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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Remarks:
43037 RSR
Type of information:
experimental study
Adequacy of study:
key study
Study period:
08 January 2016 - 10 March 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report date:
2016

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Dimethyl sebacate
EC Number:
203-431-4
EC Name:
Dimethyl sebacate
Cas Number:
106-79-6
Molecular formula:
C12H22O4
IUPAC Name:
1,10-dimethyl decanedioate
Test material form:
other: white solid
Details on test material:

storage at room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS - Source: Janvier, le Genest-Saint-Isle, France- Sex: female - Age at study initiation: at the beginning of the treatment period, the animals were 10-11 weeks old - Weight at study initiation: the animals had a mean body weight of 278 g (range: 231 g to 334 g) - Housing: the animals were individually housed in cages (Tecniplast 2154, 940 cm2; polycarbonate with a stainless steel lid) containing autoclaved sawdust - Diet (e.g. ad libitum): free access to SSNIFF R/M-H pelleted maintenance diet - Water (e.g. ad libitum): free access to bottles containing tap water (filtered with a 0.22 µm filter) - Acclimation period: at least 4 days before the beginning of the treatment period. ENVIRONMENTAL CONDITIONS - Temperature (°C): 22 ± 2°C - Humidity (%): 50 ± 20% - Air changes (per hr): about 8 to 15 cycles/hour of filtered, non-recycled air - Photoperiod (hrs dark / hrs light): 12h/12h. IN-LIFE DATES: From: 15 February 2016 To 10 March 2016.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:Solution in the vehicle.Preparation procedure:According to a hompogeneity/stability describing the preparation procedure (stability testing) for a range of concentrations covering the lowest and highest used in this study: the test item was weighed and mixed with the required quantity of vehicle according to CiToxLAB France in house procedures. VEHICLE - Justification for use and choice of vehicle (if other than water): suitable formulation in corn oil - Concentration in vehicle: 20, 60 and 200 mg/mL - Amount of vehicle (if gavage): 5 mL/kg/day.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
High Performance Liquid Chromatography with UV detection (HPLC/UV).Once on formulations used in the first and last weeks of treatment in the study.A sample was taken from control and test item dose formulations and analyzed using the validated method.
Duration of treatment / exposure:
15 days.
Frequency of treatment:
Daily.
Duration of test:
Day 6 to Day 20 p.c.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Groups 1, 3 and 4: 24 females.Group 2: 23 females.
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose-levels were selected in agreement with the Sponsor, and are based on the results of a preliminary prenatal development study where Sprague-Dawley rats received daily the test item by gavage at 100, 300 or 1000 mg/kg/day from Days 6 to 20 p.c. in the same vehicle. There were no adverse findings in this preliminary study at any dose-level. Therefore, the same dose-levels were selected in the present study.- Rationale for animal assignment: computerized stratification procedure.

Examinations

Maternal examinations:
MORTALITY AND MORBIDITY: Yes - Time schedule: Each animal was checked for mortality and morbidity once a day before the treatment period and at least twice a day during the treatment period, including weekends and public holidays.CLINICAL OBSERVATIONS: Yes - Time schedule: From arrival, each animal was observed once a day as part of the routine examinations.From the start of the treatment period, each animal was observed once a day, at approximately the same time of day, for the recording of clinical signs. BODY WEIGHT: Yes - Time schedule: The body weight of each female was recorded on Days 2, 4, 6, 9, 12, 15, 18 and 21 p.c. FOOD CONSUMPTION: Yes - Time schedule: The quantity of food consumed by each female was recorded for the following intervals: Days 2-4, 4-6, 6-9, 9-12, 12-15, 15-18 and 18-21 p.c. POST-MORTEM EXAMINATIONS: Yes - Sacrifice on gestation Day 21 - Organs examined: principal thoracic and abdominal organs and the weight of the gravid uterus. OTHER:
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes Examinations included:- Number of corpora lutea: Yes- 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: approximately half of the fetuses in each litter- Skeletal examinations: approximately half of the fetuses in each litter- Head examinations: approximately half of the fetuses in each litter- Other: number dead and live, body weight, sex.
Statistics:
Data were compared by one-way analysis of variance and Dunnett test (mean values being considered as normally distributed and variances being considered as homogeneous) or by Fisher exact probability test (proportions).
Indices:
% Pre-implantation loss: 100 * (Number of corpora lutea - Number of implantations) / Number of corpora lutea% Post-implantation loss: 100 * (Number of implantations sites - Number of live fetuses) / Number of implantation sites

