Registration Dossier
Registration Dossier
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EC number: 240-914-9 | CAS number: 16881-77-9
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
In accordance with Column 1, Section 8.7.3 of REACH Annex IX the extended one-generation reproductive toxicity study does not need to be conducted since no adverse effects on reproductive organs and tissues were observed in a 90-day repeated dose toxicity study.
Link to relevant study records
- 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
Reference
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
According to Regulation (EC) No. 1907/2006, Annex IX, 8.7.3. column 1, an extended one-generation study for the assessment of reproductive toxicity is required if the available repeated dose toxicity studies indicate adverse effects on reproductive organs or tissues or reveal other concerns in relation with reproductive toxicity. A 13-week oral repeated dose toxicity study is available for dimethoxy(methyl)silane, as well as a pre-natal developmental toxicity study. In the 13-week study, there was no effect on oestrous cycle, nor were any other effects observed on male and female reproductive organs. In the pre-natal developmetal toxicity study, there was no effect on any reproductive or developmental parameters. Thus, no extended one-generation reproductive toxicity study with dimethoxy(methyl)silane is required.
Effects on developmental toxicity
Description of key information
OECD 414 (rat): NOAEL (maternal and developmental toxictiy) >= 1000 mg/kg bw/day
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 19 March to 9 June 2020
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- July 2018
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River UK
- Age at study initiation: 69 to 77 days old
- Weight at study initiation: 212 to 277 g
- Fasting period before study: Not reported
- Housing: Housed up to 4 animals per cage during acclimatization; housed one stock male and one female during pairing; and individually house during gestation
- Diet: SDS VRF1 Certified pelleted diet provided ad libitum
- Water: Water provided ad libitum
- Acclimation period: At least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 40-70
- Air changes (per hr): at least 15 air changes/hour
- Photoperiod (hrs dark / hrs light): 12 hours light: 12 hours dark - Route of administration:
- oral: gavage
- Vehicle:
- other: dried and de-acidified corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: A series of formulations at the required concentrations were prepared by dilution of individual weighings of the test item in ascending order of concentration. 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. The preparations were prepared twice weekly and stored at 2 to 8°C.
VEHICLE
- Amount of vehicle (if gavage): 4 mL/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Homogeneity and stability of formulations were confirmed as part of another study. The procedural recovery results during the last preparation was within ± 7.5% of the mean recovery found during validation showing the continued accuracy of the method.
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug and sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- Day 6 to 19 of gestation
- Frequency of treatment:
- Once daily
- Duration of test:
- Day 6 to 19 of gestation
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 600 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 20 females per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels for investigation in this main embryo-fetal study were selected in conjunction with the sponsor and were based on the results of a combined pilot and preliminary embryo-fetal study conducted at these laboratories. In that study, dose levels of 300, 600 and 1000 mg/kg bw/day were investigated during the preliminary embryo-fetal phase. There were no premature deaths, no signs observed in relation to dose administration, no test item-related changes in clinical condition, no adverse effects on body weight, food consumption or embryo-fetal survival and development and no treatment related macroscopic findings at any dose level investigated. Absolute and body weight adjusted liver weights were slightly higher than control for all groups of treated females, however, there was no dose response apparent.
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: A viability check was performed near the start and end of each working day. Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Cages were inspected daily for evidence of animal ill-health.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: 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
- Time schedule for examinations: The weight of each adult was recorded on Days 0, 3 and 6-20 after mating.
FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: Kidney, liver, thyroid with parathyroids, gravid uterus with cervix
OTHER: A thyroid hormone analysis was conducted. Blood sample were taken after animals were fasted overnight. Animals were anesthetized with 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 - 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:
- The following sequence of statistical tests was used for, body weight, gravid uterus weight, food consumption, corpora lutea, implantations, pre/post implantation loss, live young, sex ratio - percentage male, litter and fetal weights, ano-genital distance, organ weight data and thyroid hormones:
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. Where this was significant (p<0.05), 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 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, Dunnett's test was performed instead.
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) inter group 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, Steel's test was performed instead.
