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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No reproductive toxicity studies are available for cyclohexyl(dimethoxy)methylsilane. No adverse effects were observed on reproductive organs or tissues in a 90-day oral repeated dose toxicity study with the analogue of the hydrolysis product dicyclopentylsilanediol (see Section 7.5 for read-across justification) at dose levels up to 1000 mg/kg bw/day (Mitubishi Chemical Safety Institute, 2000), or in a number of 28-day repeated dose toxicity studies with the cyclohexyl(dimethoxy)silane (see Section 7.5.1).

Therefore, further testing for reproductive toxicity in a screening test (OECD 421/422) or an extended-one-generation reproductive toxicity study (OECD 443) is not required.

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

In a prenatal developmental toxicity study conducted according to OECD Test Guideline 414 and in compliance with GLP, the maternal and foetal NOAEL was concluded to be at least 1000 mg/kg bw/day, the highest dose tested in rats (BSL, 2014).

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 January to 15 April 2014
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
Qualifier:
according to guideline
Guideline:
other: Commission Regulation (EC) No. 440/2008, L 142, Annex Part B of 30 May 2008
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
certificate dated 22 January 2013
Limit test:
no
Species:
rat
Strain:
other: Crl:WI(Han)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River GmbH, Germany
- Age at study initiation: 12 to 13 weeks
- Weight at study initiation: males 291 - 323g; females 191 - 221g
- Fasting period before study: no
- Housing: individually in IVC cages (type II H polysulphone) except during mating period when 2 females paired with 1 male
- Diet (ad libitum): Altromin 1324 maintenance diet for rats and mice (lot 0801)
- Water (ad libitum): facility tap water, sulphuric acid acidified to pH approximately 2.8
- 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: 17 February 2014
To: 15 April 2014
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test item was weighed into a tarred plastic vial on a precision balance.

The test item was dissolved in corn oil.

The vehicle was selected as suggested by the sponsor based on the test item’s characteristics and testing guideline. The test item and control formulations were prepared once every 10 days and stored in plastic falcon vials at 2-8 °C until the day of administration. The water content (if any) in the test item container was purged with liquid nitrogen after every use.

Homogeneity of the test item in the vehicle was maintained by vortexing the prepared formulation thoroughly before every dose administration.

VEHICLE
- Justification for use and choice of vehicle: vehicle selected based on test susbtance characterisitics
- Concentration in vehicle: 0, 25, 75, 250 mg/mL
- Amount of vehicle: 4mL/kg
- Lot/batch no.: MKBP7039V
- Expiry: 24 May 2014
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 measured concentration of the test item in the vehicle was performed at various intervals.

Samples for analysis of the measured dose formulations of the test item in the vehicle were taken 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 (12 samples in total).

Samples for stability analysis were taken in the first week of the study, 0 hours after the preparation, 6 hours after the preparation (at room temperature) and 10 days after formulation preparation (formulation stored at 2-8oC) from high and low dose formulations (6 samples in total).

All formulation samples were stored at -20° C and were analysed after completion of the in-life phase of the toxicity study at BSL BIOSERVICE Scientific Laboratories GmbH.

The B samples will be retained at BSL until the completion of the final study report and will be discarded thereafter.

The determination of formualtion concentrations was based on a GC-FID method.
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1/2
- Length of cohabitation: until positive evidence of mating
- 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 5 to gestation day 19 inclusive.
Frequency of treatment:
daily
Duration of test:
6 weeks
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:
24 females (control and low dose)
25 females (intermediate and high dose)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Since little or no toxicity was anticipated for the test substance, the highest dose level was set at 1000 mg/kg body weight/day corresponding to a limit dose for this study. Thereafter, a descending sequence of dose levels was selected in an attempt to observed any dose- related response and identify a NOAEL.
- Rationale for animal assignment: random
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

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

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined as g food/animal/period: Yes
- Time schedule for examinations: gestation days 0, 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: liver

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. Foetal evaluation parameters like external, visceral, craniofacial and skeletal parameters were analysed using a Fisher’s exact test. Litter incidence was the primary unit for the statistical analysis and interpretation. The statistics were performed with GraphPad Prism V.6.01 software (p<0.05 is considered as statistically significant).
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Clinical Observations
There were clinical signs moving the bedding, salivation and piloerection observed dose responsive with respect to both frequency and severity in dose groups due to test item treatment. These signs were immediately after the dose administration and were considered to be due to local effect of test item treatment and were non adverse. Low incidences of crust, nasal discharge (red), diarrhea, alopecia and half eyelid closure were in isolated females in all groups, including control. As these findings were mostly transient and seen irrespective of the groups in isolated animals, they were considered to be incidental.

