Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
18th of April 2019 to 28th of January 2020
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2020
Report date:
2020

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
Adopted 29th of July, 2016
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: health Effects guidelines, OPPTS 870/3650
Version / remarks:
Combined repeated dose toxicity study with the reproduction / developmental toxicity screening test, EPA 712-C-00-368, July 2000.
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
tert-butylchlorodimethylsilane
EC Number:
242-042-4
EC Name:
tert-butylchlorodimethylsilane
Cas Number:
18162-48-6
Molecular formula:
C6H15ClSi
IUPAC Name:
tert-butyl(chloro)dimethylsilane
Test material form:
solid

Test animals

Species:
rat
Strain:
Wistar
Details on species / strain selection:
Crl: WI(Han) (Full barrier), derived from a controlled full-barrier maintained breeding system.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, 97633 Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approx. 14-15 weeks old
- Weight at study initiation:
males: 318 – 376 g (mean: 348.5 g, ± 20% = 278.8 – 418.2 g)
females: 221 – 258 g (mean: 238.4 g, ± 20% = 190.7 – 286.0 g)
- Fasting period before study: not specified
- Housing: Type IV polysulphone cages or in double decker IVC cages during the premating period for both males and females as well as during the post-mating period for males depending on the m ating status. During the mating period, males and females were housed together in ratio 1:1 (male to female). After the confirmation of mating, females were kept individually during gestation/lactation period in type III H, polysulphone cages and males were returned to their original cage. In each cage Altromin saw fibre was used as bedding.
- Diet: Altromin 1324 maintenance diet for rats, ad libitum
- Water: tap water, sulphur acidified to a pH of approximately 2.8, ad libitum.
- Acclimation period: at least 5 days.

DETAILS OF FOOD AND WATER QUALITY: Certificates of food, water and bedding are filed for two years at BSL Munich and afterwards archived at Eurofins Munich

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 55 ± 10 %
- Air changes (per hr): 10 x / hour
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: not specified

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test item was dissolved in dried and de-acidified corn oil and thereafter, administered daily.

VEHICLE
- Justification for use and choice of vehicle: The vehicle was selected in consultation with the sponsor based on the test item's characteristics.
- Concentration in vehicle: 0; 2.5; 7.5; 22.5 mg/mL.
- Amount of vehicle: 4 mL/kg bw/day
- Lot/batch no.: MKCG3257 and MKCH1635
- Purity: not specified
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: maximum of 14 days.
- Proof of pregnancy: sperm in vaginal smear, referred to as day 0 of gestation
- Mating period was up to 14 days long.
- Further matings after two unsuccessful attempts: up to 14 days were allowed for matings
- After successful mating each pregnant female was caged: females were kept individually during gestation/lactation period in type III H, polysulphone cages.
- Any other deviations from standard protocol: no
- other: If the vaginal smear of a particular female was not found to be sperm-positive, the actual stage of the oestrous cycle on that day was documented
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration analysis of formulation samples was performed on the three concentrations, 2.5 mg/mL, 7.5 mg/mL and 22.5 mg/mL in study weeks 1, 4, 7 and in the last week of the study. The mean recoveries observed in the low, medium and high dose groups were 98.0%, 98.6%, and 97.7% of the nominal concentration, respectively. The low recoveries found in those samples were considered due to technical error in the preparation of formulation samples. Thus, both mentioned samples were excluded from the evaluation of concentration verification.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily administration, 7 days per week
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
control
Dose / conc.:
10 mg/kg bw/day (nominal)
Remarks:
Low dose, LD
Dose / conc.:
30 mg/kg bw/day (nominal)
Remarks:
Middle dose, MD
Dose / conc.:
90 mg/kg bw/day (nominal)
Remarks:
High dose, HD
No. of animals per sex per dose:
10 females/group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The doses were based on a previous dose range finding study and in consultation with the sponsor. In the dose range-finding study inflammatory and degenerative lesions (e.g. erosion, ulceration) of the stomach were noted in male and female animals treated with 100 mg/kg bw/day and higher. Although the highest dose of 90 mg/kg bw/day may not induce toxic effects, higher doses were not considered due to animal welfare reasons. A descending sequence of dose levels were selected to demonstrate any dose-related response and to determine a NOAEL.
- Rationale for animal assignment: random
- Fasting period before blood sampling for clinical biochemistry: not reported
- Rationale for selecting satellite groups: no satellite groups were included
- Post-exposure recovery period in satellite groups: no
- Section schedule rationale: random
- Other: n/a
Positive control:
No

