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Developmental toxicity / teratogenicity

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Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
See endpoint summary for justification of read-across. Read across of the prenatal developmental toxicity study on Polysulfides was accepted by ECHA in Decision number TPE-D-2114426306-55-01/F.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
January to July 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, Germany
- Age at study initiation: 11 to 12 weeks
- Weight at study initiation: Males 296-344g Females 187-222g
- Fasting period before study: No
- Housing: individually in IVC cages (except during the mating period when two females were paired with one male), type III H, polysulphone cages
- Diet: Altromin 1324 maintenance diet ad libitum
- Water: tap water ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 45-65
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: 10 January 2013 to 15 May 2013
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test item was weighed into a tared plastic vial on a precision balance. and then dissolved in olive oil.

VEHICLE
- Justification for use and choice of vehicle: The vehicle was selected as suggested by the sponsor based on the test item’s characteristics and testing guideline
- Concentration in vehicle: 0, 25, 75, 250 mg/ml
- Amount of vehicle (if gavage): 4 ml/kg
- Lot/batch no. : BCBH9319V
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The assessment of homogeneity as well as a determination of the nominal concentration of the test item in the vehicle was performed at various intervals.
Samples for analysis of the dose formulations of the test item in the vehicle (nominal concentration) were taken from all groups in the first and last week of the study for all doses (8 samples in total).
Samples for homogeneity were taken from the top, middle and bottom of the high dose and low dose preparation. Samples were taken in the first and last week of the study (18 samples in total).
Samples for stability analysis were taken in the first week of the study, 0 hours after the preparation and another sample 6 hours after the preparation (at room temperature), from high, medium, and low dose formulations (6 samples).
From all formulation samples aliquots of 10 mL were stored at -20° C and were analysed after completion of the in-life phase of the study.
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1:2
- Length of cohabitation: not stated
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol:
Duration of treatment / exposure:
From gestational day 5 to gestational day 19 inclusive.
Frequency of treatment:
Once daily
Duration of test:
< 28 days
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The highest dose level was chosen with the aim of inducing toxic effects, but not death or severe suffering. Thereafter, a descending sequence of dose levels was selected with a view to demonstrate any dose-related response and a NOAEL.

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: gestational days 0, 5, 8, 11, 14, 17 and 20

FOOD CONSUMPTION: Yes
- Time schedule for examinations: gestational days 5, 8, 11, 14, 17 and 20


WATER CONSUMPTION: No
- Time schedule for examinations:

