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Toxicity to reproduction

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extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
data waiving: supporting information

According to ECHA decision number TPE-D-2114425282-58-01/F, there is an ongoing sub-chronic repeated dose toxicity study with the registration substance, conducted according to OECD TG 408 and in compliance with GLP. The study will be submitted as soon as possible once the final report is available.

Endpoint conclusion:
no study available (further information necessary)
Endpoint conclusion:
no study available
Endpoint conclusion:
adverse effect observed
Dose descriptor:
15 mg/m³
Study duration:
Quality of whole database:
The study was well documented and meets generally accepted scientific principles, and conducted in compliance with GLP. The relevance of these data for hazard assessment of Dichloro(diphenyl)silane is discussed in the endpoint summary.
Endpoint conclusion:
no study available
Endpoint conclusion:
no study available

Oral Route

According to ECHA decision number TPE-D-2114425282-58-01/F, there is an ongoing sub-chronic repeated dose toxicity study with the registration substance, conducted according to OECD TG 408 and in compliance with GLP. The study will be submitted as soon as possible once the final report is available.

Inhalation route

Dichloro(diphenyl)silane (CAS 80-10-4) is a highly moisture-sensitive liquid that hydrolyses rapidly in contact with water (measuredhalf-life of 6 to 10 seconds at pH 4, 7 and 9 at 1.5°C) to diphenylsilanediol and hydrogen chloride (HCl). Hydrolysis is complete within few minutes.

There are no specific data for respiratory irritation, however the key acute inhalation study revealed signs of respiratory irritation/corrosion. Therefore 'EUH071 Corrosive to the respiratory tract' (1272/2008) is proposed in accordance with these data and those of related chlorosilane substances, based on the expected respiratory tract damage caused by the hydrolysis product HCl.

In a 90-day repeated dose inhalation study in rats and mice (Toxigenics, 1984), 31 males and 21 females of each species/strain were exposed to test concentrations of 0, 10, 20 and 50 ppm hydrogen chloride gas (HCl). Treatment was whole-body exposure for six hour per day, 5 days per week. 15 males and 10 females from each group were sacrificed after four exposures and the nasal turbinates, trachea, lung and gross lesions were examined microscopically. In general, all animals in the high dose group showed adverse findings after 4-days exposure. One female high dose mouse was found dead on study day 12, and four low dose male mice were found dead on study day 92. In addition, one high dose female mouse was sacrificed in extremis on study day 20. One high dose female Sprague-Dawley rat was found dead on study day 4. However, the study authors noted that the deaths did not appear to be related to exposure to HCl. Clinical signs were consistent with the irritant/corrosive properties of HCl (appendage, tail or lip injury in the form of toe missing/swollen/open/ gelatinous, scabbed/deformed/lesion, crusty nose, tissue mass, mouth injury, scabbed nose, crusty muzzle, red stained fur, nasal discharge, crusty eye, poor coat quality); some of the observed injuries may have been mechanical and not related to test material exposure. 90-days exposure to 50 ppm HCl resulted in decreased body weights in all four strains after four exposures. Following 90 days of exposure B6C3F1 male and female mice and male Sprague-Dawley rats exposed to 50 ppm had biologically significant decreases in body weight. After four days of exposure there were statistically significant decreases in food consumption for high dose male Sprague-Dawley rats and male Fischer 344 rats. After 90 days high dose mice had the largest reduction in food consumption. The rats did not show a consistent reduction in food consumption that could be deemed exposure-related. There were no treatment-related effects on the haematology, clinical chemistry or urinalyis parameters that were examined. Decreased liver weights were observed in high dose male and female mice and Fischer 344 female rats. The authors noted that this might have been due to the overall reduced body weights. Animals exposed to all concentrations of HCl had minimal to mild rhinitis, which occurred in the anterior portion of the nasal cavity and was dose and time related. Mice also developed varying degrees of cheilitis with accumulations of haemosiderin-laden macrophages involving the perioral tissues at 50 ppm. At all exposure concentrations mice developed oesinophilic globules in epithelial cells lining the nasal turbinates after 90 days of exposure.

The No Observed Adverse Effect Concentration (NOAEC) for systemic effects was determined to be 20 ppm (approximately 30 mg/m3) based on decreased body weight following exposure to 50 ppm. No NOAEC for local effects was established as irritant/corrosive effects were observed at all dose levels tested.

