Registration Dossier

Administrative data

Description of key information

No studies were available to assess the toxicity after repeated oral or inhalation exposure of dimethoxymethylsilane. Therefore, an OECD 408 study is proposed in order to evaluate the toxicity after repeated oral exposure. In the meanwhile, repeated dose toxicity data from the closest structurally related substance trimethoxymethylsilane (CAS 1185 -55 -3) has been used as an interim measure to conduct hazard and risk assessment for the registered substance.

Oral (subacute):
Repeated dose toxicity: OECD TG 422 in rats: MW corrected NOAEL = 39 mg/kg bw/day.
Exposure to trimethoxymethylsilane was associated with organ weight and/or histomorphological changes in males (liver, thymus, thyroid, duodenum, jejunum, and red blood cell) and females (liver, thyroid, duodenum, jejunum, and adrenal gland) at dose levels at or above 250 mg/kg bw/day, a marked increase in prothrombin time was observed for males at 250 and 1000 mg/kg bw/day and exposure was associated with increased blood platelet concentrations at 1000 mg/kg bw/day.

Inhalation (subchronic):
Repeated dose toxicity: OECD TG 413 in rats with R-A substance (CAS 1185-55-3): NOAEC (systemic) = 560 mg/m³; LOAEC (systemic) = 2200 mg/m³; NOAEC (local effects) = 8900 mg/m³.
Molecular weight correction dimethoxymethylsilane/trimethoxymethylsilane = 106/136: NOAEC (systemic) = 436.8 mg/m³; LOAEC (systemic) = 1714.7 mg/m³; NOAEC (local effects) = 6936.8 mg/m³.
The increased incidence of grossly observed urinay bladder calculi along with the kidney dilation at the 2.2 mg/L exposure level warrant the above NOAEC and LOAEC for trimethoxymethylsilane vapour administered six hours per day, five days per week for a 90-day interval via whole-body inhalation to rats.

Dermal toxicity (subacute):
Repeated dose toxicity: non-guideline in rabbits: NOAEL = 171 mg/kg bw
Repeated dermal application of the test substance did not result in systemic toxicity. The only abnormal findings involved the treated skin.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.
Reason / purpose:
read-across source
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
There were two unscheduled deaths (one female each at 0 and 50 mg/kg  bw/day); both were related to dosing errors. Clinical signs included transient inactivity or salivation following dosing. Statistically significant decreases in body weight gain and food consumption were noted  for 1000 mg/kg bw/day group males. Increased liver weight was observed for male and female animals at 250 and 1000 mg/kg bw/day. Exposure to  MTMS was associated with organ weight and/or histomorphological changes in males (liver, thymus, thyroid, duodenum,  jejunum) and females (liver, thyroid, duodenum, jejunum, and adrenal gland) at dose levels at or above 250 mg/kg bw/day. A marked increase in prothrombin time was observed for males at 250 and 1000 mg/kg bw/day whereas females were unaffected. Exposure was also associated with increased blood platelet concentration for males and females at 1000 mg/kg bw/day. The NOAEL for systemic toxicity was 50 mg/kg bw/day.
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
haematology
organ weights and organ / body weight ratios
histopathology: non-neoplastic
Dose descriptor:
LOAEL
Effect level:
250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: clinical signs; organ weights; histopathology, haematology
Critical effects observed:
not specified
Conclusions:
A OECD 422 (combined Repeated Dose Toxicity Study with the Reproductive/ Developmental Screening Test) is available by the oral route for the structural analogue substance trimethoxy(methyl)silane (CAS: 1185-55-3). Exposure to methyltrimethoxysilane was associated with organ weight and/or histomorphological changes in males (liver, thymus, thyroid, duodenum, jejunum, and red blood cell) and females (liver, thyroid, duodenum, jejunum, and adrenal gland) at dose levels at or above 250 mg/kg bw/day. A marked increase in prothrombin time was observed for males at 250 and 1000 mg/kg bw/day whereas females were unaffected. Exposure was also associated with increased blood platelet concentration for males and females at 1000 mg/kg bw/day. These data support a NOAEL for systemic toxicity of 50 mg/kg bw/day which is also estimated to the target substace. As explained in the analogue justification, it is considered that the target and the source substances are unlikely to lead to differences in repeated dose toxicity potential.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
39 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The study was conducted in accordance with an appropriate OECD test guideline, and in compliance with GLP.
System:
other: glandular
Organ:
thyroid gland