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: general macroscopic examination
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- 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: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
- Head examinations: Yes: [half per litter]
Statistics:
A statistical assessment of the results of the body weight, food consumption was performed by comparing values of dosed with control animals using a one-way ANOVA and a post-hoc Dunnett Test. Fetal evaluation parameters including external, visceral, craniofacial and skeletal parameters were analysed using a Chi-square test.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related clinical signs were observed in any of the treated groups. A few spontaneous clinical signs, including alopecia on the front leg (1/25 in control and LD, 2/25 in MD) or abdomen (1/25 in Control, LD and MD) and moderate salivation (1/25 in LD), occurred infrequently, similarly in the control group, and/or in a manner that was not dose-related. In addition, one animal from control group was littered on GD 19. These various clinical signs in the treatment and control groups were not considered to be test item-related.
Mortality:
no mortality observed
Description (incidence):
All animals survived to the scheduled necropsy.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weight and body weight gain were unaffected by test item administration during gestation with the exception of a statistically significant increase in body weight gain during gestation day interval 17-20 in LD and HD groups when compared with controls.
Throughout the treatment period, body weights and body weight gain were within the normal range of variation for this strain.
No statistically significant treatment-related effects were observed for terminal body weight or adjusted maternal weight.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No treatment-related effect on food consumption was observed during the treatment period.
Food consumption increased during the course of the study in all groups, consistent with the increases seen in body weight and body weight gain.
Food efficiency:
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:
no effects observed
Description (incidence and severity):
No statistically significant treatment-related effects were observed for gravid uterine weight.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment-related changes were observed during the macroscopic observation for all groups. One animal from LD group showed gaseous distension of colon, rectum and anus. This gross pathological lesion was considered to be spontaneous/ incidental in nature.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
No statistically significant treatment-related effects were observed for terminal implantations or percent preimplantation loss. No statistically significant treatment-related effects were observed for post implantation loss.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
No statistically significant treatment-related effects were observed for group mean number of resorptions.
Early or late resorptions:
no effects observed
Description (incidence and severity):
No statistically significant treatment-related effects were observed for group mean number of resorptions.
Dead fetuses:
no effects observed
Description (incidence and severity):
No statistically significant treatment-related effects were observed for group mean number of live fetuses and dead fetuses.
Changes in pregnancy duration:
effects observed, non-treatment-related
Description (incidence and severity):
Animal 17 from control group was littered on GD 19 before terminal sacrifice and therefore excluded from the study. No statistically significant treatment-related effects were observed for any treatment group.
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Successful mating resulted in 23/25 pregnancies in the control, 24/25 pregnancies in LD groups, 25/25 pregnancies in MD and 24/25 pregnancies in HD groups. Pregnancy rate (No. of pregnancies achieved /No. of females mated or sperm positive x 100) was comparable) in treatment groups LD (96 %), MD (100 %) and HD (96 %) was comparable to control group (92%). The marginal difference in pregnancy rate between the groups including control was considered to be a biological variation and of no toxicological relevance.
Other effects:
no effects observed
Description (incidence and severity):
No statistically significant treatment-related effects were observed for number of corpora.
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
No statistically significant treatment-related effects were observed for group mean number of live fetuses and dead fetuses.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
No statistically significant treatment-related effects were observed for male and female fetuses or sex ratio.
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Fetal external examination on the day of terminal sacrifice revealed domed head in one fetus of the LD group. No external treatment-related effects were observed in any of the other treated or control group fetuses or the remaining fetuses from LD dose group.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Skeletal examination of the Alizarin red stained fetuses revealed a range of findings which were of a type or which occurred at an incidence comparable/lower in treated groups compared to controls. However, a statistically significant increase in the incidence of incomplete ossification of frontal skull in MD and HD, interparietal skull in LD and MD, parietal skull in LD, MD and HD, 1st sternebra in LD, 4th Sternebra in LD and HD and xiphoid in LD was observed when compared with controls. There were also statistically significant increase in the incidence of unossified 4th metacarpal (B) in LD, all forelimb phalanx (B) in LD and MD, all hind limb phalanx (B) in LD and HD, 1st metatarsal (B) in LD and HD and statistically significant decrease in fused parietal and frontal skull in LD, MD and HD was observed when compared with controls. There were also a few skeletal findings including 14th rudimentary rib (B), 14th full rib (B), unossified 1st forelimb phalanx (B), unossified 4th forelimb phalanx (B), incomplete ossification of Supraoccipital and sphenoid body which occurred in incidence higher in the treatment groups than in the controls. However, statistical significance was not achieved for these findings.
As these skeletal findings were minor variations and due to the lack of dose dependency and consistency in these findings indicates no treatment-related adverse effects. There was no indication of a test item-related trend in the type and incidences of other findings and they were, therefore, considered to be spontaneous in nature.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Internal observation of the fetal viscera by free hand microdissection technique revealed a range of visceral findings in all groups including control. However, there was a statistically significant increase in hemorrhagic bladder wall and convoluted right ureter in the MD group and statistically significant decrease in hemorrhagic heart in LD and extra tissue at median liver lobe in LD and HD was observed when compared with controls. The remaining visceral findings observed in the treated groups were in frequencies comparable, slightly higher or even less in numbers compared to controls. As observed findings are minor variations, due to lack of dose dependency and therefore no serious toxicological significance can be attributed to these findings and they are considered to be spontaneous in nature.
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Craniofacial examination by a razor blade serial sectioning technique revealed a range of visceral findings in all groups including controls. Statistical analysis of the data revealed a statistically significant decrease in the incidence of hemorrhagic ear - cochlea (B) in HD and slightly enlarged lateral ventricles (B) in MD group when compared with controls. Since, these findings were considered to be minor variations and frequencies were even less in numbers compared to controls. Therefore, these findings are not to be considered as treatment-related and solely spontaneous in nature.
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No findings attributable to treatment at any dose.
Abnormalities:
no effects observed
Developmental effects observed:
no

Concentration analysis of formulation samples was determined in study week 1 and 8 for all dose groups. The mean recoveries observed in LD, MD and HD groups were 97.9%, 109.4% and 112.9% of the nominal concentration, respectively.

