Polysulfides, bis[3-(triethoxysilyl)propyl]

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

January to July 2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reaction Mass of 4,4,15,15-tetraethoxy-3,16-dioxa-8,9,10,11-tetrathia-4,15-disilaoctadecane and 4,4,14,14-tetraethoxy-3,15-dioxa-8,9,10-trithia-4,14-disilaheptadecane and 4,4,13,13-tetraethoxy-3,14-dioxa-8,9-dithia-4,13-disilahexadecane

EC Number:

915-673-4

Cas Number:

211519-85-6

Molecular formula:

For the substance, C18H42O6SnSi2 (n = 2 – 4) Constituent 1 (S2): C18H42O6S2Si2 Constituent 2 (S3): C18H42O6S3Si2 Constituent 3 (S4): C18H42O6S4Si2

IUPAC Name:

Reaction Mass of 4,4,15,15-tetraethoxy-3,16-dioxa-8,9,10,11-tetrathia-4,15-disilaoctadecane and 4,4,14,14-tetraethoxy-3,15-dioxa-8,9,10-trithia-4,14-disilaheptadecane and 4,4,13,13-tetraethoxy-3,14-dioxa-8,9-dithia-4,13-disilahexadecane

Test material form:

other: liquid

Test animals

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

Administration / exposure

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: not stated

Duration of treatment / exposure:

From gestational day 5 to gestational day 19 inclusive.

Frequency of treatment:

Once daily

Duration of test:

< 28 days

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

100 mg/kg bw/day

Remarks:

Low Dose (LD)

Doses / concentrations 2

Dose / conc.:

300 mg/kg bw/day

Remarks:

Medium Dose (MD)

Doses / concentrations 3

Dose / conc.:

1 000 mg/kg bw/day

Remarks:

High Dose (HD)

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.

Examinations

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

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's Test. Fetal evaluation parameters including external, visceral, craniofacial and skeletal parameters were analysed using a Chi-square test.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

no effects observed

Description (incidence and severity):

No test item-related clinical signs were observed in any of the treated groups compared with controls. A few spontaneous clinical signs, including alopecia on the front leg or abdomen and moderate salivation, occurred infrequently, similarly in the control group, and/or in a manner that was not dose-related.

Dermal irritation (if dermal study):

not examined

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 when compared to controls, with the exception of a statistically significant increase in body weight gain during gestation day interval 17-20 in LD and HD groups.

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 gestation compared with controls. 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

Water consumption and compound intake (if drinking water study):

not specified

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 terminal body weight, gravid uterine weight, and adjusted maternal weight.

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Maternal developmental toxicity

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

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:

no effects observed

Changes in number of pregnant:

no effects observed

Other effects:

not specified

Effect levels (maternal animals)

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: No effects attributable to treatment noted at any dose.

Maternal abnormalities

Key result

Abnormalities:

no effects observed

Results (fetuses)

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

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

no effects observed

External malformations:

no effects observed

Description (incidence and severity):

Fetal external examination on the day of terminal sacrifice revealed a 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 the LD group.

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

An 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 hindlimb 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. Due to the lack of dose dependency and consistency in these findings, these observations are not considered adverse or treatment-related.
A decrease in the incidence of hemorrhagic ear- cochlea (B) in HD and slightly enlarged lateral ventricles (B) in MD group. 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.

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

An increase in the incidence of 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. Since these visceral abnormalities were not observed to occur in a dose-response relationship, these findings were considered to be spontaneous in nature.

Other effects:

not specified

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 findings attributable to treatment noted at any dose.

Fetal abnormalities

Key result

Abnormalities:

no effects observed

Overall developmental toxicity

Key result

Developmental effects observed:

no

Applicant's summary and conclusion

Conclusions:

In a prenatal developmental toxicity study in pregnant female Wistar rats with bis[3-(triethoxysilyl)polysulfides conducted according to OECD Test Guideline 414 and in compliance with GLP, the NOAEL for maternal toxicity and fetal toxicity was concluded to be 1000 mg/kg/day based on no major toxicological findings in the females or fetuses treated orally by gavage from gestation day 5 to 19.