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: General clinical observations were made at least once per day, preferably at the same time each day. The health condition of the animals was recorded. Twice daily, all animals were observed for morbidity and mortality except on weekends and public holidays when observations were made once daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before the first exposure and at least once a week thereafter. Clinical observations included spontaneous activity, lethargy, recumbent position, convulsions, tremors, apnoea, as phyxia, 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: once before the assignment to the experimental groups, on the first day of dosing and thereafter, weekly as well as at the end of the study. During pregnancy, females were weighed on gestation days 0, 7, 14 and 20 and within 24 hours of parturition (day 0 pos t-partum), on PND 4, PND 9 and PND 13 along with pups. In total, 2 animals from the control group; 4 animals from the low dose group and 2 animals from the middle dose group were weighed on GD 21 instead of GD 20. All animals were weighed directly before termination. Any animals prematurely sacrificed were weighed prior to the sacrifice.

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
Food consumption was measured on the corresponding days of the body weight measurements after the beginning of the dose administration. Food consumption was not measured during the mating per iod in males and females and the post-mating period in males.

FOOD EFFICIENCY: No

WATER CONSUMPTION AND COMPOUND INTAKE: No
Oestrous cyclicity (parental animals):
60 females were screened for regular oestrous cycles for 14 days before the treatment initiation and 40 females only (10 females/ group) showing regular oestrous cycles were continued in the study.
Sperm parameters (parental animals):
Parameters examined in male parental generations:
testis weight, epididymis weight and a detailed qualitative examination taking into account the tubular stages of the spermatogenic cycle at evaluation of additional haematoxylin-PAS (Periodic Acid Schiff) stained slides.
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of pups, stillbirths, runts born, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance AGD, pup weight on the day of AGD and presence of nipples/areolae in male pups. For 2 dams, litter observations scheduled for PND 0 were performed on PND 1 and PND 3, respectively.

GROSS EXAMINATION OF DEAD PUPS:
yes, external surface of the body, all orifices and the cranial, thoracic and abdominal cavities and their contents were examined.

ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: no

ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: no
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: Males were dosed for a minimum of four weeks until up to one day before the scheduled sacrifice (this includes a minimum of two weeks prior to mating, during the mating period and up to two weeks post-mating). The males were sacrificed after completion of the mating period on treatment days 29 and 30.
- Maternal animals: a maximum exposure of 63 days in total in females (at least 14 days pre-mating, up to 14 days mating, approximately 22 days of gestation and up to post-natal day 12). The females along with their pups were sacrificed on PND 13. Non-pregnant females were sacrificed on day 26.

GROSS NECROPSY
- Gross necropsy consisted of: external surface body examination as well as examination of all orifices, the cranial, thoracic and abdominal cavities and their contents.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 1 were prepared for microscopic examination and weighed, respectively.
Postmortem examinations (offspring):
GROSS NECROPSY - Gross necropsy consisted of external examination as well as examination of all orifices, the cranial, thoracic and abdominal cavities and their contents.

ORGAN WEIGTHS
Thyroid/parathyroid glands from 1 pup/sex/litter/group (sacrificed on PND 13). Weight of thyroid/ parathyroid glands was measured after fixation.
Statistics:
A statistical assessment of the results of body weight, food consumption and litter data was performed for each gender by comparing values of dosed with control animals using an one-way ANOVA and a post-hoc Dunnett Test. Results of absolute and relative organ weights, parameters of haematology, blood coagulation and clinical biochemistry were 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 homogenei ty and normality tests. These statistics were performed with GraphPad Prism V.6.01 software or Ascentos 1.3.4 software (p<0.05 was considered as statistically significant).

