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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
20 November 2019 to 13 March 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 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
Adopted 25 June 2018
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Version / remarks:
August 1998
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, 12 Nohsan No. 8147, Agricultural Production Bureau
Version / remarks:
November 24, 2000
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Decamethyltetrasiloxane
EC Number:
205-491-7
EC Name:
Decamethyltetrasiloxane
Cas Number:
141-62-8
Molecular formula:
C10H30O3Si4
IUPAC Name:
2,2,4,4,6,6,8,8-octamethyl-3,5,7-trioxa-2,4,6,8-tetrasilanonane
Test material form:
liquid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl:CD(SD)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd.
- Age at study initiation: 68 to 81 days old
- Weight at study initiation: 203 to 300 g
- Fasting period before study: not specified
- Housing: During acclimatisation the animals were housed in groups of four; during mating the animals were housed in groups of two (one (stock) male and one female); during gestation the pregnant females were housed individually.
- Diet (e.g. ad libitum): SDS VRF1 Certified pelleted diet, ad libitum
- Water (e.g. ad libitum): Potable water from the public supply, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 40-70%
- Air changes (per hr): Not specified. Filtered fresh air which was passed to atmosphere and not recirculated.
- Photoperiod (hrs dark / hrs light): 12 hours light: 12 hours dark

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Remarks:
dried and de-acidified
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Formulation were prepared in a glove box under nitrogen. An appropriate volume of vehicle was dispensed into
containers prior to starting test formulations. Then a series of formulations at the required concentrations were prepared by adding an appropriate volume of test item to an appropriate volume of dried and de-acidified corn oil. The dose formulations were prepared weekly.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on the test item characteristics and in consultation with the study Sponsor.
- Concentration in vehicle: 0, 29.5, 88.5, 295 mg/mL
- Amount of vehicle (if gavage): 4 mL/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Before commencement of treatment, the suitability of the proposed mixing procedures was determined and specimen formulations were analysed to assess the stability and homogeneity of the test item in the liquid matrix.
Samples of each formulation prepared for administration on the first and last preparations of treatment were analysed for achieved concentration of the test item.
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1:1 ratio
- Length of cohabitation: not specified
- 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
Duration of treatment / exposure:
During gestation days 6 to 19
Frequency of treatment:
daily
Duration of test:
20 days
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Control group
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Remarks:
Low dose (LD)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Remarks:
Middle dose (MD)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Remarks:
High dose (HD)
No. of animals per sex per dose:
20 females per group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The doses used in this study (0, 100, 300 and 1000 mg/kg bw/day) were selected in conjunction with the Sponsor based on the findings of a preliminary embryo-foetal study (Covance Study Number: FD94JJ; Covance CRS Limited, 2020). In that study, doses of 500, 750 or 1000 mg/kg bw/day were generally well tolerated in life with no adverse effects on general condition, body weight gain or food intake. No changes were seen in tissues during macroscopic examination, however liver weights were increased at all dose levels. On Day 20 of gestation, mean number of implantations, resorptions and the number of live young was considered to be unaffected by treatment.
- Rationale for animal assignment (if not random): random

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Cages and cage-trays were inspected daily for evidence of animal ill-health among the occupant(s). Signs associated with dosing were recorded daily at pre-dose administration, 1 to 2 hours after dosing and as late as possible on the working day after dosing.
- Cage side observations checked included: general health and signs associated with dosing

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Days 0, 5, 12, 18 and 20 after mating to monitor general health

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

FOOD CONSUMPTION: Yes
- Time schedule: 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, 6-7, 8-10, 11-13, 14-16 and 17-19 after mating inclusive.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: At necropsy thyroid with parathyroids, liver, kidneys and any macroscopic abnormalities were collected; thyroid with parathyroids, liver, kidneys (weighed together) and gravid Uterus (with cervix) were weighed at necropsy; thyroid with parathyroids were examined at histology and pathology (light microscopy).

