week treatment period, similar bodyweight gain was seen for animals in all groups. Significantly higherbody weight gain was seen in the 5000 ppm band durings weeks 5 and 6 of the treatment period, but as this was only seen in the 5000 ppm level, it was considered not to be test-substance related.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
No effect was seen in females dosed at any of the treatment levels dosed. No effects in food consumption were seen at 5000 ppm in males, however significantly higher food consumption was seen in males at the 15000 and 50000 ppm levels during weeks 0, 10, and 12. As these changes appeared sporadically they were not thought to be related to test material.

FOOD EFFICIENCY
No effect on food efficiency was seen in the 13 week treatment period.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
No treatment-related changes in water intake were seen.

HAEMATOLOGY
Haematological effects were seen, but they were not considered to have been caused by the test material.

CLINICAL CHEMISTRY
Changes were seen in some animals but they were not dose related

URINALYSIS
No effects were seen on Urinalysis at any dose level.

ORGAN WEIGHTS
The increased absolute and relative kidney weight was recorded in males fed 50000 ppm and in females fed 15000 ppm, and absolute kidney weight also increased in females fed 50000 ppm. The decreased absolute and relative spleen weight was recorded in males fed 50000 ppm. The increased absolute pituitary weight and thymus weight and decreased relative testis weight were recorded in males fed 5000 ppm. These changes in the 5000 ppm group were not dose related changes. There were no other significant changes in organ weight parameters in treated groups.

GROSS PATHOLOGY
Abnormalities were seen in a few animals at necrospy, however they were considered to be spontaneous, and not treatment related.

HISTOPATHOLOGY: NON-NEOPLASTIC
Histopathological changes were seen in the pituitary, thymus, liver, kidney, adrenal, pancreas, stomach and eye of treated or control animals. These abnormalities were thought to be spontaneous or accidental damage.

Effect levels

1

Dose descriptor:

NOEL

Effect level:

50 000 ppm

Sex:

male/female

2

Dose descriptor:

NOEL

Effect level:

7 280 mg/kg bw/day (actual dose received)

Sex:

male

Basis for effect level:

other: Equivalent dose based on food intake/bodyweight

3

Dose descriptor:

NOEL

Effect level:

10 710 mg/kg bw/day (actual dose received)

Sex:

female

Basis for effect level:

other: Equivalent dose based on food intake/bodyweight

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

No mortalities or toxic effects were observed in this 13-week repeated dose toxicity study in mice. The No Effect Level was 50000 ppm by dietary administration; this was eqivalent to 7.28 g/kg/day in males, and 10.71 g/kg/day in females.