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
At 1000 mg/kg/day, ptyalism, observed in 21/22 pregnant females for 2 days to the entire treatment period, was considered to be related to the test item treatment and of minor toxicological significance. At 100 and 300 mg/kg/day, there were no test item-related clinical signs. Clinical signs recorded at these dose-levels (reflux at dosing, ptyalism and/or reddish vaginal discharge) were noted in comparable incidences with controls.
The summary table is enclosed to this RSS in table 1 in the following attached file: 106-79-6 OECD 414 rat_summary tables.pdf.
Mortality:
no mortality observed
Description (incidence):
There were no premature deaths.
The summary table is enclosed to this RSS in table 1 in the following attached file: 106-79-6 OECD 414 rat_summary tables.pdf.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There were no effects on mean body weight and mean body weight change at any dose-levels.
The summary tables are enclosed to this RSS in tables 2, 3 and 4 in the following attached file: 106-79-6 OECD 414 rat_summary tables.pdf.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no effects on mean food consumption at any dose-levels.The high food consumption noted for one control female from Days 12 to 15 p.c. (about three times more than the other control females at the same period) was considered to be an aberrant value.
The summary table is enclosed to this RSS in table 5 in the following attached file: 106-79-6 OECD 414 rat_summary tables.pdf.
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):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no necropsy findings considered to be test item treatment-related (no dose-relationship or isolated finding).
The summary table is enclosed to this RSS in table 6 in the following attached file: 106-79-6 OECD 414 rat_summary tables.pdf.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
The summary table is enclosed to this RSS in table 7 in the following attached file: 106-79-6 OECD 414 rat_summary tables.pdf.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
When compared with controls, higher mean pre-implantation losses noted at 100 and 1000 mg/kg/day were not ascribed to the test item treatment as treatment started after implantation (implantation completed in rats on Day 6 p.c.). Slightly higher mean post-implantation loss at 1000 mg/kg/day was considered to be incidental (no statistical significance, increase due to 2/22 dams which also had a high pre-implantation loss and thus less implantation sites).
The summary table is enclosed to this RSS in table 7 in the following attached file: 106-79-6 OECD 414 rat_summary tables.pdf.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
The summary table is enclosed to this RSS in table 7 in the following attached file: 106-79-6 OECD 414 rat_summary tables.pdf.
Early or late resorptions:
no effects observed
Description (incidence and severity):
The summary table is enclosed to this RSS in table 7 in the following attached file: 106-79-6 OECD 414 rat_summary tables.pdf.
Dead fetuses:
no effects observed
Description (incidence and severity):
The summary table is enclosed to this RSS in table 7 in the following attached file: 106-79-6 OECD 414 rat_summary tables.pdf.
Changes in pregnancy duration:
not examined
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
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): The summary table is enclosed to this RSS in table 7 in the following attached file: 106-79-6 OECD 414 rat_summary tables.pdf.
Changes in number of pregnant:
not examined

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
clinical signs
Remarks on result:
other: no relevant effect observed at the top dose
Remarks:
no relevant effect observed at the top dose