OTHER: Thyroid hormone analysis
- Time schedule: Blood samples were collected at scheduled termination.
- Parameters analysed: Triiodothyronine (T3) Thyroxine (T4) Thyroid stimulating hormone (TSH)
- Fasting before collection of blood samples: No overnight deprivation of food.
- Anaesthetic used: Isoflurane
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: foetuses (live or dead): 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: Yes: [half per litter]
- Other: anogenital distance
Statistics:
Data relating to food consumption were analysed on a cage basis. For all other adult parameters, the analyses were carried out using the individual animal as the basic experimental unit. For litter/foetal findings the litter was taken as the treated unit and the basis for statistical analysis and biological significance was assessed with relevance to the severity of the anomaly and the incidence of the finding within the background control population.
The following sequence of statistical tests was used for body weight, gravid uterus weight, food consumption, implantations, litter size, sex ratio - percentage male, post implantation survival index, ano-genital distance and organ weight data:
A parametric analysis was performed if Bartlett's test for variance homogeneity was not significant at the 1% level. The F1 approximate test was
applied. If the F1 approximate test for monotonicity of dose-response was not significant at the 1% level, Williams' test for a monotonic trend 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. The H1 approximate test, the non-parametric equivalent of the F1 test, 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, Steel's test was performed instead.
For organ weight data, analysis of covariance was performed using terminal body weight, unless non-parametric methods were applied. The treatment comparisons were made on adjusted group means. Similarly, for the litter average anogenital distance, analysis of covariance was performed using the average pup body weight/foetal weight for each litter.
Significant differences between the groups compared were expressed at the 5% (p<0.05) or 1% (p<0.01) level.
Historical control data:
See attached files.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
There were no clinical signs considered related to treatment and no signs seen in association with dosing with decamethyltetrasiloxane at dose levels up to 1000 mg/kg bw/day.
Mortality:
no mortality observed
Description (incidence):
No mortality was observed for any test group.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There was no adverse effect of treatment on body weight gain during gestation at 100, 300 or 1000 mg/kg bw/day.
Mean body weight and overall body weight gain of treated females was slightly higher than the control females, although statistical significance was only attained for gains. When overall body weight gain was adjusted for the contribution of the gravid uterus, differences from the control group no longer attained statistical significance. In the absence of any consistent dose-response, these differences in body weight gains were considered to be incidental and unrelated to treatment.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There was no effect of treatment with decamethyltetrasiloxane on food intake at 100, 300 or 1000 mg/kg bw/day.
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, treatment-related
Description (incidence and severity):
The mean gravid uterine weight for treated females on Day 20 was marginally higher than control, and consistent with small differences in litter size rather than any treatment-related effect.
The group mean weight of the liver adjusted by terminal body weights was higher in treated females, when compared with the controls (between 114 – 123%). The group mean values for kidney weights or thyroid and parathyroid weights were similar to Control.
Gross pathological findings:
no effects observed
Description (incidence and severity):
The macroscopic examination performed on Day 20 after mating revealed no test item-related findings.
The incidence and distribution of all findings were considered to be unrelated to treatment.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Changes related to treatment with decamethyltetrasiloxane given by oral gavage were seen in the thyroid glands. An increase in the incidence of diffuse follicular cell hypertrophy, when compared to controls, was seen in females given 300 or 1000 mg/kg bw/day.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
The analysis of serum TSH concentrations performed at scheduled termination on Day 20 of gestation revealed slightly higher concentrations in all treated groups, although there was no dose-response.
There was a slight decrease in the mean serum thyroxine (T4) and triiodothyronine (T3) concentration in all treated groups, although there was no dose-response.
Details on results:
Increased liver weights were anticipated, based on the findings of a 28-day study (ECHA), and were evident in this study. The increase in liver weights seen in all treated females may indicate a non-adverse, adaptive response to general toxic insult, and may be the major factor contributing to the elevated thyroid stimulating hormone (TSH) levels. Consequently, the levels of thyroxine (T4) or triiodothyronine (T3) were reduced, as would be expected in a normal physiologically functioning system. Furthermore, the higher incidence of follicular cell hypertrophy was considered secondary to the increase in TSH, although no increase in hypertrophy was evident at 100 mg/kg bw/day.

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
effects observed, non-treatment-related
Description (incidence and severity):
All animals were found to be pregnant at macroscopic examination, with the exception of animal No. 38 receiving 100 mg/kg bw/day, therefore, reproductive assessment is based on 20, 19, 20 and 20 litters from the control, 100, 300 and 1000 mg/kg bw/day groups, respectively.
Details on maternal toxic effects:
There was no effect of maternal treatment on embryo-foetal survival, as assessed by the number of resorptions or incidence of post-implantation losses, or subsequent live litter size at 100, 300 or 1000 mg/kg bw/day.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: No adverse effects were observed.

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
Litter and foetal weights were unaffected by maternal treatment with decamethyltetrasiloxane at 100, 300 and 1000 mg/kg bw/day.
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
At 1000 mg/kg bw/day there was a slight increase in incidence of variation in contralateral lens shape and oval lenses. All incidences are within historical control data range. Incomplete lens shape variation is a transient stage in foetal development, indicative of foetal immaturity and considered not to be adverse.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The incidence of major abnormalities showed no relationship to maternal treatment. Across the treated groups and compared to concurrent control, there was an increase in foetal and litter incidences of delayed ossification affecting the cranial centres, hyoid, 1st to 4th sternebrae, thoracic and sacral/caudal vertebrae and pelvic bones. All incidences are within historical control data range. Incomplete ossification is a transient stage in foetal development, indicative of foetal immaturity and considered not to be adverse.
Visceral malformations:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
Anogenital distances were unaffected by treatment with decamethyltetrasiloxane at 100, 300 and 1000 mg/kg bw/day.
Details on embryotoxic / teratogenic effects:
There was no effect of maternal treatment on embryo-foetal survival and subsequent live litter size at 100, 300 or 1000 mg/kg bw/day. Sex ratio was similar to the control group in all treated groups indicating no selective effect of sex on embryo-foetal survival.
There were no major abnormalities that were considered treatment-related at foetal examination. Minor abnormalities included an increase in incidence of delayed ossification across all treated groups and lens shape variation at 1000 mg/kg bw/day. These abnormalities are considered transient stages in foetal development, indicative of foetal immaturity and considered not to be adverse.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse developmental effects were observed.

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

The mean analysed concentrations of decamethyltetrasiloxane were within 5% of the nominal values, confirming the accuracy of formulation preparation.

Table 1: Summary of findings in the thyroid gland for animals killed on Day 20 after mating

Group/sex

1F

2F

3F

4F

Dose (mg/kg bw/day)

0

100

300

1000

Hypertrophy, Follicular Cells

 

 

 

 

Minimal

2

3

8

13

Total

2

3

8

13

Number of tissues examined

20

20

19

20

See attachments for results tables.

Applicant's summary and conclusion

Conclusions:
In a prenatal developmental toxicity study for decamethyltetrasiloxane in rats, conducted according to OECD Test Guideline 414 and in compliance with GLP, the NOAEL for maternal and developmental toxicity was concluded to be equal to or greater than 1000 mg/kg bw/day (the highest dose tested) based on no treatment-related adverse effects observed. Liver weights were slightly increased at all dose levels of 100 mg/kg/day, or above. The increase in liver weights may indicate a non-adverse, adaptive response to general toxic insult, and may be the major factor contributing to the elevated thyroid stimulating hormone (TSH) levels. Consequently, the levels of thyroxine (T4) or triiodothyronine (T3) were reduced, as would be expected in a normal physiologically functioning system. Furthermore, the higher incidence of follicular cell hypertrophy was considered secondary to the increase in TSH, although no increase in hypertrophy was evident at 100 mg/kg bw/day.