Tocopherols

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented study report which meets basic scientific principles; according to OECD Guideline 414 and pre-GLP study, please refer to IUCLID section 13 for read across justification.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1973

Report date:

1973

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

no

Remarks:

pre-GLP study

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-benzopyran-6-yl acetate

EC Number:

231-710-0

EC Name:

3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-benzopyran-6-yl acetate

Cas Number:

7695-91-2

IUPAC Name:

2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-3,4-dihydro-2H-chromen-6-yl acetate

Constituent 2

Reference substance name:

D,L-alpha-tocopheryl acetate

IUPAC Name:

D,L-alpha-tocopheryl acetate

Details on test material:

dl-alpha-tocopheryl acetate; no further data

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: virgin adult; no further data
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: individually in mesh bottom cages
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS: no data

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

days 6 through 15 of gestation

Frequency of treatment:

daily

Duration of test:

until day 20 of gestation

Doses / concentrations

Remarks:

Doses / Concentrations:
16, 74.3, 345, 1600 mg/kg bw/d
Basis:
no data

No. of animals per sex per dose:

24-25

Control animals:

yes, sham-exposed

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: day 0, 6, 11, 15, 20 of gestation

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake 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

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: urogenital tract

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: one third per litter
- Skeletal examinations: Yes: two thirds per litter
- Head examinations: No data
- Other: number of dead and live fetuses, weight of live fetuses

Statistics:

no data

Historical control data:

no data

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

> 1 600 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Effect levels (fetuses)

1

Dose descriptor:

NOAEL

Effect level:

> 1 600 mg/kg bw/day

Basis for effect level:

other: embryotoxicity

2

Dose descriptor:

NOAEL

Effect level:

> 1 600 mg/kg bw/day

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

No deaths occurred. Treatment with the test substance had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities of soft or skeletal tissues of the test group was not significantly different from sham-treated controls.

Survival of dams at gd 20:

25/25 (16 mg/kg tocopheryl acetate)

25/25 (74.3 mg/kg tocopheryl acetate)

25/25 (345 mg/kg tocopheryl acetate)

24/24 (1600 mg/kg tocopheryl acetate)

25/25 (sham treated control group)

25/25 (positive control group)

Maternal body weight at gd 0:

211 - 228 g (tocopheryl acetate groups)

204 g (sham treated control group)

214 g (positive control group)

Maternal body weight at gd 20:

333 - 348 g (tocopheryl acetate groups)

316 g (sham treated control group)

298 g (positive control group)

Pregnancies:

21 - 23 (tocopheryl acetate groups)

25 (sham treated control group)

23 (positive control group)

Abortions until gd 20:

0 (tocopheryl acetate groups)

0 (sham treated control group)

0 (positive control group)

Total number of live litters:

21 - 22 (tocopheryl acetate groups)

25 (sham treated control group)

19 (positive control group)

Total number of implantation sites:

246 - 266 (tocopheryl acetate groups)

241 (sham treated control group)

262 (positive control group)

Total numbers of resorptions:

1 - 7 (tocopheryl acetate groups); no complete resorption was observed

5 (sham treated control group); no complete resorption was observed

79 (positive control group); complete resorption was observed in 17.4% of the dams

Total number of live fetuses:

239 - 257 (tocopheryl acetate groups)

236 (sham treated control group)

180 (positive control group)

Average number of live fetuses per dam:

10.9 - 11.5 (tocopheryl acetate groups)

9.44 (sham treated control group)

7.83 (positive control group)

Sex ratio (m/f):

0.80 - 1.05 (tocopheryl acetate groups)

0.79 (sham treated control group)

0.87 (positive control group)

Total number of dead fetuses:

8 (74.3 mg/kg bw tocopheryl acetate group), 0 (other tocopheryl acetate groups)

0 (sham treated control group)

3 (positive control group)

Average fetus weight:

3.83 - 3.95 g (tocopheryl acetate groups)

3.82 g (sham treated control group)

2.49 g (positive control group)

There were no significant differences in any parameter between the groups treated with the test substance. No dose-response relationship was noted. Malformations of the sternebrae, ribs, vertebrae, skull, and extremities were recorded; however, the incidence of these malformations in vitamin E-treated groups were not significantly different from those observed in sham-treated control. Soft tissue variations in the tocopheryl acetate groups were distributed over all groups without indicating any dose-response. These variations included cardiomegaly (3 fetuses), anophthalmia (1 fetus), hydrocephalus (3 fetuses), gastroschisis (2 fetuses), apulmonism (1 fetus), and petechiae (1 fetus). No soft tissues are reported for the sham-treated control fetuses. In the positive control group treated with Aspirin, the expected statistically significant increase in the incidence of skeletal malformations and soft tissue variations was observed.

Applicant's summary and conclusion

Executive summary:

The administration of up to 1600 mg/kg bw of the test material to pregnant rats for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival . The number of-abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.