For organ weight data, analysis of covariance was performed using terminal body weight as covariate, unless non-parametric methods were applied. For the litter average ano-genital distance, analysis of covariance was performed using the average pup body weight/fetal weight for each litter as the covariate. - Indices:
- Pre-implantation loss (%) = ((Number of corpora lutea - Number of implantations)/Number of corpora lutea) X 100
Post-implantation loss (%) = ((Number of implantations - Number of live fetus)/Number of implantations) X 100 - Historical control data:
- Historical control data were presented for fetal external, skeletal, and visceral examinations.
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no clinical signs or signs observed following dose administration that were considered to be related to the test item.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One high-dose female was sacrified prior to study termination due to signs of decreased activity, irregular breathing, piloerection, whole body pallor and being abnormally cold to touch.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There was no statistically significant adverse effect of treatment on body weight gain at any dose level investigated as compared to the control.
Overall body weight gain throughout the treatment period (Days 6 to 20 of gestation) for all groups of treated females was slightly higher than control.
Mean gravid uterine weight and mean adjusted maternal body weight gain were higher than control in all groups of treated females, however, the extent of these changes were not considered adverse.(Table 1). - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- There was no statistically significant adverse effect of treatment on food consumption as compared to the control because the food intake of all groups of treated females appeared generally slightly higher than or similar to control throughout the treatment period.
- 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):
- Absolute and body weight adjusted liver weights were higher than control in all groups of treated females with a dose-response apparent and statistical significance attained at 1000 and 300 mg/kg bw/day. This change is considered to be an adaptive change largely observed in the rat.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no maternal findings observed at macroscopic examination that were considered to be related to the test item.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There was an increased incidence of minimal/slight follicular cell hypertrophy of the thyroid at 300 and 1000 mg/kg bw/day. This effect coupled with the others observed suggest hepatic microsomal enzyme induction. This change is considered to be an adaptive change largely observed in the rat.
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- At 1000 mg/kg bw/day, the mean serum triiodothyronine (T3) concentration was slightly lower than control with statistical significance attained. There was no effect of treatment on mean serum T3 concentrations at 300 or 100 mg/kg bw/day or on mean serum T4 concentrations at any dose level investigated. However, following a review of the individual data, a majority of the control and high dose values were within the same range and without a dose response, suggesting this difference is not considered to be adverse.
At 1000 mg/kg bw/day, the mean serum thyroid stimulating hormone (TSH) concentration was statistically significantly higher than control. This change is considered to be an adaptive change largely observed in the rat. - Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- The extent of pre- and post-implantation losses were not adversely effected by maternal treatment at 100, 300 or 1000 mg/kg bw/day.
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- Litter data as assessed by the mean numbers resorptions were not adversely effected by maternal treatment at 100, 300 or 1000 mg/kg bw/day.
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- Litter data as assessed by the mean numbers resorptions were not adversely effected by maternal treatment at 100, 300 or 1000 mg/kg bw/day.
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- not examined
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- One control female and one female that received 1000 mg/kg bw/day were found not to be pregnant at macroscopic examination; therefore, taking into account the one premature death at 1000 mg/kg bw/day, there were 19, 20, 20 and 18 females at 0, 100, 300 or 1000 mg/kg bw/day with live fetuses at necropsy for evaluation, respectively.
- Other effects:
- no effects observed
- Details on maternal toxic effects:
- At microscopic examination of the thyroids, increased incidence and severity, compared to controls, of follicular cell hypertrophy was observed at 300 and 1000 mg/kg bw/day. The increased body weight relative liver weights observed at these dose levels, in conjunction with the increased mean serum TSH concentration at 1000 mg/kg bw/day, suggest this finding may be indicative of hepatic microsomal enzyme induction leading to increased metabolism of thyroid hormones and chronic TSH stimulation of the thyroid gland. This change is considered to be an adaptive response that is largely specific to the rat and, therefore, not considered to be adverse. At 1000 mg/kg bw/day the mean serum T3 concentration was statistically significantly lower than control, however following a review of the individual data, a majority of the control and high dose values were within the same range and without a dose response, this difference is not considered to be adverse.
- 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 observed
- Key result
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- There was no statistically significant adverse effect of treatment on litter or fetal weights.
The total litter weight at 1000 mg/kg bw/day was slightly higher than control, likely reflecting the slightly higher number of live young in this dose group. - Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- The mean numbers of live young were not adversely effected by maternal treatment at 100, 300 or 1000 mg/kg bw/day.
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Anogenital distance of all rodent fetuses:
- no effects observed
- Description (incidence and severity):
- There was no statistically significant effect of treatment on ano-genital distance as compared to the control.