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.
Reason / purpose:
read-across source
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
Average measured methyltrimethoxysilane exposure concentrations included below the limit of quantitation (BLQ), 25 +/- 0.8, 99 +/- 3.2, 398 +/- 12.8, and 1612 +/- 35.6 ppm for groups 1 through 5, respectively. Calculated nominal concentrations included 23 +/- 0.4, 94 +/- 1.6, 383 +/- 10.4, and 1570 +/- 48.9 ppm for groups 2 through 5, respectively. Mean measured methyl alcohol concentrations were below the limit of calibration (8.7 ppm) for all exposure groups except group 5 which was 19 +/- 3.7 ppm.
Clinical observations were recorded for each animal daily with body weights and food consumption measured on a weekly basis throughout the exposure and recovery periods. Two animals were found dead (one group 4 male on study day 25; one group 5 male on study day 72) and one animal (control group male on study day 65) was sacrificed moribund prior to terminal sacrifice. There were no abnormal clinical or gross pathological findings for the group 4 male. Test article-related clinical signs for the group 5 male included decreased activity, soiling around muzzle, abdomen and urogenital regions with gross pathological findings including dilation of kidneys and urinary bladder with calculus in bladder. Test article-related clinical signs reported for all surviving animals were limited to groups 4 and 5 and primarily included soiling of the urogenital and abdominal regions of both sexes.
Mean body weights trended lower than controls over the exposure period for group 5 males (~6%) and groups 4 and 5 females (~5%). Statistically significant decreases were noted during week one for group 3 and week two for group 5 only. A statistically significant decrease in mean body weight was measured in the group 5 recovery group females beginning exposure week four. This difference persisted through the completion of exposures and into week one of the post exposure recovery period. Although not statistically significant, body weights remained decreased from controls for males (~4%) and females (~6%) during the recovery period. There were no differences in food consumption for either sex, in any of the 90-day exposure groups. Weekly comparison of recovery group food consumption yielded statistical differences during weeks 6, 7, 8 and 10 for group 5 males and weeks 4 and 5 for group 5 females. Food consumption was similar to controls for both sexes in group 5 during each week of the 28-day post exposure period. There were no test article-related ophthalmic finding at the end of the 90-day exposure period.
Test article-related gross necropsy findings were primarily limited to the group 4 and 5 animals and included moderate dilation of the kidney and calculi in the urinary bladder. Histomorphologic changes included minimal to moderate urinary bladder hyperplasia and inflammation in all group 5 males and 9/10 females. Kidney changes were characterized by hyperplasia of the pelvic epithelium and/or granulomatous inflammation. The one group 5 male animal found dead on study day 72, demonstrated an apparent urinary obstruction possibly leading to acute uremia, with calcification of the aorta and pulmonary hemorrhagic edema as secondary effects. Additional changes included prostatic inflammation in moderate or severe degrees in two 1600 ppm exposure group 5 rats.
Following the 28-day recovery period, calculi were observed in the group 5 males only. Minimal to moderate hyperplasia of urinary bladder epithelium persisted in most rats, and exposure-related urinary bladder calculi were observed in several. Chronic or granulomatous inflammation in the renal pelvis was observed in several female rats. In male rats, there was no histomorphological evidence of a residual effect on the kidneys after the recovery period. In females, the incidence of pelvic epithelial hyperplasia and inflammation was modestly increased over controls. There were no indications of a residual effect on the prostate gland following the recovery period. No animals had more than mild inflammation of the prostate gland, and the incidence of inflammation was higher in control animals.
In females, absolute adrenal gland weights were statistically increased in group 4 (18%) and group 5 (25%). Relative to body weight, female adrenal glands were statistically increased (27%) for group 5. There was no histological correlate and the finding was not present in males or in recovery group females. In males, group 4 kidney weight was increased, but a comparable effect was not seen in group 5.

Also in males, the weights of testes and epididymides were statistically decreased in recovery group rats exposed to 1600 ppm. This finding correlated histologically with two recovery group males showing marked testicular seminiferous tubule degeneration and corresponding epididymal oligospermia (one unilateral, one bilateral). In regular study (90-day) rats, seminiferous tubule degeneration was observed only in one control and one low-exposure (25 ppm) rats. These findings were considered common spontaneous findings in young Sprague-Dawley rats and not test article-related. There were no test article-related changes in clinical pathology or serum chemistry.
Dose descriptor:
NOAEL
Effect level:
560 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
gross pathology
Dose descriptor:
LOAEL
Effect level:
2 200 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on the increased incidence of grossly observed urinary bladder calculi along with the kidney dilation at the 400 ppm exposure level.
Critical effects observed:
not specified
Conclusions:
A sub-chronic inhalation toxicity study is available for the structural analogue substance trimethoxy(methyl)silane (CAS: 1185-55-3), according to OECD 413. Based on the increased incidence of grossly observed urinary bladder calculi along with the kidney dilation at the 400 ppm exposure level, the No Observable Adverse Effect Level (NOAEL) for methyltrimethoxysilane vapour administered six hours per day, five days per week for a 90-day interval via whole-body inhalation exposure to male and female Sprague-Dawley rats, was 100 ppm. As described in the Analogue Justification similar results can be expected with the target substance and thus the NOAEL for the target substance is considered to be 100 ppm.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
436.8 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study was conducted according to the appropriate OECD guideline and in compliance with GLP and is therefore considered to be reliability 1.
System:
urinary
Organ:
bladder

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.
Reason / purpose:
read-across source
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
Average measured methyltrimethoxysilane exposure concentrations included below the limit of quantitation (BLQ), 25 +/- 0.8, 99 +/- 3.2, 398 +/- 12.8, and 1612 +/- 35.6 ppm for groups 1 through 5, respectively. Calculated nominal concentrations included 23 +/- 0.4, 94 +/- 1.6, 383 +/- 10.4, and 1570 +/- 48.9 ppm for groups 2 through 5, respectively. Mean measured methyl alcohol concentrations were below the limit of calibration (8.7 ppm) for all exposure groups except group 5 which was 19 +/- 3.7 ppm.
Clinical observations were recorded for each animal daily with body weights and food consumption measured on a weekly basis throughout the exposure and recovery periods. Two animals were found dead (one group 4 male on study day 25; one group 5 male on study day 72) and one animal (control group male on study day 65) was sacrificed moribund prior to terminal sacrifice. There were no abnormal clinical or gross pathological findings for the group 4 male. Test article-related clinical signs for the group 5 male included decreased activity, soiling around muzzle, abdomen and urogenital regions with gross pathological findings including dilation of kidneys and urinary bladder with calculus in bladder. Test article-related clinical signs reported for all surviving animals were limited to groups 4 and 5 and primarily included soiling of the urogenital and abdominal regions of both sexes.
Mean body weights trended lower than controls over the exposure period for group 5 males (~6%) and groups 4 and 5 females (~5%). Statistically significant decreases were noted during week one for group 3 and week two for group 5 only. A statistically significant decrease in mean body weight was measured in the group 5 recovery group females beginning exposure week four. This difference persisted through the completion of exposures and into week one of the post exposure recovery period. Although not statistically significant, body weights remained decreased from controls for males (~4%) and females (~6%) during the recovery period. There were no differences in food consumption for either sex, in any of the 90-day exposure groups. Weekly comparison of recovery group food consumption yielded statistical differences during weeks 6, 7, 8 and 10 for group 5 males and weeks 4 and 5 for group 5 females. Food consumption was similar to controls for both sexes in group 5 during each week of the 28-day post exposure period. There were no test article-related ophthalmic finding at the end of the 90-day exposure period.
Test article-related gross necropsy findings were primarily limited to the group 4 and 5 animals and included moderate dilation of the kidney and calculi in the urinary bladder. Histomorphologic changes included minimal to moderate urinary bladder hyperplasia and inflammation in all group 5 males and 9/10 females. Kidney changes were characterized by hyperplasia of the pelvic epithelium and/or granulomatous inflammation. The one group 5 male animal found dead on study day 72, demonstrated an apparent urinary obstruction possibly leading to acute uremia, with calcification of the aorta and pulmonary hemorrhagic edema as secondary effects. Additional changes included prostatic inflammation in moderate or severe degrees in two 1600 ppm exposure group 5 rats.
Following the 28-day recovery period, calculi were observed in the group 5 males only. Minimal to moderate hyperplasia of urinary bladder epithelium persisted in most rats, and exposure-related urinary bladder calculi were observed in several. Chronic or granulomatous inflammation in the renal pelvis was observed in several female rats. In male rats, there was no histomorphological evidence of a residual effect on the kidneys after the recovery period. In females, the incidence of pelvic epithelial hyperplasia and inflammation was modestly increased over controls. There were no indications of a residual effect on the prostate gland following the recovery period. No animals had more than mild inflammation of the prostate gland, and the incidence of inflammation was higher in control animals.
In females, absolute adrenal gland weights were statistically increased in group 4 (18%) and group 5 (25%). Relative to body weight, female adrenal glands were statistically increased (27%) for group 5. There was no histological correlate and the finding was not present in males or in recovery group females. In males, group 4 kidney weight was increased, but a comparable effect was not seen in group 5.

