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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
24 April 2014 - 23 October 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2014
Report date:
2014

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
A mixture of: bis(2,2,6,6-tetramethyl-1-octyloxypiperidin-4-yl)-1,10-decanedioate; 1,8-bis[(2,2,6,6-tetramethyl-4-((2,2,6,6-tetramethyl-1-octyloxypiperidin-4-yl)-decan-1,10-dioyl)piperidin-1-yl)oxy]octane
EC Number:
406-750-9
EC Name:
A mixture of: bis(2,2,6,6-tetramethyl-1-octyloxypiperidin-4-yl)-1,10-decanedioate; 1,8-bis[(2,2,6,6-tetramethyl-4-((2,2,6,6-tetramethyl-1-octyloxypiperidin-4-yl)-decan-1,10-dioyl)piperidin-1-yl)oxy]octane
Cas Number:
129757-67-1
Molecular formula:
C44 H84 N2 O6 + C80 H150 N4 O12 737.16 g/mol + 1360.1 g/mol
IUPAC Name:
2,2,6,6-tetramethyl-1-(octyloxy)piperidin-4-yl 2,2,6,6-tetramethyl-1-{[8-({2,2,6,6-tetramethyl-4-[(10-oxo-10-{[2,2,6,6-tetramethyl-1-(octyloxy)piperidin-4-yl]oxy}decanoyl)oxy]piperidin-1-yl}oxy)octyl]oxy}piperidin-4-yl decanedioate; 2,2,6,6-tetramethyl-1-(octyloxy)piperidin-4-yl 2,2,6,6-tetramethyl-4-{[8-({2,2,6,6-tetramethyl-1-[(10-oxo-10-{[2,2,6,6-tetramethyl-1-(octyloxy)piperidin-4-yl]oxy}decanoyl)oxy]piperidin-4-yl}oxy)octyl]oxy}piperidin-1-yl decanedioate; bis[2,2,6,6-tetramethyl-1-(octyloxy)piperidin-4-yl] decanedioate
Details on test material:
- Physical state: Colourless to yellow clear liquid
- Storage condition of test material: Ambient temperature

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Italy S.p.A., Calco (Lecco), Italy.
- Age at study initiation: 9 weeks
- Weight at study initiation: 196-222 g
- Housing: During the pre-pairing period, the animals were housed no more than 5 of one sex to a cage in polysulfone cages measuring 59.5x38x20 cm (Code 1354 G, Techniplast Gazzada S.a.r.l., Buguggiate, Varese); during the mating period, the rats were housed on the basis of 1 male to 1
female in clear polysulfone cages measuring 42.5x26.6x18.5 cm with a stainless steel mesh lid and floor (Techniplast Gazzada S.a.r.l., Buguggiate, Varese). After the mating period, the rats were housed individually in clear polysulfone cages measuring 42.5x26.6x18.5 cm.
- Diet: laboratory rodent diet (4 RF 21, Mucedola S.r.l., Via G. Galilei, 4, 20019, Settimo Milanese (MI), Italy) was offered ad libitum
- Water: ad libitum, water bottles
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 5
- Air changes (per hr): 15 to 20
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: aqueous solution of carboxymethylcellulose (1%w/v) + 0.1% Tween 80 in purified water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The required amount of test substance was suspended in the vehicle. The formulations were prepared daily (concentrations of 10, 30 and 100 mg/mL) and the concentrations were calculated and expressed in terms of test item as supplied.

VEHICLE
- Amount of vehicle (if gavage): 10 ml/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chemical analysis including stability of the formulations was carried out by the Analytical Chemistry Department at RTC according to a validated method (RTC Study No. 98160 BASF Project No: 10Y0397/13X183). The proposed formulation procedure for the test item was checked in the range from 4 to 40 mg/mL by chemical analysis (concentration and homogeneity) in RTC Study No. 98160 which was extended up to 100 mg/mL in the present study to confirm that the method was suitable. Final results for all levels were within the acceptability limits, stated in Study Protocol no. 98160 for concentration (90-110%) and homogeneity (<10.00%). In RTC Study No. 98160, a 24 hour stability at room temperature was verified in the range from 4 to 40 mg/mL. In addition, in the present study stability after 24 hour at room temperature was extended up to 100 mg/mL. According to the validation Study Protocol no. 98160, suspensions are considered to be stable if concentration and homogeneity after the defined period of storage, is still acceptable (90-110% and CV <10.00% respectively).
Samples of the formulations prepared during the study were analysed to check the homogeneity and concentration (the first and the last week of treatment). Results of the analyses were within the acceptability limits, stated in Study Protocol no. 98160 for concentration of suspensions (90- 110%) and homogeneity (<10.00%).
Details on mating procedure:
Females were paired one to one in the home cage of the male and left overnight. Vaginal smears were taken daily in the morning from the day after pairing until a positive identification of mating was made. The day of mating, as judged by the presence of sperm in the vaginal smear or by the presence of a copulation plug, was considered as Day 0 of gestation (or Day 0 post coitum). Full mating records were maintained.
Duration of treatment / exposure:
All animals were dosed once a day from Day 6 through Day 19 post coitum.
Frequency of treatment:
daily
Duration of test:
The animals were euthanised on Day 20 post coitum
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
24 females per dose group
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
MORTALITY CHECK: Yes
- Time schedule: Throughout the study, all animals were checked early in each working day and again in the afternoon. At weekends and Public Holidays a similar procedure was followed except that the final check was carried out at approximately mid-day.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Each animal was observed at least once daily

BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed on Days 0, 3, 6, 9, 12, 15, 18 and 20 post coitum.

FOOD CONSUMPTION: Yes
Food consumption was measured on Days 3, 6, 9, 12, 15, 18 and 20 post coitum starting from Day 0 post coitum.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
A detailed post mortem examination was conducted (including examination of the external surface and orifices). Changes were noted and the abnormalities preserved in 10% neutral buffered formalin.

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
– Gravid uterine weight;
– number of corpora lutea;
– number of implantation sites;
– number, sex and weight of all live foetuses;
– number and sex of dead foetuses (foetuses at term without spontaneous movements and breathing);
– number of intra-uterine deaths;
– gross evaluation of placentae.
Intra-uterine deaths were classified as:
– Early resorptions: only placental remnants visible.
– Late resorptions: placental and foetal remnants visible.
Uteri or individual uterine horns without visible implantations were immersed in a 20% solution of ammonium sulphide to reveal evidence of embryonic death at very early stages of implantation.
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
Statistics:
Standard deviations were calculated as appropriate. For continuous variables the significance of the differences amongst group means was assessed by Dunnett’s test or a modified t test, depending on the homogeneity of data. Statistical analysis of non-continuous variables were carried out by means of the Kruskal Wallis test and intergroup differences between the control and treated groups assessed by a non-parametric version of the Williams test. The mean values, standard deviations and statistical analysis were calculated from actual values in the computer without rounding off.
Indices:
Pre-implantation loss, Post-implantation loss, Total implantation loss, Sex ratios

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related clinical signs were observed in all treated groups. Hairloss was noted in control and treated females. In addition, rales and pale aspect were also recorded, occasionally, in one control female and in one receiving 300 mg/kg bw/day, respectively.
Mortality:
no mortality observed
Description (incidence):
No mortality of females occurred during the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weight and body weight gain were unaffected by treatment.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No differences in food consumption were observed between control and treated groups throughout the study.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No differences in terminal body weight, gravid uterus or corrected body weight gain (terminal body weight at necropsy minus gravid uterine weight, minus body weight at Day 6 post coitum) were observed in any treated animal compared to controls.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment-related macroscopic changes were observed in females sacrificed on Day 20 post coitum. The changes observed are suggested to be incidental, having a comparable incidence in control and treated groups, and/or are characteristically seen in untreated Wistar Hannover rats of the same age.

Maternal developmental toxicity

Details on maternal toxic effects:
Five females proved not to be pregnant at necropsy: one in the control group, three in Group 2 receiving 100 mg/kg bw/day and one in Group 3 receiving 300 mg/kg bw/day. In addition, four females had unilateral implantation (1 control, 2 receiving 100 mg/kg bw/day and 1 receiving 300 mg/kg/day). The number of females with live foetuses on Day 20 post coitum was 23 in the control group, 21 in the low dose group (100 mg/kg bw/day), 23 in the mid-dose group (300 mg/kg bw/day) and 24 in the high dose group (1000 mg/kg bw/day).

