Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study under GLP
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report date:
2010

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: OECD 416: 2-generation reproductive toxicity study
Principles of method if other than guideline:
In addiiton to a reproductive and developmental toxicity study (OECD 414), the F1 generation of animals is exposed and mated, producing an F2 generation which is assessed for toxicity.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
A mixture of: 2,2,6,6-tetramethylpiperidin-4-yl-hexadecanoate; 2,2,6,6-tetramethylpiperidin-4-yl-octadecanoate
EC Number:
415-430-8
EC Name:
A mixture of: 2,2,6,6-tetramethylpiperidin-4-yl-hexadecanoate; 2,2,6,6-tetramethylpiperidin-4-yl-octadecanoate
Cas Number:
86403-32-9
Molecular formula:
C25H49NO2 and C27H53NO2
IUPAC Name:
Reaction mass of 2,2,6,6-tetramethylpiperidin-4-yl hexadecanoate and 2,2,6,6-tetramethylpiperidin-4-yl octadecanoate

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
Additional information on the study is forthcoming.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
olive oil
Details on exposure:
Parental males were dosed for 70 days before mating. Parental females were dosed 14 days prior to mating, no more than 21 days during the mating process, 22-24 days during gestation, and 21-28 days during lactation up until the weaning of F1 pups. F1 males and F1 females were dosed according to the this same schedule.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
no data. Additional information on the study is forthcoming.
Details on mating procedure:
Additional information on the study is forthcoming.
Duration of treatment / exposure:
Parental males were dosed for 70 days before mating. Parental females were dosed 14 days prior to mating, no more than 21 days during the mating process, 22-24 days during gestation, and 21-28 days during lactation up until the weaning of F1 pups. F1 males and F1 females were dosed according to the this same schedule.
Frequency of treatment:
once daily
Duration of test:
approximately 180 days
No. of animals per sex per dose:
12 males/group; 24 females/group
Control animals:
yes, concurrent vehicle
Details on study design:
P and F1 adults were weighed weekly. Pups of F1 and F2 generation were weighed 24 hours after birth, and on days 4,7,14 and 21 post-parturition. For mating, F1 offspring were selected litters of the same dose level at weaning to produce F2 generation. Age difference between selected pups was about one week. Since F1 pups were too small in day 21 post-partum, they were weaned in day 28 post-parturition. All animals were monitored for the signs of toxicity during the application of the test substance.

Examinations

Maternal examinations:
During the study, clinical observations and food consumption were recorded. Body weights were measured. Organ weights and gross and histological examinations on selected organs were undertaken after termination of the study.
Ovaries and uterine content:
Not monitored in P generation, as females were allowed to deliver naturally. The number of corpora lutea and implantation sites in F1 females were assessed. Functional effects were assessed in the P and F1 generations. Additional information on the study is forthcoming.
Fetal examinations:
F1 pups were examined for externally-viewed malformations, then weaned, and mated.
Statistics:
separately for P and F1 males, females and litters;
Test for homogeneity of the groups: Barlett´s test
in the way of homogeneity: one way analysis with consecutive Multiple Rangers test
no homogeneity: Kruskal-Wallis one way Analysis by ranks
Indices:
Since the study is a 2 generation study, only obvious malformations were detected
Historical control data:
Historical data is available.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No important visible signs of intoxication were noted. Alopecia and smooth stool in P and F1 generations were registered, with no dose-response relationship.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One animal died due to a gavage accident.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food intake in P females at 250 mg/kg bw/d after the first and second week, and in dose group 125 mg/kg bw/d after the second week pre-mating period was decreased compared to controls.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Females of 250 mg/kg bw/d showed increased relative liver weight.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
not examined
Total litter losses by resorption:
no effects observed
Early or late resorptions:
not specified
Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
Control: 12/153 (dead/alive), 25 mg/kg bw: 7/199 (dead/alive), 125 mg/kg bw: 9/185 (dead/alive), 250 mg/kg bw: 11/184 (dead/alive)
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: Food intake and relative liver weights were increased in the P generation at the high dose of 250 mg/kg bw/d.

Details on maternal toxic effects:
Food intake in P females at 250 mg/kg bw/d after the first and second week, and in dose group 125 mg/kg bw/d after the second week pre-mating period was decreased compared to controls. While there were no significant changes histologically in the P generation, it was noted that there was an increased relative liver weight in females of the 250 mg/kg bw/d group, compared to controls.

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
not examined
Visceral malformations:
not examined
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No adverse effects were noted in offspring.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
> 250 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects observed

Fetal abnormalities

Key result
Abnormalities:
not examined

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
A two-generation reproductive toxicity study in Wistar rats on Dastib 845, at doses of 25, 125 and 250 mg/kg bw/d, was undertaken according to OECD guideline 416. Results indicate there was no test article-related changes based on the evaluation of the survival, clinical signs, body weight, production parameters, and organ weights, except for elevated relative liver weights in P females. The NOAEL for the P generation males and F1 generation is greater than 250 mg/kg bw/d; for P females is 125 mg/kg bw/d.