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- The incidence of major and minor abnormalities and skeletal variants showed no relationship to treatment.
At 1000 mg/kg bw/day there was a slightly increased incidence of short supernumerary cervical rib compared to concurrent control and just outside of HCD range, however, these are an ossified site rather than a fully formed rib and considered to be transient in rodents (Chernoff et al., 1991). This isolated finding was considered incidental and therefore not adverse (tables 11). - Visceral malformations:
- no effects observed
- Other effects:
- not examined
- Details on embryotoxic / teratogenic effects:
- There were no adverse effects on anogenital distance or fetal and litter weights, and there were no major or minor abnormalities or skeletal variants considered related to treatment at any dose level investigated.
- 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 effects observed
- Key result
- Abnormalities:
- no effects observed
- Key result
- Developmental effects observed:
- no
- Conclusions:
- In an OECD 414 (prenatal developmental toxicity study) study conducted in accordance to GLP, the test substance, dimethoxy(methyl)silane (CAS RN 16881-77-9) was not associated with developmental toxicity via oral exposure. The findings support a NOAEL of 1000 mg/kg bw/day.
Reference
TABLE 1 Body weight and body weight change - group mean values (g) during gestation
|
Control |
Dimethoxy(methyl)silane |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg bw/day) |
0 |
100 |
300 |
1000 |
Group |
Day |
|
|
|
|
|
|
|
|
|
|
|
|
|
/Sex |
0 |
3 |
6 |
7 |
8 |
9 |
10 |
11 |
12 |
13 |
14 |
15 |
16 |
|
Statisticstest |
Av |
Av |
Av |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
|
1F |
Mean |
254 |
271 |
285 |
286 |
293 |
297 |
302 |
307 |
314 |
317 |
324 |
331 |
342 |
|
SD |
12.8 |
12.8 |
13.3 |
13.7 |
15.1 |
15.7 |
14.5 |
15.6 |
16.1 |
17.4 |
17.6 |
19.3 |
21.6 |
|
N |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
2F |
Mean |
254 |
271 |
285 |
287 |
291 |
297 |
303 |
311 |
317 |
322 |
328 |
336 |
347 |
|
SD |
10.0 |
10.2 |
12.6 |
12.0 |
13.1 |
12.2 |
15.1 |
13.8 |
14.0 |
14.3 |
15.1 |
15.4 |
15.6 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
3F |
Mean |
251 |
267 |
282 |
285 |
291 |
296 |
304 |
310 |
317 |
322 |
328 |
338 |
348 |
|
SD |
13.4 |
15.1 |
15.4 |
16.2 |
17.1 |
17.1 |
18.6 |
19.8 |
19.6 |
21.0 |
21.3 |
22.5 |
24.0 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
4F |
Mean |
249 |
265 |
278 |
280 |
283 |
286 |
293 |
299 |
303 |
308 |
314 |
323 |
333 |
|
SD |
16.6 |
16.3 |
17.9 |
19.5 |
20.0 |
23.4 |
23.4 |
22.9 |
22.6 |
21.5 |
21.0 |
21.3 |
22.9 |
N 19 19 19 19 19 19 19 19 19 19 19 19 19 |
||||||||||||||
TABLE 1 (cont) Body weight and body weight change - group mean values (g) during gestation
Group |
Day |
|
|
|
Change |
Change |
|
/Sex |
17 |
18 |
19 |
20 |
0-6 |
6-20 |
|
Statistics test |
Wi |
Wi |
Wi |
Wi |
Av |
Wi |
|
1F |
Mean |