Also in males, the weights of testes and epididymides were statistically decreased in recovery group rats exposed to 1600 ppm. This finding correlated histologically with two recovery group males showing marked testicular seminiferous tubule degeneration and corresponding epididymal oligospermia (one unilateral, one bilateral). In regular study (90-day) rats, seminiferous tubule degeneration was observed only in one control and one low-exposure (25 ppm) rats. These findings were considered common spontaneous findings in young Sprague-Dawley rats and not test article-related. There were no test article-related changes in clinical pathology or serum chemistry.
Dose descriptor:
NOAEL
Effect level:
560 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
gross pathology
Dose descriptor:
LOAEL
Effect level:
2 200 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on the increased incidence of grossly observed urinary bladder calculi along with the kidney dilation at the 400 ppm exposure level.
Critical effects observed:
not specified
Conclusions:
A sub-chronic inhalation toxicity study is available for the structural analogue substance trimethoxy(methyl)silane (CAS: 1185-55-3), according to OECD 413. Based on the increased incidence of grossly observed urinary bladder calculi along with the kidney dilation at the 400 ppm exposure level, the No Observable Adverse Effect Level (NOAEL) for methyltrimethoxysilane vapour administered six hours per day, five days per week for a 90-day interval via whole-body inhalation exposure to male and female Sprague-Dawley rats, was 100 ppm. As described in the Analogue Justification similar results can be expected with the target substance and thus the NOAEL for the target substance is considered to be 100 ppm.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
6 936.8 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study was conducted according to the appropriate OECD guideline and in compliance with GLP and is therefore considered to be reliability 1.