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
A female animal from the control group which was euthanized in moribund condition had previously shown clinical findings of apathy, reduced spontaneous activity, abnormal breathing dehydration, piloer ection, half eyelid closure, lacrimation, exophthalmos and chromodacryorrhea on the day of sacrifice. Other observed clinical signs in treatment animals included moving the bedding and increased salivation, however, this appeared directly after the administration and thus, considered to be a sign of discomfort or a local reaction of the test item and not adverse systemic effects.
Furthermore, piloerection, crust, hairless area and diarrhoea occurred in single animals without any dose dependency and therefore, not considered as test substance related
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One female in the control group was euthanized in moribund condition. In the histopathological examination, necrotising inflammation along with foreign materials containing feed composition in the lesions was observed in the tissues around the intrathoracic organs and tissues. Such inflammatory lesions were noted in the thymus and lungs (recorded as pleuritis), and observed in the subcutis at the neck region, as well. From these findings, the cause of animal’s morbidity was considered to be technical error that happened during the oral gavaging procedure. All remaining animals survived the scheduled study period.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Treatment with the test item showed no statistically significant or toxicologically relevant effects on body weights or body weight development of male and female animals. Body weight development was co mparable between test item-treated groups and their respective control group throughout the treatment period. Slight changes were not considered to be of toxicological relevance. There were no statistically significant differences in final body weights in both sexes.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No considerable and statistically significant difference in food consumption of male and female animals between the dose groups and the control group were observed. Slight differences between the test item-treated animals and corresponding controls were only temporary and without a clear dose-dependent trend and thus were not assumed toxicologically relevant.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
The mean percentage of reticulocytes was slightly lower in males compared to control groups, however, due to a lack of dose dependency and without statistical significance, the finding was not considered test substance related. Moreover, the percentage of eosinophils was higher in males in all dose groups with a statistical significance in the low dose group when compared to the control group. Furthermore, higher mean percentage of basophils and higher mean percentage of large unstained cells were observed to be higher in males in the middle dose group compared to the control group. In both cases, the elevated values were mainly based on the results of one single animal and therefore, not considered to be toxicologically relevant.
The mean percentage of monocytes in females was higher in all dose groups compared to female controls. Middle dose group females had a statistically significantly lower percentage of lymphocytes and a statistically significant higher percentage of neutrophils compared to the females in the control group. In the low dose group females, the mean percentage of basophils was higher in females compared to the control group. In the middle and high dose group females, the mean percentage of large unstained cells was lower compared to the females control group. Due to the lack of dose-dependency or gender consistency, these finding were not considered as toxicologically relevant.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Lower serum TBA levels were observed in the males in all dose groups whereas slightly higher serum ALAT levels were found in the high group when compared to the control group. Nevertheless, no statistical significance or dose dependency were observed and therefore, these differences were assumed to be not test substance-related.
Statistically higher urea levels in females were observed in the low dose group compared to the control females. Additionally, lower serum AP levels were observed in females in all the test substance treated groups. None of these findings were considered to be toxicologically relevant due to gender inconsistency or dose-dependency.
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
Findings of nitrite in the urine and glucose were considered incidental and not test substance related.
Behaviour (functional findings):
effects observed, non-treatment-related
Description (incidence and severity):
Statistically significant lower body temperature in high dose group males was observed compared to that of the control group males before the treatment. However, lower temperature in the HD group was observed prior to treatment start and thus was not considered test-item related. Statistically significant lower body temperature in middle dose group males was observed compared that of the control group males during the last week of treatment. Lower temperature in the MD group in the last week of treatment was not considered toxicologically relevant as LD and HD group showed no statistically significant differences and no dose-dependent trend was observed.
Immunological findings:
effects observed, non-treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
In the forestomach, inflammation with focal submucosal haemorrhage was observed in one low dose group male as well as in one middle dose group male. Focal/single ulceration in the lesion was also seen for the latter animal. No forestomach lesions were observed in any high dose group animals. In the preliminary study doses higher than 90 mg/kg bw/day were administered to male and female rats and stomach injuries indicating local irritative effects of the test item were observed at all dose levels for both sexes. The forestomach lesions observed in the study were identical to the lesions in the dose range-finding study and therefore they were considered to be treatment-related and adverse changes. Mucous neck cell hyperplasia was observed in the glandular stomach in three high dose males and one high dose female, but it was considered to be an adaptive response to local stimuli and not to be adverse as no necrotic/degenerative or inflammatory changes were noted.
In the kidneys of high dose group males, hyaline droplet accumulation with sporadic single cell death in the proximal tubules as well as increased incidence of tubular basophilia were observed. No such effects were observed in any of the female animals. Hyaline droplets were due to an excessive accumulation of secondary lysosomes within the cytoplasm containing alpha-2u-globulin. This is considered to be a male rat specific effect.
Moreover, the hyaline droplet accumulation in high dose males was accompanied by tubular single cell necrosis and increased incidence of tubular basophilia. These effects were considered to be male rat-specific and non-human-relevant.
No histomorphological changes could be detected in the reproductive organs and tissues. Squamous hyperplasia and hyperkeratosis were observed in one low dose group male as well as one middle dose group male.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
Treatment with the test item had no effect on serum T4 levels of parental males. No considerable differences were found between dose groups and the corresponding control group of this study.

