Hexamethylene bis[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:

1978-06-29 to 1978-10-18

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: None GLP but equivalent to guideline study.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1978

Report date:

1978

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: WILSON, J.G., in: Teratology, Principles and Techniques; J.G. Wilson and J. Warkany eds., The University of Chicago Press, Chicago and London, 1965, pp. 265-277.

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: DAWSON, A.B., Stain Tech. 1 (1926), 123-124.

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: SALEWSKI, E.., Arch. exp. Path. Pharmak. 247 (1964), 367-368.

Deviations:

no

Test guideline 4

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Hexamethylene bis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate]

EC Number:

252-346-9

EC Name:

Hexamethylene bis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate]

Cas Number:

35074-77-2

Molecular formula:

C40H62O6

IUPAC Name:

6-{[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanoyl]oxy}hexyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanoate

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Female albino rats (Tif: RAIf (SPF)) obtained from a closed breeding colony
- Age at study initiation: 2 months
- Weight at study initiation: ca. 190 g
- Housing: Throughout the experiment the successfully mated females were kept in groups of 5 in Macrolon cages in an air-conditioned room.
- Diet: ad libitum, Nafag No. 890
- Water: ad libitum, tap water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 1
- Humidity (%): 60 ± 5
- Photoperiod (hrs dark / hrs light): 14/10

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

VEHICLE
- Amount of vehicle: 2 % solution from own stocks

Analytical verification of doses or concentrations:

no

Details on mating procedure:

Before test start the female rats were mated overnight with males of proven fertility in a ratio of 1 male : 3 females. The day on which spermatozoa were found in the vaginal smear or a vaginal plug has occurred was designated as "Day 0" of pregnancy.

Duration of treatment / exposure:

Day 6 to day 15 of pregnancy

Frequency of treatment:

daily

Duration of test:

21 days

Doses / concentrations

Remarks:

Doses / Concentrations:
150, 750 and 2000 mg/kg bw/d
Basis:
nominal conc.

No. of animals per sex per dose:

25 female animals per dose

Control animals:

yes

Details on study design:

In order to determine the dose levels for the main study, a preliminary experiment was carried out on 10 fertilized albino rats at the dose of 2500 mg/kg, given orally by intubation from day 6 until day 15 of pregnancy, inclusive. The dams of this high dose group reacted to treatment by a marked decrease in body-weight gain and food consumption. So far as the progeny were concerned, a reduction in foetal average weight was noted.

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily examination

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily examination

BODY WEIGHT: Yes
- Time schedule: daily examination

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined at a dose-related fashion.
- Time schedule: examinations on days 6, 11, 16 and 21

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: ovaries, uterus

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- 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 live foetuses
- Skeletal examinations: Yes: 2/3 live foetuses
- Head examinations: No

Statistics:

The Chi-square test was used together with the Yates correction to compare the sex ratios of the litters with the vehicle controls.

Indices:

No indices were determined.

Historical control data:

Yes

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Throughout the period of treatment food intake was reduced in the three dose groups. At the 750 mg/kg bw/d dose and the 2000 mg/kg bw/d dose the body weight gain was diminished, in addition.
The implantation rates were comparable for all groups. In one dam of the 750 and 2000 mg/kg bw/d dose group each haemorrhagic degeneration of implantation sites (deciduomata) was noted. One dam with deciduomata was observed among the rats of the cumulative control.
The rates of foetalethality (resorptions) were comparable for all groups.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

2 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

2

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
The sex ratios of the foetuses were not significantly altered when compared with the vehicle control. At the highest dosing group the average weight of the foetuses was slightly but significantly diminished. The gross examination of the foetuses revealed one omphalocele in one foetus of the highest dosing group and the control group each. This type of malformation was also found in 2 out of 3533 foetuses of the historical control data.
No pathological changes of viscera were found in the experimental groups, including the vehicle control. Some anomalies were noted, however, in the historical control.
Regarding the skeletal assessment, the only clearcut deviation from the vehicle control is assumed to manifest in an increased number of not yet ossified phalangeal nuclei at the 2000 mg/kg bw/d dose. Some skeletal anomalies were observed in the historical control.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified