Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

There are no reproductive toxicity data for the registered substance, 1,1,3,3-tetramethyldisiloxane. There is currently an ongoing 90-day inhalation repeated dose toxicity study, conducted according to OECD Test Guideline 413 and in compliance with GLP. In addition, there is a prenatal developmental toxicity study for the registered substance, conducted according to OECD Test Guideline 414 and in compliance with GLP, in which no effects were noted on the maternal reproductive parameters at any of the test doses of 0, 50, 250 or 750 mg/kg bw/day (Covance Laboratories Limited, 2020). The need for further testing for reproductive toxicity will be assessed when the results from the 90-day inhalation repeated dose toxicity study are 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
Additional information

Data for the final hydrolysis product, dimethylsilanediol (DMSD), have been included in the dossier to allow risk characterisation for exposure of humans via the environment.

In the combined repeated dose toxicity study with the reproduction / developmental toxicity screening test with dimethylsilanediol, conducted according to OECD Test Guideline 422 and in compliance with GLP, dimethylsilanediol was administered by oral gavage in corn oil for 28 (toxicity group females) or 29 (males) days to 10 rats/sex/group (exception, female 50 mg/kg group where N=9) at 0, 50, 250 or 500 mg/kg bw/day (Dow Corning Corporation, 2009).  A single group of males was used for both the toxicity and reproductive phases of the study.  Reproductive group females were treated (10 rats/dose group) for 14 days prior to the mating period, during the mating period and through post-partum day 3. Clinical observations were performed daily immediately following exposure.  Body weight measurements were performed weekly.  All animals received a detailed physical examination once before the first dose (to allow for within-subject comparisons), and weekly thereafter. Additional body weights on reproductive females were obtained on gestational days (GD) 0, 7, 14, and 20, within 24 hours of parturition, and on post-partum day four. Individual food consumption was recorded at least weekly, except during the cohabitation period. Functional observational battery (FOB) and motor activity evaluations were performed on males and toxicity group females once prior to initiation of exposures and during the fourth week of exposure.  Blood samples for haematology and serum chemistry evaluations were collected at the scheduled necropsy from males and toxicity group females. Complete necropsies were performed on the males and the toxicity group females and selected organs were weighed. Microscopic examination was performed on protocol specified tissues on all toxicity group animals from the control and 500 mg/kg bw/day dose groups. Target tissues examined from the low- and mid-dose levels included liver, lung, prostate gland and thyroid gland from male rats and liver and lung from female rats.  

Mating was initiated after the first two weeks of exposure by pairing reproductive group females with males of the same treatment group until positive evidence of mating was obtained. Reproductive and developmental parameters evaluated included evidence of mating, pregnancy, duration of gestation, mean litter size, mean live litter size, mean litter weight, and mean ratio of live births/litter size. Dams and pups were euthanized on post-partum day 4 and examined for external gross lesions. The number of corpora lutea, and the number of uterine implantation sites were determined for all reproductive group females.

Oral gavage administration of dimethylsilanediol to male and female Sprague-Dawley rats at concentrations of up to 500 mg/kg bw/day for 28 (toxicity females) or 29 (males) consecutive days was generally well tolerated. For the toxicity group males at 250 and 500 mg/kg bw/day significant soiling was observed (abdominal region and urogenital soiling).  Soiling of the muzzle was a significant abnormal observation in the toxicity group females at 500 mg/kg bw/day. Both abdominal soiling and urogenital soiling were significant abnormal observations in the reproductive group females at 500 mg/kg bw/day.  

There were no statistically significant differences across exposure groups in the mean body weights on any day for toxicity group females and reproductive toxicity group females. In the male group there was a significant difference across treatment groups in week 2, however, there was not a significant difference between control and any of the treatment groups for that week. With respect to body weight gain, male group 4 animals had a significant decrease in body weight gain during week 4 and in total gain from day 1 to 29. For toxicology females there was significant decrease in body weight gain during week 3. There were no statistically significant differences in body weight gain for the reproductive females in any of the treatment groups during any of the measured intervals. There were no differences in the average daily food consumption between control and treatment groups for the reproductive females group or the toxicity male and female groups for any of the measured time periods. There were no significant differences of toxicological significance between the control and treatment groups in either sex for the FOB ranked tests. There were no significant differences between either male or female treatment groups and their respective controls for the FOB continuous test and motor activity. There were no treatment-related changes associated administration on rat neurobiological function as evaluated with FOB and motor activity parameters. The significant changes that were noted in haematological parameters and prothrombin times for toxicity group males and females were within or slightly below historical control values. The significant changes that were noted in clinical chemistry parameters for toxicity group males and females were within or slightly below historical control values. The increased liver weights in toxicity males and females at 250 and 500 mg/kg bw/day correlated with the histopathologic finding of centrilobular hypertrophy. There were no other treatment-related differences in organ weights, absolute and relative for toxicity group males and females.  