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
no guideline followed
Principles of method if other than guideline:
Rabbits were exposed dermally (occlusive) to the test substance for 9 doses over a time of 11 days. Animals were euthanized at the end of exposure period. 5 animals from high-dose and control group were kept as satellite groups for 2 weeks of recovery. Observations were made for clinical effects, gross and macroscopic lesions, haematology, clinical chemistry and urinalysis.
GLP compliance:
not specified
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazelton Research Products, Inc., Denver
- Age at study initiation: 17 - 19 weeks old
- Weight at study initiation: 3.0 - 4.0 kg
- Housing: individually in stainless steel cages with wire mesh floors
- Diet: Agway Pro-Lab Certified Rabbit Formula (Agway Inc. Waverly, NY), ad libitum
- Water: tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 - 21 °C
- Humidity (%): 40 - 70%
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Type of wrap if used: polyethylene sheeting, secured with waterproof tape before treatment; after application of test substance usig a syringe with gavage needle, entire treatment area was overwrapped with VETRAP bandaging tape
- Area of exposure: no data
- % coverage: no data
- Time intervals for shavings or clipplings: no details given

REMOVAL OF TEST SUBSTANCE
- Washing: no washing, area was cleaned by wiping with a dry cloth
- Time after start of exposure: 6 h
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
11 days, and 2 weeks post exposure (satellite control and high dose groups)
Frequency of treatment:
5 consecutive days of exposure, followed by a 2 days rest period, followed by 4 consecutive days of exposure
Dose / conc.:
0.05 other: mL/kg bw (nominal)
Dose / conc.:
0.1 other: mL/kg bw (nominal)
Dose / conc.:
0.2 other: mL/kg bw (nominal)
Dose / conc.:
43 mg/kg bw/day (nominal)
Dose / conc.:
85 mg/kg bw/day (nominal)
Dose / conc.:
171 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10 per gender
5 per gender for 43 mg/kg dose group
Control animals:
yes, sham-exposed
Details on study design:
- Post-exposure recovery period in satellite groups: 14 days
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily before dosing

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: daily before dosing

BODY WEIGHT: Yes
- Time schedule for examinations: on day 1, 8 and 12 during dosing and weekly during recovery period

FOOD CONSUMPTION:
- Food consumption for each animal determined throughout the study

WATER CONSUMPTION: Yes
- Time schedule for examinations: determined throughout the study

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination of study
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- How many animals: all
- Parameters checked in table [No.1] were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination of study
- Animals fasted: No
- How many animals: all
- Parameters checked in table [No.1] were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: at termination of study
- Metabolism cages used for collection of urine: No data
- Animals fasted: No
- Parameters checked in table [No.1] were examined.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (selected tissues, not further specified, wet weights of brain, liver, kidneys, heart, spleen, adrenals and testes)
HISTOPATHOLOGY: Yes (selected tissues, not further specified but including skin)
Other examinations:
scanning electron microscopy/energy-dispersive x-ray analysis (SEM/EDX) was performed on treated skin of one high-dose rabbit per gender from the recovery group to determine the nature of the pigmented material observed in the skin by light microscopy.
Statistics:
The data for quantitative continuous variables were intercompared for the three treatment groups and the control group by use of Levene's test for equality of variances, analysis of variance (ANOVA) and t-test. The t-test was used when the F-value from the ANOVA was significant. When Levene's test indicated simialr variances and the ANOVA was significant a pooled t-test was used for pairwise comparisons. When Levene's test indicated heterogenous variances, all groups were compared by an ANOVA for unequal variances followed when necessary by a separate variance test for pairwise comparison.
Nonparametric data were statistically evaluated using the Kruskal-Wallis test followed by Mann-Whitney U test when appropriate. Incidence data were compared using the Fisher's exact test. For all statistical tests, the probability value of p<0.05 (two-tailed) was used as the critical level of significance.
Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
moderate to severe skin irritation, females more affected than males, lesion severity correlated with dose
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
no treatment-related effects, except decrease in monocytes for high dose group males, which may have been due to sequestration of circulating leukocytes at the site of skin irritation
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
the only finding were lesions to the skin
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
skin lesions were found
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
Treatment-related clinical lesions were limited to the the treated skin. Females tended to be affected slightly more than males. There was moderate to severe skin irritation as evidenced by exfoliation, fissures, and ecchymoses for both genders in the high-dose group, with ulceration and necrosis found only in high-dose group females. In addition, Draize scoring of skin irritation revealed barely perceptible to well-defined erythema and edema in the mid- and high-dose groups of male animals and barely perceptible to moderate erythema in all dose groups of female animals. In general, lesion severity correlated with dose.

