Dicyclopentyldimethoxysilane

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No reproductive toxicity studies are available for dicyclopentyl(dimethoxy)silane (CAS 126990-35-0). No adverse effects were observed on reproductive organs or tissues in a 90-day oral repeated dose toxicity with its hydrolysis product dicyclopentylsilanediol at dose levels up to 1000 mg/kg bw/day (Mitsubishi Chemical Safety Institute, 2000), or in a number of 28-day repeated dose toxicity studies with dicyclopentyl(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.

Link to relevant study records

Reference

Reference 1

Endpoint:

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:

the extended one-generation reproductive toxicity study does not need to be conducted because there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity

Reproductive effects observed:

not specified

Reference 2

Endpoint:

screening for reproductive / developmental toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because a pre-natal developmental toxicity study is available

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 (BSL, 2014), there were no adverse developmental effects noted. The NOAEL for maternal and foetal effects was therefore considered to be 1000 mg/kg bw/day, the highest dose tested (BSL, 2014).

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

15 October 2013 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

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

other: Wistar Crl:WI(Han)

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Germany
- Age at study initiation: approximately 11 to 12 weeks
- Weight at study initiation: males 307 - 340 g; females 194 - 227 g
- Fasting period before study: no
- Housing: individually (except during mating when 2 females paired with 1 male) in IVC cages, type III H.
- Diet (ad libitum): Altromin 1324 maintenance diet for rats and mice
- Water (ad libitum): facility tap water (sulphur acidified to approx pH 2.8)
- Acclimation period: at least 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: 21 October 2013
To: 07 January 2014

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The test item was weighed into a tared plastic vial on a precision balance and dissolved in corn oil. The test item formulation was prepared freshly on each administration day before the administration procedure. The time of preparation was recorded for all dosing formulations. Homogeneity of the test item in the vehicle was maintained by vortexing the prepared suspension thoroughly before every dose administration.


VEHICLE
- Justification for use and choice of vehicle (if other than water): The vehicle was selected as suggested by the sponsor based on the test item’s characteristics and testing guideline.
- Concentration of test substance in vehicle: 0, 25, 75, 250 mg/mL
- Amount of vehicle: 4mL/kg
- Lot/batch no.: MKBH4894V, MKBP7039V

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 were performed at various intervals using GC-FID.

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 toxicity study.

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:

Gestation Day 5 to gestation Day 19 inclusive.

Frequency of treatment:

Daily

Duration of test:

Until gestation Day 20.

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 females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: doses were based on a previous dose-range-finding developmental toxicity study in which no adverse maternal or foetal effects were noted at doses up to 1000 mg/kg bw/day

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once daily

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

FOOD CONSUMPTION: Yes
- Time schedule for examinations: gestation days 0, 5, 8, 11, 14, 17 and 20
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/day: Yes

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: macroscopic examination, liver weight also recorded

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 Chi-square test. The statistics were performed with GraphPad Prism V.6.01 software (p<0.05 is considered as statistically significant).

Historical control data:

Not included.

Clinical signs:

no effects observed

Description (incidence and severity):

No test item-related adverse clinical signs were observed in any of the treated groups.
A few spontaneous clinical signs, including alopecia at various body locations, moving the bedding, red nasal discharge, slight to severe salivation, moderate piloerection and slight to moderate abnormal breathing) occurred infrequently, similarly in the control group, and/or in a manner that was not dose-related.
These various clinical signs in the treatment and control groups were not considered to be adverse and clinically irrelevant.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, non-treatment-related

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 decrease in body weight gain during gestation day interval 8-11 in the 1000 mg/kg bw/day group. However, overall (GD 0-20) body weight gain in all treatment groups was comparable with the controls.
Throughout the treatment period, body weights and body weight gain were within the normal range of variation for this strain.

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

No treatment-related effect on food consumption was observed during the treatment period, except for a statistically significant decrease in food consumption during gestation interval 8-11 in 1000 mg/kg bw/day group when compared with the 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. Therefore this marginal but statistically significant difference during gestation interval 8-11 in the 1000 mg/kg bw/day group was not considered to be biologically relevant.

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:

effects observed, treatment-related

Description (incidence and severity):

Group mean and individual animal absolute and relative (to terminal body weight) maternal liver weights were statistically significantly increased in the 300 and 1000 mg/kg bw/day groups when compared to the controls.

Gross pathological findings:

no effects observed

Description (incidence and severity):

No treatment-related changes were observed during the macroscopic observation for all groups. A few findings such as distension of the uterus with liquid, distension of the uterus with fluid, blood coagulated in the uterus due to rupture of the uterine artery and a blood filled right uterine horn were observed. These gross pathological lesions were considered to be spontaneous common background findings and incidental in nature.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Number of abortions:

no effects observed

Description (incidence and severity):

None of the females showed signs of abortion or premature delivery prior to the scheduled sacrifice.

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

No statistically significant treatment-related effects were observed for pre- and post- implantation loss. The mean number of implantations per dam were 11.20, 12.00, 11.68 in order of ascending dose level. The mean incidence of post-implantation loss as a percentage of total implantations was 9.05, 4.23, 5.17% in order of ascending dose level.
The mean incidence of pre-implantation loss as a percentage of total implantations was 14.36, 8.97, 8.15% in order of ascending dose level.