Maternal abnormalities

Abnormalities:
not specified

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
There were no test item-related effects on mean fetal body weight.
The summary table is enclosed to this RSS in table 7 in the following attached file: 106-79-6 OECD 414 rat_summary tables.pdf.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
The summary table is enclosed to this RSS in table 7 in the following attached file: 106-79-6 OECD 414 rat_summary tables.pdf.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
There were no test item-related effects on mean sex ratio.
The summary table is enclosed to this RSS in table 7 in the following attached file: 106-79-6 OECD 414 rat_summary tables.pdf.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
The summary table is enclosed to this RSS in table 7 in the following attached file: 106-79-6 OECD 414 rat_summary tables.pdf.
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were no external variations.The only fetal external malformation was an anasarca (generalized edema) in one litter at 100 mg/kg/day. In absence of dose-relationship and as this finding was in an isolated incidence, it was not attributed to the test item treatment.
The summary tables are enclosed to this RSS in tables 8 and 9 in the following attached file: 106-79-6 OECD 414 rat_summary tables.pdf.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Cartilages of unossified or incomplete/bipartite ossification of bones were present, with the following exceptions:- a bipartite centrum of one thoracic vertebra in one litter of each group treated at 0 or 1000 mg/kg/day, - a 13th rib in one litter at 300 mg/kg/day (leading to a short rib).These findings being isolated and/or also noted in a control litter, they were not attributed to the test item treatment.At 1000 mg/kg/day, there were higher incidences of litters with fetuses having dumbbell ossification of thoracic vertebra(e) centrum and/or unossified distal phalanx of hindpaw and/or forepaw. As the variations from controls were generally slight and not statistically significant, and in absence of effects on mean fetal body weight, these tendencies were considered to be of no toxicological significance.The other skeletal variations were not considered to be test item treatment-related (they were noted in comparable or lower incidence than in controls or historical control data, were noted in isolated occurrence and/or were not dose-related).There were no fetal skeletal malformations in test item-treated groups.
The summary tables are enclosed to this RSS in tables 12, 13 and 14 in the following attached file: 106-79-6 OECD 414 rat_summary tables.pdf.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were no fetal soft tissue variations considered to be test item treatment-related. The variations noted in test item groups were of comparable incidence of controls (of the current study or of recent similar studies), isolated and/or not dose-related.These malformations were noted in isolated fetuses, at different dose-levels and on different organs. Right sided aortic arch has already been observed spontaneously in our laboratory (in a control fetus of Historical control data of 2012) and the variation: dilatation of one lateral cerebral ventricle was noted in one control fetus in this study remaining the malformation noted at 1000 mg/kg/day. Therefore, a relationship of these malformations with the test item treatment was considered unlikely.
The summary tables are enclosed to this RSS in tables 10 and 11 in the following attached file: 106-79-6 OECD 414 rat_summary tables.pdf.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The test item, Dimethyl Sebacate, was administered by gavage, once daily, from Days 6 to 20 p.c. inclusive, to pregnant Sprague-Dawley rats at dosages of 100, 300 and 1000 mg/kg/day.Under the experimental conditions and results of this study:- the No Observed Adverse Effect Level (NOAEL) for maternal parameters was considered to be 1000 mg/kg/day in absence of adverse effects in the dams, - the NOAEL for embryo-fetal development was considered to be 1000 mg/kg/day in absence of adverse effects in the litters,- the test item did not elicit a teratogenic potential.
Executive summary:

The objective of this GLP study was to evaluate the potential toxic effectsof the test item, Dimethyl Sebacate, on the pregnant female and on embryonic and fetal development, following daily oral administration (gavage) to pregnant female rats from implantation to the day before scheduled hysterectomy [Day 6 to Day 20 post-coitum (p.c.) inclusive].

 

Methods

Three groups of 23 (one female excluded before study beginning) or 24 time-mated female Sprague-Dawley rats received the test item, Dimethyl Sebacate, at 100, 300 or 1000 mg/kg/day by oral route (gavage) once daily from Days 6 to 20 p.c. A constant dosage-volume of 5 mL/kg/day was used. Another group of 24 rats received the vehicle alone (corn oil) under the same experimental conditions, and acted as a control group.

 

Formulation concentrations were checked in the first and last weeks of treatment in the study.

 

The animals were checked daily for mortality and clinical signs. Body weight and food consumption were recorded every 2 to 3 days. On Day 21 p.c., females were sacrificed and submitted to a macroscopic post-mortem examination. Hysterectomy was performed and the numbers of corpora lutea, uterine scars, implantations, early and late resorptions, and live and dead fetuses were recorded. The fetuses were sexed, weighed and examined for external, soft tissues and skeletal (cartilages + bones) abnormalities.

 

Results

The test item concentrations analyzed were within an acceptable range of variations when compared to the nominal values and no test item was observed in the control dose formulations.

 

At 1000 mg/kg/day, ptyalism, observed in 21/22 pregnant females for 2 days up to the entire treatment period, was considered to be related to the test item treatment and of minor toxicological significance.

 

There were no premature deaths and notest item-relatedeffects onpregnancy status,mean body weight, mean body weight gain, mean food consumption, mean gravid uterus weight, mean carcass weight, mean net body weight change and mean hysterectomy data. There were no necropsy findings considered to be test item treatment-related.

 

In litters, there were no test item-related effects on mean fetal body weight or mean sex ratio.

There were no fetal external variations or skeletal malformations, and no test item-related external malformations or soft tissue variations/malformations or effects on cartilages. There were no toxicologically significant skeletal variations.

 

Conclusion

The test item, Dimethyl Sebacate, was administered by gavage, once daily, from Days 6 to 20 p.c.inclusive, to pregnant Sprague-Dawley rats at dosages of 100, 300 and 1000 mg/kg/day.

 

Under the experimental conditions and results of this study:

.         the No Observed Adverse Effect Level (NOAEL) for maternal parameters was considered to be 1000 mg/kg/day in absence of adverse effects in the dams,

.         the NOAEL for embryo-fetal development was considered to be 1000 mg/kg/day in absence of adverse effects in the litters,

.         the test item did not elicit a teratogenic potential.