Body Weight
There were no statistically significant changes in body weight or body weight gain in dose group animals compared to control. A markedly lower mean weight gain in the 1000 mg/kg bw/day group (1.83 g) compared to control (4.24 g) was observed for GD 5-8, but this reduction was not statistically significant. This was a transient change and was considered to be of minor toxicological relevance. The terminal and adjusted maternal body weight was not affected due to treatment as there were no statistically significant changes between the control and the dose groups.

Food Consumption
There was statistically significantly lower food consumption observed in 1000 mg/kg bw/day group when compared to control after GD 5-8, GD 8-11, GD 17-20 and GD 0-20. The food consumption in this group was lower by 5.6 % to 16.6% when compared to control. However, all mean and most individual values were within recent historical control ranges reported in this laboratory. This finding was not considered adverse as the terminal and adjusted maternal body weight was not statistically significantly different in the 1000 mg/kg bw/day group compared to control group.

Pathology
No findings of toxicological relevance were observed in treated animals when compared to the controls. However, there was a single isolated incidence of dark red and soft liver with cyst on lobus sinister lateralis in 100 mg/kg bw/day group. There was also single isolated incidence of ovary cyst (unilateral, right) in the same group. These findings were considered to be incidental.

Organ Weight
There were statistically significantly higher absolute and relative (to terminal body weight) liver weights in the 300 and 1000 mg/kg bw/day groups when compared to the control group. Based on the interpretation of a similar effect in the 28 days oral repeated dose toxicity study with same test item, this was not considered to be an adverse effect of treatment.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: No adverse general and developmental effects in maternal animals
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
External examination
There were no statistically significant external observations in any of the dose groups compared to the controls. The few abnormalities were observed (hematoma in fore- or hindpaw, head or leg) were considered to be incidental in nature and unrelated to treatment.

Skeletal examination
Skeletal examination of the Alizarin red stained foetuses revealed a range of observations which were generally of a type or which occurred at an incidence comparable to or lower in dose groups when compared to the control group or were seen only at the MD or LD dose groups and were not dose dependent.

There was a statistically significantly higher incidence of “full 14th rib (bilateral)” at 1000 mg/kg bw/day (18 incidences in 9 litters) when compared to the concurrent control (2 incidences in 2 litters). This observation was above the historical control data range. This observation is a skeletal variation and in rats is a result of developmental delays in a labile region of the axial skeleton and not a manifestation of a teratogenic event. Therefore, this observation was not considered to be an adverse effect of test item treatment.

Thirteenth vertebral thoracic arch and centra were absent in 2 litters at 1000 mg/kg bw/day, but were none observed in the concurrent control group. This observation is a rare event and in the absence of statistically significant differences between the dose and control groups, the observation was not considered to be an adverse effect of test- item treatment.

There were also higher incidences of “full 14th rib (right)” and “pelvic girdle ilium (B) shift” in the dose groups when compared to concurrent and historical controls (except “ pelvic girdle ilium shift” at 300 mg/kg bw/day wherein the percent litter incidence was within historical control range). In the absence of statistically significant differences and dose response relation, the observation was not considered to be an adverse effect of test- item treatment.

Visceral examination
Internal examinations of foetal viscera by the free-hand-microdissection technique revealed a range of visceral observations which were generally of a type or which occurred at an incidence comparable to or lower in dose groups when compared to the control group or were seen only at 300 or 100 mg/kg bw/day and were not dose dependent.

There was a statistically significantly higher incidence of “thymus- cervical remnants” at 1000 mg/kg bw/day when compared to controls. The thymic remnant is a visceral variation thought to be a change suggesting growth inhibition rather than teratogenicity. It is considered that the indices for evaluation of growth fetuses are related to morphological development of external differentiation and viscera and progress of ossification. In this study there were no changes suggestive of fetal growth inhibition considering fetal and litter weights. Therefore, this observation was not considered to be an adverse effect of test item treatment .

