Octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1975

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable with guideline, acceptable with restrictions (gravid uterus weight, number of corpora lutea and fetal sex were not examined)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1975

Report date:

1975

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

gravid uterus weight, number of corpora lutea and fetal sex were not examined

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate

EC Number:

218-216-0

EC Name:

Octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate

Cas Number:

2082-79-3

Molecular formula:

C35H62O3

IUPAC Name:

octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: ca. 240 g
- Housing: 5/cage
- Diet (e.g. ad libitum): standard diet, Nafag No.890
- Water (e.g. ad libitum): tap water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±0.5
- Humidity (%): 56±5
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

VEHICLE
- Concentration in vehicle: 2%
- Amount of vehicle (if gavage): 1 ml/100 g bw

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:3
- Length of cohabitation: overnight
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Frequency of treatment:

single

Duration of test:

GD 6-15

Doses / concentrations

Remarks:

Doses / Concentrations:
150, 500, 1000 mg/kg bw
Basis:
actual ingested

No. of animals per sex per dose:

25 for all test groups, 30 for control group

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: general condition, symptoms, mortality

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: ovaries and uterus (mucosa and contents, including amniotic fluid and placentae), the foetuses were subjected to careful external inspection and the condition of their body orifices was checked.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- 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: 1/3 per litter (using slicing technique)
- Skeletal examinations: Yes: 2/3 per litter

Statistics:

t-test was used for comparison between treated and control groups.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Body-weight gain was slightly (non-specific) depressed following the 500 mg/kg bw and 1000 mg/kg bw doses. At the three dose levels, particularly in the intermediate and high-dose group, feed consumption was reduced during the period of treatment. No further signs of intolerability of the compound were noted. The data on the rates of implantation and embryolethality (resorptions) were comparable for all groups.

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
The average weight of the foetuses was significantly (p<0.01) diminished in the 500 mg/kg bw (-1.7%) and 1000 mg/kg bw (-2.5%) dose group when compared with the control. The mean weight of live fetuses in the control, 150, 500 and 1000 mg/kg bw dose groups were 5.18, 5.16, 5.09 and 5.05 g, respectively. By applying the slicing technique in a few foetuses of the experimental groups minor anomalies were detected which have also occurred in a cumulative of "untreated" controls. Concerning skeletal assessment the only clear-cut deviation from the control group was increase in the number of not yet ossified phalangeal nuclei of the hindlimb following the administration of 1000 mg/kg bw. However, this deviation was not dose-related (Table 1).

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw/day (actual dose received)

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

Table 1. Skeletal examinations

Dose groups (mg/kg bw/day)	No. of skeletons examined	Phalangeal Nuclei
		Fore-limb	Hind-limb
150	193	4 (2.1 %)	52 (26.9%)
500	197	6 (3.0%)	33 (16.8%)
1000	192	2 (1.0%)	74 (38.5%)
control	238	0	36 (15.1%)

Applicant's summary and conclusion

Conclusions:

Based on the results, no teratogenic effects were observed. The NOAEL for teratogenic effects was considered to be >1000 mg/kg bw.