There were three primary effects of the test article observed in the liver, including centrilobular hypertrophy in both sexes, periportal hepatocellular vacuolation (microvascular lipidosis, females only), and brown pigment accumulation (males only) which was accompanied by chronic inflammation and bile duct hyperplasia. Centrilobular hypertrophy is considered an adaptive change. Hepatic lipidosis, unless severe, is generally considered non-adverse. Hepatic brown pigment is considered an adverse effect. Follicular cell hypertrophy was observed in the thyroid gland of mid- and high-dose male rats. This may reflect an adaptive secondary effect and adverse in the rat, but the mechanism is generally not applicable to species with significant levels of thyroid binding globulin (Capen, et al., 2002). Lung (males and females) and prostate gland were considered possible target tissues; however, further examination and inclusion of animals from the mid- and low-dose groups did not support this interpretation. There were no treatment-related effects apparent for any of the reproductive endpoints:  gestation length, litter size, litter weight, ratio live births/litter size, litter sex ratio, number of implantation sites, number of corpora lutea, mating and fertility indices.  

Based on the results of this study, the systemic toxicity NOAEL (No-Observed-Adverse-Effect-Level) for dimethylsilanediol in rats via oral administration in corn oil is considered to be 250 mg/kg bw/day based on hepatic brown pigment accumulation in and around the bile ducts, with associated bile duct hyperplasia and chronic inflammation at 500 mg/kg bw/day.  In the absence of adverse effects on reproductive or developmental parameters in this study, a NOAEL of ≥500 mg/kg bw/day is assigned for reproductive and developmental toxicity.

Effects on developmental toxicity

Description of key information

In the key prenatal developmental toxicity study in rats for 1,1,3,3-tetramethyldisiloxane, conducted according to OECD Test Guideline 414 and in compliance with GLP, the reported NOAEL for maternal toxicity was 750 mg/kg bw/day, the highest dose tested. The NOAEL for developmental toxicity was concluded to be 250 mg/kg bw/day based on major abnormalities observed at 750 mg/kg/day (Covance Laboratories Limited, 2020).

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
18th of December 2019 to 12th of June 2020
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
July 2018
Deviations:
yes
Remarks:
The measured concentration of the first formulation prepared at 12.5 mg/ml for the 50 mg/kg bw/day group was -18.4% of nominal, equating to an approximate dose of 41 mg/kg bw/day. This formulation was administered for up to seven days (GD 6-13).
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl: CD(SD)
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd
- Age at study initiation: 70 to 76 days.
- Weight at study initiation: 214 to 262 grams
- Fasting period before study: not specified
- Housing: Cages comprised of a polycarbonate body with a stainless steel mesh lid. Solid (polycarbonate) bottom cages were used during the acclimatisation and gestation periods. Grid bottomed cages were used during pairing. Cages were suspended above absorbent paper which was changed daily during pairing. Solid bottom cages contained softwood based bark-free fiber bedding which was changed at appropriate intervals each week. During the acclimatisation, up to four animals were caged together. During pairing, one (stock) male and one female were together and during gestation, one female was caged.
- Diet: SDS VRF1 Certified pelleted diet, ad libitum. The diet did not contain any added antibiotic or other chemotherapeutic or prophylactic agent. A soft white untreated Aspen chew block was provided to each cage throughout the study and replaced when necessary.
- Water: water was supplied from the public supply via polycarbonate bottles with sipper tubes. Bottles were changed at appropriate intervals, ad libitum.
- Acclimation period: 7 days before commencement of pairing.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 15 to 25°C
- Humidity (%): 40-70%
- Air changes (per hr): at least 15 air changes / hour. Filtered fresh air which was passed to atmosphere and not recirculated.
- Photoperiod (hrs dark / hrs light): 12 hours light / 12 hours dark

