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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

Data waiving:

other justification

Justification for data waiving:

other:

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

In a developmental toxicity study conducted in albino rats no teratogenicity was observed. (BASF, 1978)

Link to relevant study records

Reference

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.

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

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

no

Limit test:

no

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

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

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.

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

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.

Dose descriptor:

NOAEL

Effect level:

2 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

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.

Abnormalities:

not specified

Developmental effects observed:

not specified

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Scientifically acceptable and guideline compliant study report.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

A developmental toxicity study was conducted in female Sprague-Dawley rats equivalent or similar to OECD guideline 414. 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 bw/d, 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.

On the basis of these results the dosage for the main study was selected at 150, 750 and 2000 mg/kg bw/d. Again, the compound was administered orally by intubation from day 6 until day 15 of pregnancy to 25 animals. During the period of treatment, general condition, weight gain and symptomatology were checked daily. Food consumption was noted on Days 6, 11, 16 and 21 of pregnancy. The rats of the three dose groups reacted to treatment by a reduction in food consumption at a dose related fashion. In both the 750 mg/kg bw/d and 2000 mg/kg bw/d dose groups body weight gain of the dams was diminished, in addition. The progeny of both the low dose group and the intermediate dose group were not found to be adversely affected by the treatment. The foetuses of the 2000 mg/kg bw/d dose group appeared to be slightly retarded in their physiological growth, as indicated by a decrease in average weight and a higher number of still unossified phalangeal nuclei as compared to the vehicle control. These slight effects on the embryo or foetus are assumed to be entirely non-specific and due to toxic effects on the dams. One instance of malformation (omphalocele) was noted each in the high-dose group and the vehicle control and considered to be of a spontaneous origin. This sort of malformation was also observed among the foetuses of the historical (cumulative) control. To summarize, the test substance did not exhibit either a teratogenic potential or an increased embryolethality rate in the albino rat under the conditions of the present experiment. A NOAEL for developmental toxicity of 2000 mg/kg bw/d was determined.

Justification for selection of Effect on developmental toxicity: via oral route:
Scientifically acceptable and guideline compliant study report.

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available study is considered reliable and suitable for classification purposes under 67/548/EEC. As a result the substance does not need to be classified and labelled for developmental toxicity under Directive 67/548/EEC, as amended for the 31st time in Directive 2009/2/EC.

 

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available study is reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance does not need to be classified and labelled for developemental toxicity under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation EC No 605/2014.