HAEMATOLOGY
In animals euthanised after a 2 week recovery period, the only noteworthy finding was a statistically significant decrease in monocytes for high-dose group males, which may have been due to sequestration of circulating leukocytes at the site of skin irritation.

GROSS PATHOLOGY
The only gross lesions found involved the treated skin of rabbits of both genders from all exposure groups at both necropsies. Necropsy findings were similar to clinical observations. The most common lesion was exfoliation or scaling, which was present in most intermediate and high-dose group rabbits, and five of five females and one of five males from the low-dose group from the primary necropsy, as well as in four of five high-dose group rabbits/gender from the recovery group necropsy. Discoloration of the skin, either erythema or ecchymoses, was observed sporadically (more frequently in females) in intermediate and high-dose group rabbits euthanized on day 12, but not observed in the recovery group animals. Lesions indicative or more serious skin irritation, such as ulceration and necrosis (females only), or fissures (both sexes), were noted sporadically in the high-dose group animals euthanized on day 12. Four intermediate dose group females also had fissures and one had ulceration as well.

HISTOPATHOLOGY: NON-NEOPLASTIC
Statistically significant treatment-related microscopic lesions were observed in the treated skin of MDMS-exposed rabbits from all three dose groups of female animals and from the interrnediate and high-dose groups of male animals euthanized immediately following the exposure period. Lesions indicative of treatment-induced irritation of the skin included hyperkeratosis (corresponding to the exfoliation reported grossly), acanthosis, dermal congestion, edema, hemorrhage, epidermitis, ulceration, dermatitis, and dermal fibrosis. The only lesions seen in low-dose group rabbits were hyperkeratosis and dermatitis. Slight dermatitis (lymphocytic infiltrates) was also seen in a few control group rabbits. Acute inflammation in the intermedite and high-dose group animals was often most intense at the epidermal junction, even when the overlying epidermis was intact. Dermal fibrosis was associated with phagocytosed foreign material within macrophages, which appeared as a brown crystalline substance (dermal pigmentation) on H & E-stained sections. Significant residual lesions of treated skin were also present in all high-dose group rabbits euthanized after the 2-week recovery period. Lesions included hyperkeratosis, dermal fibrosis, and granulomatous dermatitis, in which phagocytic giant cells containing pigmented foreign material were prominent.
Scanning electron microscopy of the superficial dermis revealed numerous electron-dense deposits that were proven by elemental analysis to contain silicon. This material is believed to represent a polymer derived from absorbed MDMS or its breakdown products.


Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
171 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no systemic effects observed at the highest dose tested, the only abnormal finding involved the treated skin
Dose descriptor:
LOAEL
Remarks:
local effects
Effect level:
43 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
dermal irritation
Dose descriptor:
LOAEL
Remarks:
local effects
Effect level:
0.051 mg/cm² per day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified

table1: Summary of clinical observations of rabbits

   Males           Females         
 group [mg/kg bw] 0  43  85  171  0  43  85  171

 Treated skin

               
 total number examined  10  5  10  10  10  5  10  10

 Number affected

               
 Exfoliation  0  1  10  10  0  5  10  10
Ecchymoses   0  0  0  3  0  0  3  9
 Ulceration  0  0  0  0  0  0  0  2
 Fissures  0  0  0  8  0  0  4  10
 Necrosis  0  0  0  0  0  0  0  3

table2: Necropsy Findings for rabbits euthanized on day 12

   Males         Females         

 group [mg/kg bw]