IN-LIFE DATES: Not specified
Route of administration:
oral: gavage
Vehicle:
corn oil
Remarks:
Dried and de-acidified corn oil (50% silica gel desiccant, 25% aluminium oxide neutral and 25% aluminium activated acidic (40 grams, 20 grams and 20 grams respectively per litre of oil).
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: A series of formulations at the required concentrations were prepared by dilution of individual weightings of the test item in ascending order of concentration. The humidity within the glove box, used for all formulation procedures, was checked to ensure it was 10% or below. The required amount of test item was added to the required volume of vehicle. Each formulation was stirred using a magnetic stirrer until uniformly mixed and then transferred to final glass containers, via syringe, whilst magnetically stirring.
Each glass container of formulation was filled to reduce the volume of air (head space) and was then purged with nitrogen. Formulations were issued daily and were issued in a cool box containing ice although, the dose containers did not come into contact with the ice.The formulations were prepared weekly and stored refrigerated (2 to 8°C).

VEHICLE
- Justification for use and choice of vehicle: The vehicle, dried and de-acidified corn oil, was selected in conjunction with the sponsor and according to the appropriate OECD guideline.
- Concentration in vehicle: Nominal concentrations: 0, 12.5, 62.5 and 187.5 mg/mL. Formulated concentrations: 0, 16.5, 82.5 and 247.5 μL/mL.
- Amount of vehicle: 4 mL/kg
- Purity: Not specified
- Preparation of vehicle: Dried and de-acidified corn oil was mixed and placed in a vented oven set to 250ºC overnight or for at least eight hours and then allowed to dry in a dessicator. The oil and dry materials were mixed in a suitable container, using a stir bar on a magnetic stirring plate, for at least two hours under a nitrogen purge. The oil and dry materials mix was allowed to settle for a minimum of 30 minutes. The oil was filtered with 0.22 μm cellulose acetate filter system with vacuum to remove the alumina and silica. The filtered dried and de-acidified corn oil was kept in amber glass bottles, topped with a nitrogen purge, sealed with parafilm and stored with desiccant material at room temperature.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The homogeneity and stability of formulations during storage were confirmed as part of another study. Samples of each of the first and last preparation formulations were analysed for achieved concentration of the test item.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused: A female was taken to a male's cage
- M/F ratio per cage: 1:1 with identified stock males
- Length of cohabitation: until mating was confirmed.
- In case of unsuccessful mating, the female was taken back to its original cage and mating of the female with another male or at another time was considered
- Verification of same strain and source of both sexes: Yes
- Proof of pregnancy: Ejected copulation plugs in cage tray and vaginal smears were checked for the presence of sperm referred to as day 0 of pregnancy. Only females showing at least two copulation plugs were allocated.
- Any other deviations from standard protocol: No
Duration of treatment / exposure:
Between GD 6 to 19
Frequency of treatment:
Daily
Duration of test:
20 days
Dose / conc.:
0 mg/kg bw/day
Remarks:
nominal concentration: 0 mg/mL
Dose / conc.:
50 mg/kg bw/day
Remarks:
nominal concentration: 12.5 mg/mL
Dose / conc.:
250 mg/kg bw/day
Remarks:
nominal concentration: 62.5 mg/mL
Dose / conc.:
750 mg/kg bw/day
Remarks:
nominal concentration: 187.5 mg/mL
No. of animals per sex per dose:
90 females, 20 animals per group. Spare animals were removed from the study room after treatment commenced.
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels for this study (0, 50, 250 and 750 mg/kg bw/day) were selected in conjunction with the Sponsor and based on the results from the preliminary dose range finding study (Covance Laboratories, 2020). In the study pregnant female rats were given daily oral (gavage) administration of 1,1,3,3-tetramethyldisiloxane in corn oil at doses of 0, 300, 600 and 1000 mg/kg bw/day.
- At 1000 mg/kg bw/day overall body weight gain and gravid uterine weight were lower compared to control. The numbers of pre- and post-implantation losses were higher and resulted in a low mean litter size at 1000 mg/kg bw/day compared to control. Pre-implantation loss was higher at 600 mg/kg/day compared to control also. Liver weights appeared to be marginally higher at 600 or 1000 mg/kg bw/day compared to control; however, no definite relationship to treatment was inferred. The majority of foetuses in one litter at 600 mg/kg bw/day and some or the majority of litters at 1000 mg/kg bw/day showed the major foetal abnormality of domed craniums. At 1000 mg/kg/day, the majority of foetuses in one litter and one foetus from each of two litters had whole body oedema and protruding tongue or short snout was evident in one or two foetuses, respectively.
- Rationale for animal assignment: randomised
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: The health conditions of the animals were recorded at least twice daily, preferably at the same time each day. Once daily all animals were observed for morbidity and mortality. Signs associated with dosing were also recorded daily.