354 |
369 |
383 |
397 |
31 |
112 |
|
SD |
24.7 |
27.4 |
30.0 |
32.6 |
6.5 |
22.6 |
|
N |
19 |
19 |
19 |
19 |
19 |
19 |
2F |
Mean |
361 |
375 |
391 |
408 |
31 |
123 |
|
SD |
17.5 |
17.9 |
19.4 |
21.4 |
10.0 |
14.8 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
3F |
Mean |
362 |
377 |
391 |
411 |
31 |
129* |
|
SD |
24.6 |
25.0 |
27.8 |
29.7 |
7.2 |
18.6 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
4F |
Mean |
349 |
367 |
381 |
400 |
29 |
123* |
|
SD |
22.7 |
24.0 |
24.4 |
25.4 |
8.3 |
13.5 |
N 18 18 18 18 19 18 |
|||||||
TABLE 2 Gravid uterine weight, adjusted body weight and adjusted body weight change - group mean values (g) on Day 20 of gestation
|
Control |
Dimethoxy(methyl)silane |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg bw/day) |
0 |
100 |
300 |
1000 |
Group |
Body weight |
Terminal body weight |
Body weight |
Gravid uterine |
Adjusted body weight |
Adjusted body weight |
|
/Sex |
Day 6 |
Day 20 |
change 6-20 |
weight |
Day 20 |
change 6-20 |
|
Statistics test |
Av |
Wi |
Wi |
Sh |
Wi |
Du |
|
1F |
Mean |
285 |
397 |
112 |
83.6 |
313 |
28 |
|
SD |
13.3 |
32.6 |
22.6 |
23.12 |
17.2 |
7.1 |
|
N |
19 |
19 |
19 |
19 |
19 |
19 |
2F |
Mean |
285 |
408 |
123 |
86.2 |
322 |
36* |
|
SD |
12.6 |
21.5 |
14.8 |
17.31 |
16.0 |
9.1 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
3F |
Mean |
282 |
410 |
128* |
88.3 |
322 |
40** |
|
SD |
15.4 |
29.4 |
18.2 |
15.18 |
24.7 |
12.5 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
4F |
Mean |
277 |
400 |
123* |
92.2 |
308 |
30 |
|
SD |
18.1 |
26.0 |
13.7 |
9.10 |
25.3 |
11.3 |
N 18 18 18 18 18 18 |
|||||||
TABLE 3 Food consumption - group mean values (g/animal/day) during gestation
|
Control |
Dimethoxy(methyl)silane |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg bw/day) |
0 |
100 |
300 |
1000 |
Group |
Day |
|
|
|
|
|
|
/Sex |
0-3 |
3-6 |
6-10 |
10-14 |
14-18 |
18-20 |
|
Statistics test |
Av |
Av |
Sh |
St |
Wi |
Wi |
|
1F |
Mean |
20 |
22 |
20 |
21 |
23 |
22 |
|
SD |
1.5 |
1.9 |
1.6 |
1.5 |
2.7 |
2.0 |
|
N |
19 |
19 |
19 |
19 |
19 |
19 |
2F |
Mean |
21 |
22 |
20 |
22 |
24 |
23 |
|
SD |
2.6 |
2.7 |
1.8 |
2.0 |
2.3 |
2.1 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
3F |
Mean |
20 |
23 |
21 |
23* |
25 |
24* |
|
SD |
2.5 |
1.6 |
1.9 |
2.4 |
2.7 |
2.4 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
4F |
Mean |
21 |
23 |
19 |
20 |
23 |
24** |
|
SD |
2.6 |
2.3 |
3.9 |
3.5 |
3.4 |
2.5 |
N 19 19 19 19 18 18 |
|||||||
TABLE 4 Organ weights - group mean absolute and adjusted values (g) on Day 20 of gestation
|
Control |
Dimethoxy(methyl)silane |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg bw/day) |
0 |
100 |
300 |
1000 |
Group /Sex |
Terminal Body weight |
Kidneys |
Liver |
Thyroids and Parathyroids |
||
Statistics test |
Wi |
|
|
|
||
1F |
Mean |
397.0 |
1.992 |
16.232 |
0.013 |
|
|
SD |
32.6 |
0.214 |
1.564 |
0.004 |
|
|
N |
19 |
19 |
19 |
19 |
|
2F |
Mean |
407.7 |
2.032 |
17.173 |
0.013 |
|
|
SD |
21.5 |
0.206 |