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw (total dose)
Based on:
test mat.
Basis for effect level:
other: no effects observed up to the high dose

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Mean foetal weight was not affected by treatment. A total of 7 small foetuses (< 2.7 g) were detected: 2 out of 282 in the control group, 3 out of 237 in females receiving 100 mg/kg bw/day, 1 out of 268 in females receiving 300 mg/kg bw/day and 1 out of 324 in females receiving 1000 mg/kg bw/day. One dead foetus was observed in the control group.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
mean foetal sex ratios were not affected by treatment
External malformations:
no effects observed
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The following findings were observed both in control and treated groups with similar incidence: short 14th rib, rudimentary 14th rib, incomplete ossification of the skull bones (parietal, interparietal, supraoccipital, temporal, frontal, zygomatic), incomplete ossification, asymmetrical ossification or no ossification of the sternal elements (particularly 5th and/or 6th), incomplete ossification of the sacral arch(es) and thoracic centra, no ossification of the 4th metacarpal. The other findings, such as, 14 rib, dumbell shape of the thoracic centra, metacarpal incomplete ossification, no ossification of hyoid, incomplete ossification of the tympanic bulla, asymmetrical or bipartite ossification of thoracic centra or rudimentary or no ossification of the sternal elements were recorded with low incidence in treated groups, without dose-relation and therefore considered incidental.
Wavy ribs occurred in the treated groups at a low incidence. Since wavy ribs are a common finding in rat foetuses, and there was no dose-dependency, this finding was considered as incidental. In addition, misshaped, rudimentary and incomplete ossification of the ribs were also noted occasionally in the intermediate groups. Major findings included: one foetus in each treated group with absence of one rib (11th or 13th) and one mid-dose foetus (300 mg/kg bw/day) with cleaved sternum. Taking into consideration that these alterations were observed with similar incidence in a limited number of treated foetuses and that no additional major alterations were noted, they were considered incidental.
Visceral malformations:
no effects observed
Description (incidence and severity):
No relevant changes that could be considered treatment-related were observed at visceral examination of foetuses between the control and treated groups.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects observed up to the high dose

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
On the basis of the results obtained in this study, it could be concluded that the test article did not induce signs of maternal toxicity or embryo/foetal toxicity. Therefore, the high dose level (1000 mg/kg bw/day) was considered the NOAEL (No Observed Adverse Effect Level) for maternal and developmental toxicity.
Executive summary:

In a developmental toxicity study following OECD guideline 414, the effects of the test article on pregnancy and embryo-foetal development in the Wistar rat following oral administration was investigated. Females were dosed starting from Day 6 until Day 19 post coitum at dose levels of 0, 100, 300 and 1000 mg/kg body weight. The test item was administered, by oral route, at a dose volume of 10 mL/kg. The vehicle was an aqueous solution of carboxymethylcellulose (1% w/v) + 0.1% Tween 80 in purified water. The following investigations were performed: mortality check, clinical signs, body weight, food consumption and macroscopic observation of the females. On Day 20 post coitum at necropsy, gravid uterus, corrected body weight (terminal body weight minus gravid uterus weight), corrected body weight gain (terminal body weight minus body weight at Day 6 post coitum minus gravid uterus weight), corpora lutea, implantation sites, number, sex and weight of all live foetuses were determined. Gross evaluation of the placenta was also performed. Visceral and skeletal examinations were also performed in foetuses of all groups.

No mortality occurred during the study. Five females proved not to be pregnant at necropsy: one in the control group, three in Group 2 receiving 100 mg/kg bw/day and one in Group 3 receiving 300 mg/kg bw/day. In addition, four females had unilateral implantation (1 control, 2 receiving 100 mg/kg bw/day and 1 receiving 300 mg/kg bw/day). The number of females with live foetuses on Day 20 post coitum was 23 in the control group, 21 in the low dose group (100 mg/kg bw/day), 23 in the mid-dose group (300 mg/kg bw/day) and 24 in the high dose group (1000 mg/kg bw/day). No treatment-related clinical signs were revealed during the study. No differences in body weight and food consumption were observed during the study between control and treated groups. There were no compound-related effects in terminal body weight, gravid uterus or corrected body weight gain. Litter data, mean foetal weight and sex ratio were unaffected by treatment. No treatment-related changes were noted during macroscopy. A total of 7 small foetuses (< 2.7 g) were detected in females: 2 in the control group, 3 receiving 100 mg/kg bw/day, 1 receiving 300 mg/kg bw/day and 1 receiving 1000 mg/kg bw/day. One dead foetus was observed in the control group. No relevant changes were recorded at the skeletal examination of treated foetuses, when compared to the control groups. No treatment-related differences were seen at visceral examination of foetuses between the control and treated groups. On the basis of the results obtained in this study, it could be concluded that the test article did not induce signs of maternal toxicity or embryo/foetal toxicity. Therefore, the high dose level (1000 mg/kg bw/day) was considered the NOAEL (No Observed Adverse Effect Level) for maternal and developmental toxicity.