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
There was no test item-related statistically significant or biologically relevant effect on the oestrous cycle of any of the female animals when analysed during the 2 weeks premating period. There were no considerable differences in the mean length or sequence of cycle stages. An abnormal cycle was noted for one high dose group female which was considered incidental.
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
Description (incidence and severity):
There were slight differences in the reproductive indices of test item-treated females when compared to control females. The changes followed no dose-dependency and were within the normal range of variation and therefore, were considered to not be toxicologically relevant.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Remarks:
systemic and reproductive effects
Effect level:
>= 90 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No adverse effects were observed
Dose descriptor:
LOAEL
Remarks:
local effects
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic

Target system / organ toxicity (P0)

Critical effects observed:
yes
Lowest effective dose / conc.:
10 mg/kg bw/day (nominal)
System:
gastrointestinal tract
Organ:
kidney
stomach
Treatment related:
yes
Dose response relationship:
yes

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
One control group pup was found dead on postnatal day 1. This was within the normal range of variation and therefore, not considered as toxicologically relevant. No other pup mortality was observed during the study duration.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Male litter weight was statistically significantly lower in the low dose group compared to the control group on postnatal day 0 and 4. However, males of higher dose groups showed no relevant differences in litter weight compared to the control group. Thus, lower male litter weight was not considered toxicologically relevant.
Food consumption and compound intake (if feeding study):
not examined
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
Sexual maturation:
not examined
Anogenital distance (AGD):
effects observed, treatment-related
Description (incidence and severity):
A statistically significantly shorter absolute and relative anogenital distance was observed in middle and high dose group males when compared to the control group. Similarly, shorter absolute and relative anogenital distance was observed in high dose group female animals compared to the control group. Since all values were within the historical control data range and no changes were seen in several other parameters, e.g. histopathology of parental reproductive organs and their weights, litter seize, sex ration, pup thyroid /parathyroid weight and thyroxine hormone (T4), these effects were not considered adverse.
Nipple retention in male pups:
effects observed, treatment-related
Description (incidence and severity):
A statistically significantly higher nipple retention was noted in high dose male pups on postnatal day 12 when compared to the control group. Since the values are within the historical control data range, this change was considered non-adverse.
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
No test item-related gross external abnormalities of toxicological relevance were observed in the pups of any of the groups on PND 0-12 or the day of sacrifice/death.
Histopathological findings:
not examined
Other effects:
no effects observed
Description (incidence and severity):
Treatment with the test item had no effect on serum T4 levels in 13 day old pups. No considerable differences were found between dose groups and the corresponding control group of this study.

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Remarks:
systemic effect
Generation:
F1
Effect level:
>= 90 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
In the combined repeated dose oral toxicity study with the reproduction / developmental toxicity screening test, with the test substance tert-butyl(chloro)dimethylsilane, conducted according to OECD Test Guideline 422 and in compliance with GLP, a NOAEL for reproductive toxicity was concluded to be ≥90 mg/kg bw/day based on no adverse effects on reproduction and developmental parameters. Effects on the anogenital distance (AGD) and the nipple retention were within the historical control data, although a statistically significant difference was noted. In addition, AGD is not the only parameter to confirm potential endocrine disruption. No effects were reported for several other parameters, such as histopathology of parental reproductive organs and their weights, litter size, sex ratio, pup thyroid /parathyroid weight and thyroxine hormone (T4) to support a possible endocrine disruption modality of the test item..