0.960 |
0.004 |
|
|
N |
20 |
20 |
20 |
20 |
|
3F |
Mean |
410.1 |
2.066 |
17.777 |
0.015 |
|
|
SD |
29.4 |
0.222 |
1.576 |
0.004 |
|
|
N |
20 |
20 |
20 |
20 |
|
4F |
Mean |
399.9 |
2.018 |
17.572 |
0.013 |
|
|
SD |
26.0 |
0.200 |
1.780 |
0.003 |
|
N |
18 |
18 |
18 |
18 |
||
Statistics test |
|
Wi |
Wi |
Wi |
||
1F |
Adjusted Mean |
2.019 |
16.521 |
0.013 |
||
2F |
Adjusted Mean |
2.018 |
17.012 |
0.013 |
||
3F |
Adjusted Mean |
2.042 |
17.515** |
0.015 |
||
4F |
Adjusted Mean |
2.033 |
17.736** |
0.014 |
||
TABLE 5 Macropathology - group distribution of findings on Day 20 of gestation
|
Control |
Dimethoxy(methyl)silane |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg bw/day) |
0 |
100 |
300 |
1000 |
|
|
Number of animals affected |
|||
|
Group/Sex |
1F |
2F |
3F |
4F |
Tissue/Organ and Findings |
No. of animals |
19 |
20 |
20 |
18 |
Number of animals within normal limits |
|
17 |
19 |
20 |
16 |
Adipose Tissue Cyst(s) |
|
0 |
0 |
0 |
1 |
Kidneys Cyst(s) |
|
0 |
1 |
0 |
0 |
Depression(s) |
|
0 |
1 |
0 |
0 |
Ovaries Periovarian sac distention |
|
1 |
0 |
0 |
0 |
Placenta Enlarged |
|
1 |
0 |
0 |
0 |
Thyroids and Parathyroids Small |
|
0 |
0 |
0 |
1 |
TABLE 6 Histopathology - group distribution of findings on Day 20 of gestation
|
Control |
Dimethoxy(methyl)silane |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg bw/day) |
0 |
100 |
300 |
1000 |
|
|
Number of animals affected |
|||
|
Group/Sex |
1F |
2F |
3F |
4F |
Tissue/Organ and Findings |
No. of animals |
19 |
20 |
20 |
18 |
Parathyroids |
No. examined |
19 |
19 |
20 |
17 |
Thyroids |
No. examined |
19 |
20 |
20 |
18 |
Hypertrophy, Follicular Cells |
Minimal |
4 |
5 |
4 |
5 |
|
Slight |
0 |
0 |
3 |
5 |
Total 4 5 7 10 |
|||||
TABLE 7 Litter data - group mean values on Day 20 of gestation
|
Control |
Dimethoxy(methyl)silane |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg bw/day) |
0 |
100 |
300 |
1000 |
Group |
Corpora |
Implantations |
Resorptions |
Implantation loss (%) |
Live young |
Sex ratio |
||||||
/Sex |
lutea |
|
Early |
Late |
Total |
Pre- |
Post- |
Male |
Female |
Total |
(%M) |
|
Statistics test |
Wi |
Sh |
|
|
|
sWi |
sWi |
|
|
Sh |
Wi |
|
1F |
Mean |
16.8 |
14.9 |
0.8 |
0.0 |
0.8 |
12.5 |
7.2 |
6.8 |
7.4 |
14.2 |
50.5 |
|
SD |
2.93 |
4.12 |
0.98 |
0.00 |
0.98 |
18.93 |
11.81 |
2.35 |
2.61 |
4.09 |
14.77 |
|
N |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
19 |
2F |
Mean |
17.3 |
14.9 |
0.4 |
0.0 |
0.4 |
14.5 |
2.0 |
7.1 |
7.5 |
14.5 |
48.2 |
|
SD |
2.73 |
3.44 |
0.59 |
0.00 |
0.59 |
17.69 |
3.30 |
2.21 |
2.26 |
3.20 |
10.79 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
3F |
Mean |
16.9 |
15.4 |
0.6 |
0.0 |
0.6 |
8.9 |
4.0 |
7.3 |
7.6 |
14.8 |
48.7 |
|
SD |
2.47 |
2.58 |
0.60 |
0.00 |
0.60 |
8.07 |
4.07 |
2.05 |
1.90 |
2.61 |
10.85 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
4F |
Mean |
17.4 |
16.3 |
0.8 |
0.0 |
0.8 |
7.2 |
5.1 |
8.4 |
7.1 |
15.5 |
54.1 |
|
SD |
1.88 |
1.53 |
0.79 |
0.00 |
0.79 |
7.73 |
4.63 |
2.33 |