With regard to the inhalation route of exposure, a guideline-compliant repeated-dose inhalation study should elicit systemic toxicity at the highest test concentration. Since the local corrosive effects of chlorosilanes would be significant, a valid inhalation study according to the relevant guidelines is technically not feasible. It is also unlikely that any systemic effects would be seen at dose levels made sufficiently low to prevent the known corrosive effects and/or distress in the test species, which also applies for oral studies. This hypothesis has been confirmed in a 28-day inhalation study with a chlorosilane, dichloro(dimethyl)silane (CAS 75-78-5, WIL, 2014). In this 4-week repeated dose study inhalation administration of dichloro(dimethyl)silane at targeted concentrations of 5 or 25 ppm (26 or 132 mg/m³) or hydrogen chloride at 50 ppm (75 mg/m³) to rats for 5 days per week for 4 weeks resulted in subacute inflammation, hyperplasia and/or hyperkeratosis of the squamous epithelium and mucous cell hyperplasia of the respiratory epithelium in the anterior nasal cavity. There was a clear dose-relationship in incidence and severity between the 26 or 132 mg/m³ dichloro(dimethyl)silane groups for the majority of findings. Exposure to 132 mg/m³ dichloro(dimethyl)silane or 75 mg/m³ hydrogen chloride was also associated with interstitial oedema and respiratory epithelial degeneration within the anterior nasal cavity and acute inflammation in the larynx. Generally the incidence and severity of effects were similar in the 132 mg/m³ dichloro(dimethyl)silane and 75 mg/m³ hydrogen chloride groups, or greater in the hydrogen chloride group. The incidence and severity of the effects in the hydrogen chloride exposed group were generally comparable to those noted in the 90-day inhalation study with hydrogen chloride (Toxigenics, 1983). Overall, the histopathology observations in the nasal cavity did not suggest a greater irritant effect for the 132 mg/m³ dichloro(dimethyl)silane group compared with the 75 mg/m³ hydrogen chloride group.

It is therefore concluded that hydrogen chloride will dominate the inhalation toxicity profile of chlorosilanes. Based on these conclusive data, repeated dose animal studies via the inhalation route with chlorosilanes are not considered to be ethically justifiable.

The available acute inhalation toxicity studies with chlorosilanes all meet the criteria for classification as either acutely toxic or harmful (LC50 below 20 mg/L with deaths occurring minutes after start of exposure). The local effects and mortalities observed in the studies can be attributed to hydrogen chloride (hydrolysis of the parent chlorosilanes would occur rapidly when inhaled, even if a mixture of parent and hydrolysis products were present in air) (Jean et al. 2006). The mortalities associated with the severe corrosive nature of chlorosilanes (rather than a systemic effect) have been confirmed by the findings from studies for at least fourteen chlorosilanes, which were performed according to the respective OECD guideline. In these studies, severe corrosive effects were observed even after short exposure times (e.g. 1 hour). The most common observations were respiratory irritation (labored breathing, rales, gasping and necrosis of the nose), dermal irritation, ocular effects (corneal opacities, lacrimation) as well as red/brown staining around the snout and/or eyes and scabs on snout. Substances causing these effects include the following: dichloro(methyl)(vinyl)silane (CAS 124-70-9), dichloro(dimethyl)silane (CAS 75-78-5), dichloro(methyl)silane (CAS 75-54-7), trichloro(vinyl)silane (CAS 75-94-5), chlorotri(3-methyl-propyl)silane (CAS 13154-25-1) or trichloro(methyl)silane (CAS 75-79-6). Most of the above mentioned indicators of toxicity showed marked resolution in those animals which survived to the end of the recovery period. Macroscopic observation of the animals also revealed lung injury (consolidation, haemorrhage, congestion, and ectasia), red or dark red discoloration of the lungs, fluid-filled pleural and thoracic cavities and trachea, periocular and perinasal encrustations and eye abnormalities. Substances causing the above macroscopic observations include the following: dichloro(dimethyl)silane (CAS 75-78-5), dichloro(methyl)(vinyl)silane (CAS 124-70-9), trichloro(vinyl)silane (CAS 75-94-5), dichloro(methyl)silane (CAS 75-54-7), trichloro(propyl)silane (CAS 141-57-1), chlorotrimethylsilane (CAS 75-77-4), chlorodimethylsilane (CAS 1066-35-9) or dichlorosilane (CAS 4109-96-0).The typical effects associated with exposure to corrosive substances were observed in the acute studies.

Overall, given the comparability of existing results for chlorosilanes and HCl, and the rapid hydrolysis of chlorosilanes in the atmosphere, the effects of HCl dominate local toxicity on the respiratory tract and therefore data for HCl can be used to assess the local repeated-dose toxicity of chlorosilanes.

In the absence of appropriate measured data, the substance is not classified for repeated dose toxicity.