 0  43  85  171  0  43  85  171

 treated skin

               
total number examined  5  5  10  5  5  5  10  5

 Number affected

               
 Exfoliation  0  1  9  5  0  5  10  5
 Excoriation  1  0  0  1  0  0  0  0
 Erythema  0  0  1  1  0  0  4  0
 Ecchymoses  0  0  0  1  0  0  2  2
 Ulceration  0  0  0  0  0  0  0  1
 Fissures  0  0  0  2  0  0  4  5
 Necrosis  0  0  0  0  0  0  1  2

table3: Necropsy Findings for rabbits euthanized on day 29

   Males         Females         
 group [mg/kg bw]  0  43  85  171  0  43  85  171
 treated skin                
 total number examined  -  -  5  5  -  -  5
 number affected              
Exfoliation  0  -  -  4  0  -  -  4
 Papule 0  -  -  1  0  -  -  0

table4: Microscopic Findings for rabbits euthanized on day 12

   Males         Females         
 group [mg/kg bw]  0  43  85  171  0  43  85  171

 treated skin

               
 total number examined  5  5  10  5  5  5  10  5
 examined, unremarkable  3  0  0  0  4  0  0  0

 number affected

               
 Hyperkeratosis  0  2  10**  5**  0  5**  10**  5**
 Acanthosis  1  0  10**  5*  0  1  7*  5**
 Congestion  0  0  4  0  0  0  6*  4*
 Epidermitis  0  0  7*  4*  0  0  9**  5**
 Ulceration  1  0  3  2  0  0  3  4*
 Dermal edema  0  0  0  0  0  0  1  3
 Dermal hemorrhage  0  0  4  3  0  0  7*  5**
 Dermatitis  2  5  10*  5  1  4  10**  4
 Dermal fibrosis  0  0  10**  4*  0  0  8**  5**
 Dermal pigmentation  0  0  10**  4*  0  0  9**  5**

Significantly different from control group, *p<0.05, **p<0.01

table5: Microscopic Findings for rabbits euthanized on day 29

   Males         Females         
 group [mg/kg bw]  0  43  85  171  0  43  85  171

treated skin 

               
 total number examined  5  0  0  5  5  0  0  5
 examined, unremarkable  4  -  -  0  1  -  -  0

 number affected

 
 Hyperkeratosis  0  -  -  5**  0  -  -  5**
 Acanthosis  0  -  -  0  0  -  -  2
 Ulceration  0  -  -  0  1  -  -  0
 Dermal hemorrhage  0  -  -  0  1  -  -  1
 Dermatitis  1  -  -  5* 3  -  -  4
 Granulomatous dermatitis  0  -  -  4*  0  -  -  5**
 Dermal fibrosis  0  -  -  2  0  -  -  5**
 Dermal pigmentation  0  -  -  5**  0  -  -  5**

Significantly different from control group, *p<0.05, **p<0.01

Conclusions:
Repeated dermal application of the test substance did not result in systemic toxicity. The only abnormal findings involved the treated skin.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
171 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
The study was well documented and meets generally accepted scientific principles, but was not conducted in compliance with GLP.

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
no guideline followed
Principles of method if other than guideline:
Rabbits were exposed dermally (occlusive) to the test substance for 9 doses over a time of 11 days. Animals were euthanized at the end of exposure period. 5 animals from high-dose and control group were kept as satellite groups for 2 weeks of recovery. Observations were made for clinical effects, gross and macroscopic lesions, haematology, clinical chemistry and urinalysis.
GLP compliance:
not specified
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazelton Research Products, Inc., Denver
- Age at study initiation: 17 - 19 weeks old
- Weight at study initiation: 3.0 - 4.0 kg
- Housing: individually in stainless steel cages with wire mesh floors
- Diet: Agway Pro-Lab Certified Rabbit Formula (Agway Inc. Waverly, NY), ad libitum
- Water: tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 - 21 °C
- Humidity (%): 40 - 70%
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Type of wrap if used: polyethylene sheeting, secured with waterproof tape before treatment; after application of test substance usig a syringe with gavage needle, entire treatment area was overwrapped with VETRAP bandaging tape
- Area of exposure: no data
- % coverage: no data
- Time intervals for shavings or clipplings: no details given