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

No statistically significant treatment-related effects were observed for resorptions

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 the group mean number of live foetuses and dead foetuses

Changes in pregnancy duration:

not examined

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

Pregnancy rate (No. of pregnancies achieved /No. of females mated or sperm positive x 100) was comparable between the treatment groups 100 %, 80 % and 91.67 % respectively when compared to the control group (96 %). 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:

not specified

Key result

Dose descriptor:

NOAEL

Remarks:

Maternal developmental effects

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

Higher maternal liver weights at 300 and 1000 mg/kg bw/day were considered not to be adverse

Abnormalities:

not specified

Fetal body weight changes:

not examined

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 foetuses

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):

Foetal external examination on the day of terminal sacrifice revealed no gross external abnormalities in either the control or treatment groups

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

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 treated groups when compared to the control group. However, a statistically significant increase in the incidence of unossified 1st forelimb phalanx, unossified 4th forelimb phalanx and unossified all hindlimb phalanx in the 1000 mg/kg bw/day group, incomplete ossification of xiphoid and unossified 4th cervical vertebra centrum in the 300 mg/kg bw/day group, unossified 5th cervical vertebra centrum in all treated groups and a decrease in unossified 1st cervical vertebra centrum in the 300 and 1000 mg/kg bw/day groups was observed when compared with the controls. These unossified abnormalities were presumed to be due to a slight generalized delay in ossification. From a developmental perspective, these findings are considered of minimal significance and therefore considered to be non-adverse and transient in nature.
There were also statistically significant increases observed in incomplete ossification of interparietal bone and parietal bone in the 300 mg/kg bw/day group and incomplete ossification of supraoccipital bone in the 100 and 300 mg/kg bw/day groups when compared with the controls. Due to a lack of dose dependency and consistency in these abnormalities, no relevance with treatment is ascribed and these parietal and interparietal abnormalities were considered to be variations and therefore not adverse.
Furthermore, interparietal and parietal bones are among the regions that ossify rapidly during late gestation. In rodents, variable ossification of these late ossifying bones is normal and considered not to be adverse or treatment related.

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. However, there was a statistically significant increase in the incidence of hemorrhagic liver and a decrease in left sided umbilical artery in the 300 and 1000 mg/kg bw/day groups when compared with controls. Although a statistically significant increase in the incidence for hemorrhagic liver was observed in these groups, the litter incidence (15 in controls, 19, 17, and 19 in treated groups respectively) was almost comparable with the controls. There was also a statistically significant increase in the convoluted right ureter at 300 mg/kg bw/day and white lines on liver at 100 mg/kg bw/day when compared with controls. The remaining visceral findings observed in the treated groups were in frequencies comparable, slightly higher or even fewer in numbers compared to controls. As observed findings are either minor variations and/ or due to a lack of dose dependency and consistency, no serious toxicological significance was 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 abnormalities in all groups including controls. Statistical analysis of the data revealed no significant effect in any of the findings except incidental statistically significant decrease in slightly dilated 3rd ventricles of the brain in the 300 and 1000 mg/kg bw/day groups when compared with the controls. Since this finding was observed at a frequency less than that of the controls, it was not considered as treatment-related, but spontaneous in nature.

Key result

Dose descriptor:

NOAEL

Remarks:

Fetuses developmental effects

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

The foetal skeletal observations noted were considered to be attributable to a generalised delay in ossification and therefore not adverse. The foetal visceral and craniofacial observations were considered to be spontaneous in origin and not attributable to treatment.

Abnormalities:

no effects observed

Developmental effects observed:

not specified

Conclusions:

In a prenatal developmental toxicity study conducted according to OECD Test Guideline 414 and in compliance with GLP, oral administration of dicyclopentyl(dimethoxy)silane to pregnant rats from gestation day 5 to 19 at doses of 0, 100, 300 or 1000 mg/kg bw/day resulted in increased absolute and relative maternal liver weight at 300 and 1000 mg/kg bw/day which was considered not to be adverse. The foetal skeletal observations noted were considered to be attributable to a generalised delay in ossification and therefore not adverse. The foetal visceral and craniofacial observations were considered to be spontaneous in origin and not attributable to treatment. Therefore the maternal and foetal no-observed-adverse-effect-levels were both considered to be 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 the key prenatal developmental toxicity study conducted according to OECD Test Guideline 414 and in compliance with GLP, administration of dicyclopentyl(dimethyl)silane (CAS 126990-35-0) at doses of 0, 100, 300 or 1000 mg/kg bw/day by oral gavage to pregnant female rats from gestation days 5 to 19 resulted in increased absolute and relative maternal liver weight at 300 and 1000 mg/kg bw/day which was considered not to be adverse. Foetal skeletal observations noted were considered to be attributable to a generalised delay in ossification and therefore not adverse. Foetal visceral and craniofacial observations recorded were considered to be spontaneous in origin and not attributable to treatment. Therefore the maternal and foetal no-observed-adverse-effect-levels were both considered to be 1000 mg/kg bw/day, the highest dose tested (BSL, 2014).

In a preliminary dose range finding developmental toxicity study (BSL, 2013), conducted at the same doses, there were no maternal or foetal effects noted and 1000 mg/kg bw/day was considered to be an appropriate high dose for the subsequent definitive OECD Test Guideline 414 study.

Justification for classification or non-classification

Based on the available data, dicyclopentyl(dimethoxy)silane does not require classification for reproductive or developmental toxicity according to Regulation (EC) No 1272/2008.