1.89 |
1.65 |
13.16 |
N 18 18 18 18 18 18 18 18 18 18 18 |
||||||||||||
TABLE 8 Litter and fetal weights - group mean values (g) on Day 20 of gestation
|
Control |
Dimethoxy(methyl)silane |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg bw/day) |
0 |
100 |
300 |
1000 |
Group |
Total litter |
Male fetal |
Female fetal |
Overall fetal |
|
/Sex |
weight |
weight |
weight |
weight |
|
Statistics test |
Sh |
Wi |
Wi |
Wi |
|
1F |
Mean |
52.86 |
3.87 |
3.64 |
3.77 |
|
SD |
15.007 |
0.259 |
0.312 |
0.279 |
|
N |
19 |
19 |
18 |
19 |
2F |
Mean |
53.93 |
3.87 |
3.60 |
3.72 |
|
SD |
12.294 |
0.305 |
0.197 |
0.163 |
|
N |
20 |
20 |
20 |
20 |
3F |
Mean |
54.93 |
3.83 |
3.59 |
3.71 |
|
SD |
10.389 |
0.199 |
0.198 |
0.186 |
|
N |
20 |
20 |
20 |
20 |
4F |
Mean |
57.20 |
3.80 |
3.58 |
3.70 |
|
SD |
5.964 |
0.238 |
0.238 |
0.227 |
N 18 18 18 18 |
|||||
TABLE 9 Ano-genital distance - group mean absolute and adjusted values for fetuses on Day 20 of gestation
|
Control |
Dimethoxy(methyl)silane |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg bw/day) |
0 |
100 |
300 |
1000 |
Group |
|
Fetal weight (g) |
Ano-genital |
/Sex |
|
|
distance (mm) |
Statistics test |
|
Wi |
|
1M |
Mean |
3.9 |
3.9 |
|
SD |
0.26 |
0.39 |
|
N |
19 |
19 |
2M |
Mean |
3.9 |
3.8 |
|
SD |
0.30 |
0.39 |
|
N |
20 |
20 |
3M |
Mean |
3.8 |
3.9 |
|
SD |
0.20 |
0.35 |
|
N |
20 |
20 |
4M |
Mean |
3.8 |
4.0 |
|
SD |
0.24 |
0.25 |
|
N |
18 |
18 |
Statistics test |
|
|
Wi |
1M |
Adjusted Mean |
3.9 |
|
2M |
Adjusted Mean |
3.8 |
|
3M |
Adjusted Mean |
3.9 |
|
4M Adjusted Mean 4.0
|
|||
TABLE 9 (cont) Ano-genital distance - group mean absolute and adjusted values for fetuses on Day 20 of gestation
Group |
|
Fetal weight (g) |
Ano-genital |
/Sex |
|
|
distance (mm) |
Statistics test |
|
Wi |
|
1F |
Mean |
3.6 |
2.4 |
|
SD |
0.31 |
0.19 |
|
N |
18 |
18 |
2F |
Mean |
3.6 |
2.4 |
|
SD |
0.20 |
0.23 |
|
N |
20 |
20 |
3F |
Mean |
3.6 |
2.4 |
|
SD |
0.20 |
0.20 |
|
N |
20 |
20 |
4F |
Mean |
3.6 |
2.6 |
|
SD |
0.24 |
0.20 |
|
N |
18 |
18 |
Statistics test |
|
|
Wi |
1F |
Adjusted Mean |
2.4 |
|
2F |
Adjusted Mean |
2.4 |
|
3F |
Adjusted Mean |
2.4 |
|
4F Adjusted Mean 2 6 |
|||
TABLE 10 Fetal examinations - major abnormality findings - group incidences
|
Control |
Dimethoxy(methyl)silane |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg bw/day) |
0 |
100 |
300 |
1000 |
|
|
|
Fetuses |
|
|
Litters |
|
||
Group |
|
1 |
2 |
3 |
4 |
1 |
2 |
3 |
4 |
Number Examined |
|
269 |
290 |
296 |
279 |
19 |
20 |
20 |
18 |
Total Number Affected |
|
0 |
0 |
2 |
0 |
0 |
0 |
2 |
0 |
Cervical/Thoracic Visceral |
Right sided aortic arch |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
|
Malrotated heart |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
Lumbar (and abdominal)/Sacral/Caudal Visceral |
Dorsal hernia |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
Omphalocele 0 0 1 0 0 0 1 0 |
|||||||||
Note: Individual fetuses/litters may occur in more than one category.