Stability of formulation samples was investigated in study week 1 for all dose groups. After 6 hours storage at -20°C recovery compared to starting value was for LD and MD dose groups 101.0% and for HD dose group 100.0%.

Homogeneity of formulation samples was determined in study week 1 and 8 for all dose groups. The mean recoveries observed for LD dose group were 91.8 and 90.7% of the nominal value, for MD dose group 108.3 and 96.9% of the nominal value, and 113.2 and 107.3% for HD dose group. The coefficients of variation of the different sampling locations (top, middle, bottom) were 1.8 and 2.7% in LD dose group, 1.5 and 2.5% in MD dose group and 0.7 and 2.4% in HD dose group.

Conclusions:
The oral administration of bis[3-(triethoxysilyl)propyl]polysulfide to pregnant female Wistar rats at doses of 100, 300 or 1000 mg/kg from gestation day 5 to 19 did not result in any maternal effects or findings in the fetuses.

The No Observed Adverse Effect Level for both maternal toxicity and fetal toxicity of bis[3-(triethoxysilyl)propyl]polysulfide in Wistar rats was 1000 mg/kg bw/day.
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
23/06/2015 to 05/10/2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, 97633 Sulzfeld, Germany.
- Age at study initiation: Females: 11-12 weeks old; Males: 12-13 weeks old.
- Weight at study initiation: Females: 200 - 244 g; Males: 304 - 351 g.
- Fasting period before study:
- Housing: The animals were kept individually in type III H, polysulphone cages on Altromin saw fibre bedding (except during the pre-mating period when females were kept in groups of two animals and during mating period when two females were paired with one male)
- Diet (e.g. ad libitum): Ad libitum.
- Water (e.g. ad libitum): Ad libitum.
- Acclimation period: At least five days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 29-25
- Humidity (%): 45-65
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 18/06/2015 To: No data.
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test item was weighed into a tared plastic vial on a suitable precision balance and the vehicle was added to give the appropriate final concentration of the test item plus further vortexing for 2-3 minutes. Homogeneity of the test item in the vehicle was maintained by vortexing the prepared formulation thoroughly before every dose administration. The test item formulation was prepared freshly on each administration day before the administration procedure.

VEHICLE
- Justification for use and choice of vehicle (if other than water): The vehicle was selected based on the test item characteristics and testing guideline.
- Lot/batch no. (if required): BCBM3643V.
- Purity: No data.
- Concentration in vehicle: 0, 25, 75 and 250 mg/l.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples for analysis of concentration of test item in the dosing formulations were taken on the first (treatment day 1), third and last week of the study for all doses (12 samples in total). Samples for homogeneity were taken from the top, middle and bottom of the high dose and low dose preparation. Samples were taken in the first (treatment day 1), third and last week of the study (18 samples in total). These samples were either measured within 6 hours after arrival at the analytical department on the day of sampling (week 3 and last week samples) or were stored under appropriate conditions (-15 to -35°C) for 16 days until analysis (week 1 samples).
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:2
- Length of cohabitation: No data.
- Matings were continued until 100 'sperm positive' females were obtained.
- Further matings after two unsuccessful attempts: No data.
- Verification of same strain and source of both sexes: yes.
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy.
Duration of treatment / exposure:
15 days (gestation days 5-19)
Frequency of treatment:
Daily
Duration of test:
15 days
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
25 'sperm positive' females.
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Doses were based on the results of a dose-range finding study. The highest dose level was chosen with the aim of inducing toxic effects, but not death or severe suffering. Thereafter, a descending sequence of dose levels was selected with a view to demonstrate any dose-related response and a NOAEL.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least once per day. Twice daily all animals checked for mortality and morbidity. Clinical observations included spontaneous activity, lethargy, recumbent position, convulsions, tremors, apnoea, asphyxia, vocalisation, diarrhoea, changes in the skin and fur, eyes and mucous membranes (salivation, discharge), piloerection and pupil size. Changes in gait, posture, response to handling as well as the presence of clonic or tonic movements, stereotypes, difficult or prolonged parturition or bizarre behaviour were recorded.

BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed once before initiation of pairing to ensure that the body weights were within + 20% variation. The sperm positive females were weighed on gestations days 0, 5, 8, 11, 14, 17 and 20.

FOOD CONSUMPTION: Gestations days 5, 8, 11, 14, 17 and 20.

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20. The animals were examined macroscopically for structural abnormalities or pathological changes.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus (with cervix) weight: Yes
- 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 fetuses in each litter.
- Soft tissue examinations: Yes: half fetuses per litter.
- Skeletal examinations: Yes: half fetuses per litter.
- Head examinations: Yes: half fetuses per litter (from soft tissue examination).
Statistics:
A statistical assessment of the results of the body weight and food consumption was performed by comparing values of dosed with control animals using a one-way ANOVA and a post-hoc Dunnett Test. Fetal evaluation parameters like external, visceral, craniofacial and skeletal parameters were analysed using Fisher’s exact test. The statistics were performed with GraphPad Prism V.6.01 software (p<0.05 is considered as statistically significant).
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
There were no clinical signs of toxicological relevance in the dose groups when compared to the control group.
Low incidences of the slight clinical sign alopecia were noted in isolated females of the dose groups and the control group. This finding was considered incidental.
Moving the bedding was noted in five females of the HD group on few treatment days. Salivation was observed in one single female of the HD group on one occasion. These transient findings were noted shortly after administration and were considered to be signs of discomfort without toxicological relevance.
After littering on study day 19, female no. 23 of the control group was discarded without further observations. None of the females showed signs of abortion prior to the scheduled sacrifice.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
No mortality occurred in the control or any of the dose groups during the treatment period of this study.
One animal (no. 23 of the control group) was euthanised on study day 19 due to littering before the scheduled sacrifice. This was considered as incidental in nature.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The mean body weight increased with the progress of the study in the control, the LD, the MD and the HD group.
There were no test item-related effects of toxicological relevance noted for body weight and body weight gain. Throughout the treatment period, body weights were within the normal range of variation for this strain.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
When compared to the control group, the mean food consumption was statistically significantly lower for day 0-20 in the MD group (92%) and the HD group (93%). Statistically significantly lower food consumption was also seen on gestation day 11-14 in the MD and the HD group and gestation day 14-17 in the MD group. As differences to the control group were marginal and did not have impact on the mean body weights in either group, the lower food consumption was not considered adverse.
Food efficiency:
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:
no effects observed
Description (incidence and severity):
Prenatal parameters like group mean gravid uterus weight remained unaffected in the dose groups when compared to the control group.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No gross pathological changes of toxicological relevance were observed during the macroscopic examination of the females of any group.
A single incidence of dark spots at the liver in one female of the LD group was not assumed to be test item-related.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Prenatal parameters like group mean implantation sites and percent pre- and post-implantation loss remained unaffected in the dose groups when compared to the control group.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Description (incidence and severity):
Prenatal parameters like group mean early and late resorptions remained unaffected in the dose groups when compared to the control group.
Dead fetuses:
no effects observed
Description (incidence and severity):
No dead foetuses were noted in any of the groups.
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Prenatal parameters like group mean number of foetuses in each uterine horn remained unaffected in the dose groups when compared to the control group.
Successful mating resulted in 20/25 pregnancies in the low dose group, 22/25 in the mid dose group and 22/25 in the high dose group compared to 19/25 pregnancies in the control group. Low pregnancy rate (no. of pregnancies / no. of females mated or sperm positive x 100) of 76 % in the control group was considered to be a biological variation.
Other effects:
no effects observed
Description (incidence and severity):
Prenatal parameters like group mean number of corpora lutea remained unaffected in the dose groups when compared to the control group.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
There were no test substance-related effects of toxicological relevance for the total litter weight and male and female litter weight.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