DETAILED CLINICAL OBSERVATIONS: Yes
A detailed physical examination was performed on each animal on Days 0, 5, 12, 18 and 20 after mating to monitor general health.

BODY WEIGHT: Yes
The weight of each adult was recorded on Days 0, 3 and 6-20 after mating.

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
The weight of food supplied to each adult, that remaining and an estimate of any spilled was recorded for the periods days 0-2, 3-5, 6-9, 10-13, 14-17 and 18-19 after mating inclusive.

WATER CONSUMPTION AND COMPOUND INTAKE: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20 after mating.
- Organs examined: The kidneys, liver and thyroid gland were weighed. Gravid uterine weight was also recorded. The kidneys, liver, thyroid gland, and uterus were fixed at necropsy. The thyroid gland was examined at histopathology.

OTHER: Thyroid hormone analysis was performed prior to sacrifice. Blood samples were collected from all animals prior to termination. The animals were not fasted overnight. The samples were analysed for T3, T4 and TSH levels.
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
- Other: The number of uterine implantation sites were checked after staining with ammonium sulphide
Fetal examinations:
- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, all per litter
- Skeletal examinations: Yes, all per litter
- Head examinations: Yes, all per litter
Statistics:
A parametric analysis was performed if Bartlett's test for variance homogeneity was not significant at the 1% level. For pre-treatment data, analysis of variance was used to test for any group differences. When significant, inter group comparisons using t-tests with the error mean square from the one-way analysis of variance were made. For all other analyses, the F1 approximate test was applied. If the F1 approximate test was significant, suggesting that the dose response was not monotone, Dunnett's test was performed. A non-parametric analysis was performed if Bartlett's test was still significant at the 1% level following both logarithmic and square-root transformations. For pre-treatment data, Kruskal-Wallis’ test was used to test for any group differences. Where this was significant (p<0.05) intergroup comparisons using Wilcoxon rank sum tests were made. For all other analyses the H1 approximate test, the non parametric equivalent of the F1 test described above was applied. If the H1 approximate test for monotonicity of dose-response was not significant at the 1% level, Shirley's test for a monotonic trend was applied. If the H1 approximate test was significant, suggesting that the dose-response was not monotone, Steel's test was performed instead.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Two animals receiving 250 mg/kg bw/day and four animals receiving 750 mg/kg bw/day showed transient salivation very soon after dosing, during days 17-19 of gestation. This was considered attributed to the palatability of the test item formulations and was therefore, not considered to be toxicologically significant. There were no signs attributable to dosing at 50 mg/kg bw/day.
There were no clinical observations attributable to treatment at 50, 250 or 750 mg/kg bw/day.
One animal receiving 750 mg/kg bw/day was observed with a swollen area on the lower ventral surface on the day of termination that was determine as a firm inguinal mammary mass at necropsy.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No mortality was observed.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The group mean body weight performance and overall gain (GD 6-20) of females treated with tetramethyldisiloxane at 50, 250 or 750 mg/kg bw/day were comparable to that of the control group.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Group mean food consumption of females treated with 50, 250, or 750 mg/kg bw/day tetramethyldisiloxane was similar to the controls during gestation Days 6-20.
Food efficiency:
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, non-treatment-related
Description (incidence and severity):
Group mean adjusted kidney and liver weights were marginally higher in females treated with 750 mg/kg bw/day (111% and 112% of control, respectively). However, the difference from control was marginal and there was no macroscopic finding in either tissue and therefore, not considered as treatment related. Group mean kidney and liver weights at 50 or 250 mg/kg bw/day and thyroid weight at 50, 250 or 750 mg/kg bw/day were unaffected by treatment compared to controls.