Reason / purpose for cross-reference:
data waiving: supporting information
developmental toxicity
Data waiving:
other justification
Justification for data waiving:
according to guideline
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
25 June 2018
GLP compliance:
yes (incl. QA statement)
Limit test:
Crl: WI(Han)
Details on test animals or test system and environmental conditions:
- Source: Charles River, 97633 Sulzfeld, Germany
- Age at study initiation: approx. 11-12 weeks old for females; between 12 weeks and not older than 24 weeks for males
- Weight at study initiation:
- Housing: Housed individually in IVC cages on saw fibre bedding (except during the pre-mating period when females will be kept in groups of two animals and during mating period when two females will be paired with one male)
- Diet: Altromin 1324 maintenance diet for rats and mice provided ad libitum
- Water: Tap water, sulphur acidified to a pH of approximately 2.8 provided ad libitum
- Acclimation period: At least 5 days

- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 10
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark
Route of administration:
oral: gavage
corn oil
Details on exposure:
The test item was weighed into a tared plastic vial and the vehicle was added to give the appropriate final concentration of the test item. The formulation was vortexed and/or stirred until visual homogeneity was achieved. Formulates were constantly stirred until daily administration. The test item formulation were prepared freshly on each administration day before the administration procedure and administered directly after its preparation. The vehicle was used as control item.

- Justification for use and choice of vehicle:
The vehicle was selected in consultation with the sponsor based on the test item’s characteristics.
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Before beginning of the treatment period, formulation samples were prepared and analysed in order to obtain knowledge about stability and homogeneity of the test item.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:2
- Length of cohabitation: Females were paired for cohabitation in batches in order to control the number of animals for terminal sacrifice on a particular day. After getting 92 sperm positive females, the remaining females and males will be discarded without any observations.
- 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:
From gestation day (GD) 5 until GD 19
Frequency of treatment:
7 days per week
Duration of test:
From GD 5 until GD 20
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
200 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
20 pregnant females per group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: On the basis of a 14-day dose range finding study with dichloro(diphenyl)silane (CAS RN 80-10-4) in male and female Wistar rats with dose levels of 25, 50, 100, 500 and 375 mg/kg bw/day the following conclusions can be made: Mortality occurred in 2/2 males and 2/2 females at the dose of 500 mg/kg bw/day and 1/2 females at 375 mg/kg bw/day. Inflammatory lesions in stomach, small and large intestine were considered as the cause of morbidity. Adverse clinical signs were observed at 500 mg/kg bw/day in both males and females including, increased salivation (slight), apathy, hypotonia (muscle), reduced spontaneous activity (slight/severe), slow movements, piloerection (moderate) and half eyelid close (both), hypothermia, lacrimation (left) on treatment days. No treatment-related mortality or marked clinical signs were observed at up to 100 mg/kg bw/day. Treatment did not affect the body weight gain at up to 100 mg/kg bw/day in males and females and body weight was comparable to the respective controls. Test item-related gross lesions were noted in the stomach, small and large intestine at ≥375 mg/kg bw/day and these were evident during the histopathological examination. The test item caused inflammatory and degenerative findings in the stomach of animals at 375 and 500 mg/kg bw/day. Based on the histopathological data, the NOAEL was established at 100 mg/kg bw/day.
- Rationale for animal assignment (if not random): Females were assigned to the experimental groups with achieving a most homogenous variation in body weight throughout the groups (randomisation will be performed with IDBS Workbook 10.1.2 software).
Maternal examinations:
- Time schedule: General clinical observations were made at least once a day, preferably at the same time each day. Twice daily all animals were observed for morbidity and mortality except on weekends and public holidays when observations were made once daily.
- 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, or bizarre behaviour were recorded.

- Time schedule: At least once a day

- 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 GD 0, 5, 8, 11, 14, 17 and 20. Males were not be weighed in this study except once before initiation of pairing.

FOOD CONSUMPTION (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

- Sacrifice on gestation day # 20
- Organs examined: See table 1

OTHER: Thyroid hormones levels from samples from all dams were assessed at the end of the treatment prior to or as part of the sacrifice of the animals. At termination, blood samples were collected from the defined site will be collected in serum separator tubes and obtained serum were stored at ≤-20°C. Serum samples were assessed for serum levels for thyroid hormones (T3, T4, TSH) using ELISA.
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
A statistical assessment of the results of the body weight and food consumption will be performed by comparing values of dosed animals with control animals using a one-way ANOVA and a post-hoc Dunnett Test. Results of absolute and relative organ weights, thyroid hormones and foetal evaluation parameters like external, visceral, craniofacial and skeletal parameters will be statistically analysed by comparing values of dosed with control animals using either a parametric one-way ANOVA and a post-hoc Dunnett Test or a non-parametric Kruskal-Wallis Test and a post-hoc Dunn’s Test, based on the results of homogeneity and normality tests. The statistics will be performed with GraphPad Prism V.6.01 software or Ascentos 1.3.4 software (p<0.05 is considered as statistically significant).

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion

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