TABLE 11 Fetal examinations - minor skeletal abnormality and variant findings - group incidences
|
Control |
Dimethoxy(methyl)silane |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg bw/day) |
0 |
100 |
300 |
1000 |
|
|
|
Fetuses |
|
|
Litters |
|
||
Group |
|
1 |
2 |
3 |
4 |
1 |
2 |
3 |
4 |
Number Examined
|
|
135 |
147 |
149 |
139 |
19 |
20 |
20 |
18 |
Minor skeletal abnormalities Cranial |
sutural bone(s) |
1 |
1 |
1 |
0 |
1 |
1 |
1 |
0 |
Vertebral element abnormality |
thoracic |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
Ribs |
medially thickened/kinked |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
Sternebrae |
misaligned ossification sites |
4 |
1 |
4 |
3 |
3 |
1 |
4 |
3 |
Costal cartilage |
partially fused |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
Appendicular |
misshapen cranial margin scapula(e) |
0 |
0 |
0 |
2 |
0 |
0 |
0 |
2 |
Total affected by one or more of the above |
5 |
3 |
7 |
5 |
4 |
3 |
6 |
5 |
|
Rib and vertebral configuration Cervical rib |
short supernumerary |
1 |
0 |
2 |
4 |
1 |
0 |
2 |
4 |
|
full supernumerary |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
1st rib |
short |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
13th rib |
short with/without costal cartilage |
3 |
0 |
3 |
1 |
2 |
0 |
2 |
1 |
Number of 14th ribs |
short supernumerary |
4 |
11 |
11 |
16 |
4 |
8 |
8 |
4 |
|
full supernumerary |
0 |
0 |
2 |
0 |
0 |
0 |
1 |
0 |
|
total |
4 |
11 |
12 |
16 |
4 |
8 |
8 |
4 |
Thoracolumbar vertebrae |
18 |
1 |
0 |
1 |
0 |
1 |
0 |
1 |
0 |
20 0 0 1 0 0 0 1 0 |
|||||||||
Note: Individual fetuses/litters may occur in more than one category.
TABLE 11 (cont) Fetal examinations - minor skeletal abnormality and variants findings - group incidences
|
|
Fetuses |
|
|
Litters |
|
|||
Group |
1 |
2 |
3 |
4 |
1 |
2 |
3 |
4 |
|
Number Examined
|
135 |
147 |
149 |
139 |
19 |
20 |
20 |
18 |
|
Rib and vertebral configuration Pelvic girdle unilateral caudal shift |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
|
Delayed/Incomplete ossification/unossified Cranial large nasofrontal suture |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
|
|
cranial centres |
2 |
5 |
8 |
2 |
2 |
5 |
5 |
2 |
|
hyoid |
8 |
7 |
7 |
2 |
5 |
5 |
7 |
1 |
Sternebrae |
5th and/or 6th |
48 |
61 |
50 |
48 |
16 |
20 |
18 |
16 |
|
1st to 4th |
4 |
7 |
11 |
5 |
4 |
6 |
7 |
4 |
|
total |
49 |
63 |
54 |
50 |
16 |
20 |
18 |
16 |
Vertebrae |
cervical |
0 |
3 |
1 |
1 |
0 |
3 |
1 |
1 |
|
thoracic |
7 |
11 |
13 |
10 |
6 |
8 |
7 |
6 |
|
lumbar |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
|
sacrocaudal |
5 |
7 |
5 |
6 |
3 |
5 |
5 |
6 |
|
caudal |
0 |
1 |
1 |
2 |
0 |
1 |
1 |
2 |
Appendicular |
pelvic bones |
6 |
4 |
3 |
1 |
4 |
4 |
3 |
1 |
|
metacarpals |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
metatarsals 0 1 0 1 0 1 0 1 |
|||||||||
Note: Individual fetuses/litters may occur in more than one category.