The mean gravid uterine weight for females treated with 1,1,3,3-tetramethyldisiloxane was comparable to the mean gravid uterine weight from the control females, as was adjusted body weight and body weight gain.
Gross pathological findings:
no effects observed
Description (incidence and severity):
The macroscopic examination performed following treatment on GD 6 to 19 revealed no treatment related findings.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Minimal follicular cell hypertrophy in the thyroid glands was seen in five females treated with 750 mg/kg bw/day and in one female from the control group. All other histological changes were considered to be unrelated to treatment.
Histopathological findings: neoplastic:
not examined
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
At 750 mg/kg bw/day, there was a suggestion of a non-adverse effect on thyroid function (Table 1). Mean serum T4 and T3 concentrations were slightly but statistically significantly lower than those in the controls (no dose response was apparent) and microscopic examination of the thyroids revealed five females with follicular cell hypertrophy compared to one in the control. Individual T4 and T3 concentrations were highly variable and all T4 concentrations were within the concurrent control range. The reduction in T4/T3 concentrations was only slight and there was no obvious correlation to the occurrence of follicular cell hypertrophy and mean serum TSH concentrations were unaffected, which would have been expected to accompany reduced T4/T3 concentrations and result in thyroid follicular cell hypertrophy. Therefore, no definite effect of treatment at 750 mg/kg bw/day on thyroid function is inferred. At 50 or 250 mg/kg bw/day, the mean serum T4/T3 concentrations were slightly statistically significantly lower than the control group. Although, no dose response, supporting microscopic changes in the thyroids or increase in TSH concentrations occurred. Therefore, the slightly reduced T4/T3 concentrations are considered to be incidental and not related to treatment.
Number of abortions:
not specified
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
The numbers of pre- and post-implantation loss were unaffected by the treatment in all dose groups.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
The numbers of resorptions were unaffected by treatment at 50, 250 or 750 mg/kg bw/day.
Early or late resorptions:
no effects observed
Description (incidence and severity):
The number of early or late resorptions were unaffected by the treatment in all dose groups.
Dead fetuses:
no effects observed
Description (incidence and severity):
The number of live foetuses were unaffected by the treatment in all dose groups.
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
One animal that received 250 mg/kg bw/day was not pregnant. Therefore, reproductive assessment was assessed using 20 control animals and 20, 19 or 20 animals treated at 50, 250 or 750 mg/kg bw/day, respectively.
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
750 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: No adverse effects observed
Abnormalities:
no effects observed
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Overall foetal weight (male and female combined) was statistically significantly lower at 250 or 750 mg/kg bw/day (91% or 80% of control, respectively) and the resultant total litter weight at 750 mg/kg bw/day was statistically significantly lower (84% of control). Foetal and litter weights were unaffected by treatment at 50 mg/kg bw/day compared to control.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
There was no reduction in the number of live offspring
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The sex ratio of males to females was unaffected by the treatment in all dose groups.
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
Overall foetal weight (male and female combined) was statistically significantly lower at 250 or 750 mg/kg bw/day (91% or 80% of control, respectively) and the resultant total litter weight at 750 mg/kg bw/day was statistically significantly lower (84% of control). Foetal and litter weights were unaffected by treatment at 50 mg/kg bw/day compared to control.
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
When compared with control, there was an increase in incidence of thoracic vertebral abnormalities; medially thickened/kinked ribs; short supernumerary cervical ribs; short and full supernumerary 14th ribs; 20 thoracolumbar vertebrae; unilateral caudal shift of the pelvic girdle; a generalised delay in ossification (including cranial bones, sternebrae, all vertebrae, ribs, pelvic and digit bones) and domed cranium. All parameters exceeded the historical control data (HCD) range.

There was an increase in incidence of some of the abnormalities/variants, when compared with control, at 250 mg/kg bw/day, but to a lesser degree. These included short supernumerary 14th rib; incomplete ossification of cranial bones, sternebrae, thoracic and sacral/caudal vertebrae and pelvic bones. With the exception of incompletely ossified cranial bones, all exceeded the HCD range.