There were also higher incidences of liver- extra tissue at medium lobe and supernumerary liver lobe at 1000 mg/kg bw/day. These observations are not uncommon. Further, in the absence of statistically significant differences and dose response relation the observation was not considered to be an adverse effect of test- item treatment.

The remaining visceral abnormalities observed in the dose groups were at frequencies generally comparable to or in some cases slightly higher or lower in frequency compared to the controls and were statistically insignificant.

Craniofacial examination
The craniofacial examination by the razor blade serial sectioning technique revealed a range of abnormalities which were generally of a type or which occurred at an incidence comparable to or lower in dose groups when compared to the control group or were seen only at 300 or 100 mg/g bw/day and were not dose dependent. The statistical analysis showed no statistically significant differences.

The percent litter incidence “3rd ventricle- slightly dilated” was higher at 1000 mg/kg bw/day when compared to concurrent control. The percent litter incidence in dose groups including the concurrent control were higher than the historical control. This incidence was not statistically significantly different and was also seen in 10/21 litters of control group. Therefore, this was not considered to be an adverse effect of test item treatment.

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on no adverse developmental effects in fetuses
Abnormalities:
not specified
Developmental effects observed:
not specified

Dose Formulation Analysis

Formulation analysis was performed on samples of all dose groups collected at various intervals during the study. The concentration verification of samples of all dose groups was investigated in study weeks 1, and 6 (last week). The mean recoveries in 100, 300 and 1000 mg/kg bw/day groups were 98.9%, 106.2% and 110% of the nominal concentration, respectively.

The Stability of formulation samples of 100 and 1000 mg/kg bw/day dose groups was investigated in study week 1. The recoveries after 6 hours storage at room temperature compared to starting value was 97.3% (100 mg/kg bw/day) and 98.7% (1000 mg/kg bw/day). The recoveries after 10 days storage (2-8oC) compared to starting value was 96.5% (100 mg/kg bw/day) and 87.9% (1000 mg/kg bw/day). The formulation sample was stable at 6 hours (room temperature) and 10 days (2-8 oC).

The Homogeneity of formulation samples of 100 and 1000 mg/kg bw/day dose groups was determined in study week 1 and 6 (last week). The mean recoveries observed for 100 mg/kg bw/day dose group was between 100.8 % and 93.1% of the nominal value and between 104.9% and 108.7% of the nominal value for 1000 mg/kg bw/day dose group. The coefficients of variation of the different sampling levels (top, middle and bottom) were between 3.3% and 4.0% in 100 mg/kg bw/day dose group, between 3.6% and 1.6% in 1000 mg/kg bw/day dose group.

Conclusions:
In a prenatal developmental toxicity study conducted according to OECD Test Guideline 414 and in compliance with GLP, oral administration of cyclohexyldimethoxymethylsilane at 0, 100, 300 or 1000 mg/kg bw/day to pregnant female Wistar rats from gestation days 5 to 19 resulted in lower food consumption at 1000 mg/kg bw/day and higher liver weight at 300 and 1000 mg/kg bw/day. Foetal examination revealed a higher litter incidence of the soft tissue observation thymus-cervical remnant and the skeletal observation of 14th full rib (bilateral). None of the maternal or foetal effects were considered to be adverse, therefore the maternal and foetal no-observed-adverse-effect-level were considered to be equal to 1000 mg/kg bw/day, the highest dose tested.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In an oral prenatal developmental toxicity study conducted according to OECD Test Guideline 414 and in compliance with GLP, administration of cyclohexyl(dimethoxy)methylsilane at 0, 100, 300 or 1000 mg/kg bw/day to pregnant female Wistar rats from gestation days 5 to 19 resulted in lower food consumption at 1000 mg/kg bw/day and higher liver weight at 300 and 1000 mg/kg bw/day. Foetal examination revealed a higher litter incidence of the soft tissue observation thymus-cervical remnant and the skeletal observation of 14th full rib (bilateral). None of the maternal or foetal effects were considered to be adverse, therefore the maternal and foetal no-observed-adverse-effect-level was considered to be 1000 mg/kg bw/day, the highest dose tested (BSL, 2014).


Justification for classification or non-classification

Based on the available data, cyclohexyl(dimethoxy)methylsilane does not require classification for reproductive or developmental toxicity according to Regulation (EC) 1272/2008.

Additional information