The number of live fetuses was unaffected in the dose groups when compared to the control group. No dead fetuses were noted in any of the groups.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The number of male and female fetuses, sex ratio, number of fetuses in each uterine horn were unaffected in the dose groups when compared to the control group.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
There were no test substance-related effects of toxicological relevance for the total litter weight and male and female litter weight.
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The statistical analysis revealed no significant differences between the dose groups and the control group. However, the malformation of an absent left eye was observed in one foetus of female no. 82 of the HD group. Accordingly left-sided anophthalmia was seen at the time of craniofacial examination. With only one individual foetus being affected, this finding was considered as incidental. Besides, two foetuses of the control group and one foetus of the LD group were noted with malrotated right hindlegs at the time of external examination. By skeletal examination, no corresponding abnormality was seen. Discoloured red eye and an umbilical hernia were noted in each one foetus of the LD group. As these findings were observed only in single foetuses, they were considered to be incidental in nature and unrelated to the treatment.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Craniofacial examination
Craniofacial examination by razor blade serial sectioning technique revealed few abnormalities in all groups including control. Statistical analysis of litter incidences revealed no statistical significance of any of the findings.
Retinal folds and dilated third and lateral ventricles were observed at frequencies comparable to the control group and were considered spontaneous in nature.
Anophthalmia was noted in one foetus of female no. 82 of the HD group. With just one single foetus being affected, this finding was considered incidental and not related to the treatment with the test item.
Skeletal examination
Skeletal examination of the Alizarin red stained foetuses revealed a range of findings which occurred at an incidence generally comparable to or slightly lower or higher in the dose groups when compared to the control group.
A statistically significant decrease in litter incidence for incomplete ossification of interparietal bone in the HD group compared to the control group was considered to be incidental. Significantly higher litter incidence of 14th rudimentary rib (bilateral) was seen without dose dependency in the MD group when compared to the control group and was not considered as an effect of the test item.
There was no statistical significance and no indication of a test item-related trend in the type and incidences of other skeletal findings and they were therefore considered to be spontaneous in nature.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Internal observation of the foetal viscera by free hand microdissection technique revealed a range of visceral findings in all groups including control.
Visceral findings observed in the dose groups were at frequencies generally comparable to or in some cases slightly higher or lower in frequency compared to controls. As observed findings were either minor variations and/or due to a lack of dose dependency and consistency, no serious toxicological significance can be attributed to these findings and they were considered to be spontaneous in nature. Litter incidences were statistically insignificant except for peritoneal cavity filled with red/dark fluid which was observed at lower frequencies in the MD and the HD group in comparison to the control group. Thus, this finding was considered incidental.
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 adverse findings for developmental toxicity
Abnormalities:
no effects observed
Developmental effects observed:
no
Conclusions:
In a Prenatal Developmental Toxicity study (BSL Bioservice, 2016) conducted to OECD Test Guideline 414 and in compliance with GLP 4,4,13,13-tetraethoxy-3,14-dioxa-8,9-dithia-4,13-disilahexadecane did not induce maternal toxicity or developmental toxicity at doses up to 1000 mg/kg bw/day. Therefore the NOAEL for this study was at least 1000 mg/kg bw/day.

Data source

Materials and methods

Test material

Constituent 1
Chemical structure
Reference substance name:
4,4,13,13-tetraethoxy-3,14-dioxa-8,9-dithia-4,13-disilahexadecane
EC Number:
260-350-7
EC Name:
4,4,13,13-tetraethoxy-3,14-dioxa-8,9-dithia-4,13-disilahexadecane
Cas Number:
56706-10-6
Molecular formula:
C18H42O6S2Si2
IUPAC Name:
4,4,13,13-tetraethoxy-3,14-dioxa-8,9-dithia-4,13-disilahexadecane
Constituent 2
Chemical structure
Reference substance name:
4,4,14,14-tetraethoxy-3,15-dioxa-8,9,10-trithia-4,14-disilaheptadecane
EC Number:
260-351-2
EC Name:
4,4,14,14-tetraethoxy-3,15-dioxa-8,9,10-trithia-4,14-disilaheptadecane
Cas Number:
56706-11-7
Molecular formula:
C18H42O6S3Si2
IUPAC Name:
4,4,14,14-tetraethoxy-3,15-dioxa-8,9,10-trithia-4,14-disilaheptadecane

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: No adverse effects attributable to test substance treatment.

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects attributable to test substance treatment.

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

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