Many of these abnormalities and/or variants may be associated with the lower foetal weight observed at 750 mg/kg bw/day and to a lesser extent at 250 mg/kg bw/day. Incomplete ossification and slightly domed cranium are transient stages in foetal development and indicative of foetal immaturity.
Visceral malformations:
effects observed, treatment-related
Description (incidence and severity):
There was an increase in abnormalities affecting the heart and major blood vessels at 750 mg/kg bw/day compared to control. These included double/retroesophageal/right sided aortic arch; retroesophageal subclavian artery; dilated ascending aorta/pulmonary trunk and muscular/membranous ventricular septal defect. Minor blood vessels were also affected, with variation in the origin of the subclavian, carotid and innominate arteries from the aortic arch.
Many of these abnormalities and/or variants may be associated with the lower foetal weight observed at 750 mg/kg bw/day and to a lesser extent at 250 mg/kg bw/day. Partially undescended lobe of thymus, small renal papilla, shiny skin in foetal development and indicative of foetal immaturity. With the exception of partially undescended thymus, all exceeded the HCD range.
Other effects:
no effects observed
Description (incidence and severity):
Anogenital distance was unaffected by maternal treatment at all dose groups.
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
skeletal malformations
visceral malformations
Abnormalities:
effects observed, treatment-related
Localisation:
skeletal: skull
skeletal: rib
skeletal: vertebra
skeletal: pelvic girdle
visceral/soft tissue: cardiovascular
Description (incidence and severity):
Skeletal: an increase in incidence of thoracic vertebral abnormalities; medially thickened/kinked ribs; short supernumerary cervical ribs; short and full supernumerary 14th ribs; 20 thoracolumbar vertebrae; unilateral caudal shift of the pelvic girdle; a generalised delay in ossification (including cranial bones, sternebrae, all vertebrae, ribs, pelvic and digit bones) and domed cranium.

Visceral: abnormalities affecting the heart and major blood vessels. These included double/retroesophageal/right sided aortic arch; retroesophageal subclavian artery; dilated ascending aorta/pulmonary trunk and muscular/membranous ventricular septal defect. Minor blood vessels were also affected, with variation in the origin of the subclavian, carotid and innominate arteries from the aortic arch.
Developmental effects observed:
yes
Lowest effective dose / conc.:
750 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects in the absence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
not specified

Table 1 - Summary of adult thyroid hormone results on Day 20 of gestation

Group

1

2

3

4

Dose (mg/kg bw/day)

0

50

250

750

Triiodothyronine (pg/mL)

564

473**

482**

479**

Thyroxine (pg/mL)

19300

16000**

16000**

15600**

Thyroid Stimulating Hormone (pg/mL)

 

1530

 

1210

 

1430

 

1770

** p<0.01

Table 2 -Summary of treatment related findings in the thyroids for animals killed following treatment on Days 6 to 19 of gestation

Group/sex

1F

2F

3F

4F

Dose (mg/kg/bw/day)

0

50

250

750

Hypertrophy, Follicular Cell

 

 

 

 

Minimal

1

0

0

5

Total

1

0

0

5

Number of tissues examined

20

20

20

20

Conclusions:
In a prenatal developmental toxicity study in rats for 1,1,3,3-tetramethyldisiloxane, conducted according to OECD Test Guideline 414 and in compliance with GLP, the reported NOAEL for maternal toxicity was 750 mg/kg bw/day, the highest dose tested. The NOAEL for developmental toxicity was concluded to be 250 mg/kg bw/day based on abnormalities observed at 750 mg/kg/day.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Klimisch score 1
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 in rats for 1,1,3,3-tetramethyldisiloxane, conducted according to OECD Test Guideline 414 and in compliance with GLP, the reported NOAEL for maternal toxicity was 750 mg/kg bw/day, the highest dose tested. The NOAEL for developmental toxicity was concluded to be 250 mg/kg bw/day based on abnormalities observed at 750 mg/kg/day (Covance Laboratories Limited, 2020).

In the study, three groups of 20 pregnant females were given 1,1,3,3-tetramethyldisiloxaneat doses of 50, 250 or 750 mg/kg bw/day in corn oil by oral gavage administration, from gestation day 6 to 19. A similarly constituted control group received the vehicle, dried and de-acidified corn oil. All the animals were sacrificed on gestation day 20 for reproductive assessment and fetal examination.

Clinical observations, body weight and food consumption were recorded. Adult females were examined macroscopically at necropsy on day 20 after mating, and gravid uterus, thyroid, kidney and liver weights were recorded. A microscopic pathology investigation was performed on the thyroid from all pregnant animals. The anogenital distance, individual body weight and placental weights were recorded for all foetuses, and all foetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination or skeletal examination. Blood samples were taken at necropsy for subsequent thyroid hormone analysis in all pregnant animals.

The formulation chemistry investigation revealed that the concentration of 1,1,3,3-tetramethyldisiloxane in the first formulation prepared at 50 mg/kg bw/day was 18.4% of nominal, equating to an approximate dose of 41 mg/kg bw/day. This formulation was administered to Group 2 animals for up to seven days (GD 6-13). However, it is considered that this did not impact on the results of the study, as the NOAEL for maternal toxicity and foetal survival and development were set at a higher dose.