TABLE 12 Fetal examinations - minor visceral abnormality and necropsy findings - group incidences
|
Control |
Dimethoxy(methyl)silane |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg bw/day) |
0 |
100 |
300 |
1000 |
|
|
|
Fetuses |
|
|
Litters |
|
||
Group |
|
1 |
2 |
3 |
4 |
1 |
2 |
3 |
4 |
Number Examined |
|
134 |
143 |
147 |
140 |
18 |
20 |
20 |
18 |
Total Number Affected |
|
15 |
16 |
22 |
14 |
10 |
11 |
13 |
8 |
Visceral abnormalities Eyes |
variation in contralateral lens shape |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
|
oval lenses |
0 |
1 |
1 |
0 |
0 |
1 |
1 |
0 |
Thymus |
partially undescended lobe |
1 |
0 |
4 |
3 |
1 |
0 |
4 |
3 |
Azygos vein |
right sided |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
Caudal vena cava |
anomalous confluence with left hepatic vein |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
Kidney(s) |
small renal papilla |
5 |
1 |
4 |
0 |
3 |
1 |
2 |
0 |
Ureter(s) |
dilated |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
Testis(es) |
undescended |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
|
malpositioned |
1 |
2 |
1 |
1 |
1 |
2 |
1 |
1 |
Umbilical artery |
left |
1 |
2 |
4 |
2 |
1 |
2 |
4 |
1 |
Haemorrhages Head |
brain |
4 |
2 |
3 |
0 |
3 |
2 |
2 |
0 |
Neck/Thorax |
dorsal fat pad |
0 |
2 |
0 |
0 |
0 |
1 |
0 |
0 |
|
thoracic cavity |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
Abdomen |
abdominal cavity |
1 |
3 |
2 |
4 |
1 |
2 |
2 |
4 |
|
liver lobes |
0 |
1 |
0 |
1 |
0 |
1 |
0 |
1 |
General subcutaneous 1 0 2 0 1 0 2 0 |
|||||||||
Note: Individual fetuses/litters may occur in more than one category.
TABLE 12 (cont) Fetal examinations - minor visceral abnormality and necropsy findings - group incidences
|
Control |
Dimethoxy(methyl)silane |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg bw/day) |
0 |
100 |
300 |
1000 |
|
|
|
Fetuses |
|
|
Litters |
|
||
Group |
|
1 |
2 |
3 |
4 |
1 |
2 |
3 |
4 |
Number Examined |
|
134 |
143 |
147 |
140 |
18 |
20 |
20 |
18 |
Total Number Affected |
|
15 |
16 |
22 |
14 |
10 |
11 |
13 |
8 |
Necropsy observations (external) Skin |
shiny |
1 |
3 |
2 |
1 |
1 |
3 |
1 |
1 |
subcutaneous edema 0 0 2 1 0 0 2 1 |
|||||||||
Note: Individual fetuses/litters may occur in more than one category.
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
- Quality of whole database:
- The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex IX, 8.7, of Regulation (EC) No. 1907/2006.
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
A developmental toxicity study according to OECD 414 (rat, oral) is available with the registered substance (Covance, 2020)
Treatment was generally well tolerated with no test item-related unscheduled deaths. At microscopic examination of the thyroids, increased incidence and severity, compared to controls, of follicular cell hypertrophy was observed at 300 and 1000 mg/kg bw/day. The increased liver weights relative to body weight observed at these dose levels, in conjunction with the increased mean serum TSH concentration at 1000 mg/kg bw/day, suggest this finding may be indicative of hepatic microsomal enzyme induction leading to increased metabolism of thyroid hormones and chronic thyroid stimulating hormone (TSH) stimulation of the thyroid gland. This change is considered to be an adaptive response that is largely specific to the rat. At 1000 mg/kg bw/day the mean serum T3 concentration was statistically significantly lower than control. However, following a review of the individual data, a majority of the control and high dose values were within the same range and without a dose response, suggesting this difference is not considered to be adverse. Maternal clinical condition, overall body weight performance and food consumption were not adversely affected at any dose level investigated, and there were no test item-related changes in thyroid and parathyroid or kidney weights detected at scheduled termination.
There was no adverse effect of maternal treatment on the mean numbers of corpora lutea, implantations, resorptions, live young, the extent of pre- and post-implantation losses, sex ratio, anogenital distance or on fetal and litter weights, and there were no major or minor abnormalities or skeletal variants considered related to treatment at any dose level investigated.
Based on the results of this study, the NOAEL for maternal toxicity and embryo-fetal survival and development was concluded to be >= 1000 mg/kg bw/day.
Justification for classification or non-classification
The available data on reproduction and developmental toxicity do not meet the criteria for classification according to Regulation (EC) No. 1272/2008, and are therefore conclusive but not sufficient for classification of the registered substance.
No information is available on effects via lactation.
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