Throughout the study period, no treatment related clinical signs occurred in the maternal animals. Signs associated with dosing comprised of two animals at 250 mg/kg bw/day and four animals at 750 mg/kg bw/day with transient salivation during the final three days of treatment. This was attributed to the palatability of test item formulations. Maternal body weight gain and food intake were unaffected at any dose compared to control and there were no macroscopic findings attributed to treatment. Adjusted kidney and liver weights were higher at 750 mg/kg bw/day. However, the difference from control was marginal and there was no macroscopic finding in either tissue. Numbers of implantations, resorptions, pre- and post-implantation losses, live young and the male and female ratio were unaffected by the treatment at any dose level. Foetal weight was marginally low, or lower, at 250 or 750 mg/kg bw/day (91% or 80% of control, respectively). Anogenital distance was unaffected by maternal treatment at 50, 250 and 750 mg/kg bw/day.

At 750 mg/kg bw/day, there was a suggestion of a minor non-adverse effect on thyroid function in maternal animals. Mean serum T4 and T3 concentrations were slightly but statistically significantly lower than in the controls (no dose response was apparent) and microscopic examination of the thyroids revealed five females had minimal follicular cell hypertrophy compared to one in the control. Individual T4 and T3 concentrations were highly variable and all T4 concentrations were within the concurrent control range. The reduction in T4/T3 concentrations was only slight and there was no obvious correlation to the occurrence of follicular cell hypertrophy. The mean serum thyroid stimulating hormone (TSH) concentrations were unaffected. Therefore, TSH levels do not accompany reduced T4/T3 concentrations or thyroid follicular cell hypertrophy and suggest that no definite effects on thyroid function was observed and therefore, not considered as adverse. At 50 or 250 mg/kg bw/day, the mean serum T4/T3 concentrations were slightly statistically significantly lower than the control group. However, no dose response supporting microscopic changes in the thyroids or increase in TSH concentrations occurred. Consequently, the slightly reduced T4/T3 concentrations are considered to be incidental and not related to treatment.

At 750 mg/kg/day, foetal abnormalities affected the heart and major blood vessels (double/retroesophageal/right sided aortic arch; retroesophageal subclavian artery; dilated ascending aorta/pulmonary trunk and muscular/membranous ventricular septal defect) and there were variations in minor blood vessels, at the origin of the subclavian, carotid and innominate arteries from the aortic arch. All of these abnormalities exceeded the Historical Control Data (HCD) range. There was also a high incidence of foetuses with a slightly domed head and thoracic vertebral abnormalities and medially thickened/kinked ribs and absent lobe of thyroid.

The majority of other (non-structural) abnormalities at 250 or 750 mg/kg/day were associated with foetal immaturity, that correlated with low foetal weights at these doses and included, short supernumerary 14th ribs and a delay in ossification (cranial bones, sternebrae, all vertebrae, ribs and pelvic bones), lens shape (oval); thyroid (small lobe); thymus (partially undescended lobe); kidney (small papilla); skin (shiny) and subcutaneous oedema. All of these abnormalities exceeded the HCD range. An external review of the data obtained from the key prenatal developmental toxicity study has been initiated to help with interpretation of the study results.

In a dose range-finding study, conducted according to a protocol similar to OECD Test Guideline 414 with deviations but not in compliance with GLP, a NOAEL was not determined (Covance CRS Limited, 2020).

The purpose of this study was to assess the influence of 1,1,3,3-tetramethyldisiloxane on embryo-foetal survival and development in the Sprague Dawley rats and to establish suitable doses for a main embryo-foetal toxicity study. All treated females received 1,1,3,3 -tetramethyldisiloxane by daily oral gavage administration, from Day 6 to 19 after mating and a similarly constituted control group received the vehicle, dried and de-acidified corn oil, at the same volume dose. At Phase 1, three animals were treated at 0, 300 or 600 mg/kg bw/day. After one week of treatment the data showed that these doses were well tolerated. At Phase 2 a high dose of 1000 mg/kg bw/day was included. Phase 2 commenced two weeks after commencement of treatment to Phase 1.Clinical observations, body weight and food consumption were recorded. Adult females were examined macroscopically at necropsy on Day 20 after mating and the gravid uterus, kidneys and liver weights of the adult were recorded. All foetuses were examined macroscopically at necropsy.

Lower overall body weight gain and gravid uterine weight were noted for maternal animals at 1000 mg/kg bw/day. The numbers of pre- and post-implantation losses were higher and resulted in a low mean litter size at 1000 mg/kg bw/day compared to control. Pre-implantation loss was higher at 600 mg/kg/day compared to control also. Liver weights appeared to be marginally higher at 600 or 1000 mg/kg bw/day compared to control; however, no definite relationship to treatment was inferred. Domed craniums were seen in the majority of foetuses in one litter at 600 mg/kg bw/day and the majority of litters at 1000 mg/kg bw/day. Whole body oedema was noted in the majority of foetuses in one litter and one foetus from each of two litters at 1000 mg/kg bw/day. Protruding tongue was noted in one foetus from one litter at 1000 mg/kg bw/day; short snout was noted in two foetuses from one litter at 1000 mg/kg bw/day.

Data for the final hydrolysis product, dimethylsilanediol (DMSD), have been included in the dossier to allow risk characterisation for exposure of humans via the environment.

In the prenatal developmental toxicity study, conducted according to OECD Test Guideline 414 and in compliance with GLP, dimethylsilanediol was administered orally to pregnant female rats during gestation days 6 to 19 at doses of 0, 250, 500 or 1000 mg/kg bw/day (WIL Research, 2013).

Administration of dimethylsilanediol to pregnant rats at doses of 0, 250, 500 or 1000 mg/kg bw/day resulted in a maternal No-Observed-Adverse-Effect-Level (NOAEL) of less than 250 mg/kg bw/day based on higher mean liver weights and corresponding microscopic findings of hepatocellular hypertrophy and periportal hepatocellular vacuolation at all doses.

A higher mean litter proportion of post implantation loss, with a corresponding lower mean litter proportion of viable foetuses, was considered attributable to treatment and adverse in the 1000 mg/kg bw/day group.

Mean foetal body weights at the three doses were 5.3%, 10.5%, and 23.7% lower, respectively, than the concurrent control group. The mean foetal weight in the 250 mg/kg bw/day group was within the historical control data range and was only 0.2 g lower than the concurrent control group mean. Furthermore, litter size can be affected by treatment so additional statistical analysis of the foetal weight data using an appropriate statistical method specific for this type of data, which takes litter size into account, demonstrated that foetal weight at 250 mg/kg bw/day was comparable with control and not statistically significant and therefore unaffected by treatment at this dose.

Foetal malformations were noted in the 500 and 1000 mg/kg bw/day groups, but not in the 250 mg/kg bw/day group. Foetal variations were recorded in all dose groups with some visceral (small thyroid gland) and skeletal variations in the 250 mg/kg bw/day group showing a dose-response relationship. However, many of the foetal variations noted in the 250 mg/kg bw/day group were either recorded at an incidence that was not statistically significant and/or within the historical control incidence. Furthermore, as many, but not all, of these variations (skeletal developmental delays) correlate with foetal body weight, and foetal body weight was not affected by treatment, then the variations noted at the low dose of 250 mg/kg bw/day are also considered not to be attributable to treatment.

It is important to note that 1) malformations are alterations in foetal morphology that are expected to be permanent and to interfere with the function or viability of the organism, and 2) variations are alterations that are transient, do not interfere with the function or viability of the organism, and are often seen in control animals. Based on the fact that variations are not considered adverse the variations recorded in the prenatal developmental toxicity study on dimethylsilanediol should not be considered as adverse findings and the lowest dose of 250 mg/kg bw/day is the NOAEL based on reduced foetal body weight and malformations at the middle and high doses.

Therefore, the NOAEL for prenatal developmental toxicity was considered to be 250 mg/kg bw/day.

In the combined repeated dose toxicity study with the reproduction / developmental toxicity screening test with dimethylsilanediol, conducted according to OECD Test Guideline 422 and in compliance with GLP, the NOAEL for general systemic toxicity was 250 mg/kg bw/day based on hepatic brown pigment accumulation in and around the bile ducts, with associated bile duct hyperplasia and chronic inflammation at 500 mg/kg bw/day, and ≥500 mg/kg bw/day for reproductive and developmental toxicity (Dow Corning Corporation, 2009).

Justification for classification or non-classification

An external review of the data obtained from the key prenatal developmental toxicity study has been initiated to help with interpretation of the study results and the need to classify or not.