REMOVAL OF TEST SUBSTANCE
- Washing: no washing, area was cleaned by wiping with a dry cloth
- Time after start of exposure: 6 h
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
11 days, and 2 weeks post exposure (satellite control and high dose groups)
Frequency of treatment:
5 consecutive days of exposure, followed by a 2 days rest period, followed by 4 consecutive days of exposure
Dose / conc.:
0.05 other: mL/kg bw (nominal)
Dose / conc.:
0.1 other: mL/kg bw (nominal)
Dose / conc.:
0.2 other: mL/kg bw (nominal)
Dose / conc.:
43 mg/kg bw/day (nominal)
Dose / conc.:
85 mg/kg bw/day (nominal)
Dose / conc.:
171 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10 per gender
5 per gender for 43 mg/kg dose group
Control animals:
yes, sham-exposed
Details on study design:
- Post-exposure recovery period in satellite groups: 14 days
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily before dosing

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: daily before dosing

BODY WEIGHT: Yes
- Time schedule for examinations: on day 1, 8 and 12 during dosing and weekly during recovery period

FOOD CONSUMPTION:
- Food consumption for each animal determined throughout the study

WATER CONSUMPTION: Yes
- Time schedule for examinations: determined throughout the study

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination of study
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- How many animals: all
- Parameters checked in table [No.1] were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination of study
- Animals fasted: No
- How many animals: all
- Parameters checked in table [No.1] were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: at termination of study
- Metabolism cages used for collection of urine: No data
- Animals fasted: No
- Parameters checked in table [No.1] were examined.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (selected tissues, not further specified, wet weights of brain, liver, kidneys, heart, spleen, adrenals and testes)
HISTOPATHOLOGY: Yes (selected tissues, not further specified but including skin)
Other examinations:
scanning electron microscopy/energy-dispersive x-ray analysis (SEM/EDX) was performed on treated skin of one high-dose rabbit per gender from the recovery group to determine the nature of the pigmented material observed in the skin by light microscopy.
Statistics:
The data for quantitative continuous variables were intercompared for the three treatment groups and the control group by use of Levene's test for equality of variances, analysis of variance (ANOVA) and t-test. The t-test was used when the F-value from the ANOVA was significant. When Levene's test indicated simialr variances and the ANOVA was significant a pooled t-test was used for pairwise comparisons. When Levene's test indicated heterogenous variances, all groups were compared by an ANOVA for unequal variances followed when necessary by a separate variance test for pairwise comparison.
Nonparametric data were statistically evaluated using the Kruskal-Wallis test followed by Mann-Whitney U test when appropriate. Incidence data were compared using the Fisher's exact test. For all statistical tests, the probability value of p<0.05 (two-tailed) was used as the critical level of significance.
Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
moderate to severe skin irritation, females more affected than males, lesion severity correlated with dose
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
no treatment-related effects, except decrease in monocytes for high dose group males, which may have been due to sequestration of circulating leukocytes at the site of skin irritation
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
the only finding were lesions to the skin
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
skin lesions were found
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
Treatment-related clinical lesions were limited to the the treated skin. Females tended to be affected slightly more than males. There was moderate to severe skin irritation as evidenced by exfoliation, fissures, and ecchymoses for both genders in the high-dose group, with ulceration and necrosis found only in high-dose group females. In addition, Draize scoring of skin irritation revealed barely perceptible to well-defined erythema and edema in the mid- and high-dose groups of male animals and barely perceptible to moderate erythema in all dose groups of female animals. In general, lesion severity correlated with dose.

HAEMATOLOGY
In animals euthanised after a 2 week recovery period, the only noteworthy finding was a statistically significant decrease in monocytes for high-dose group males, which may have been due to sequestration of circulating leukocytes at the site of skin irritation.

GROSS PATHOLOGY
The only gross lesions found involved the treated skin of rabbits of both genders from all exposure groups at both necropsies. Necropsy findings were similar to clinical observations. The most common lesion was exfoliation or scaling, which was present in most intermediate and high-dose group rabbits, and five of five females and one of five males from the low-dose group from the primary necropsy, as well as in four of five high-dose group rabbits/gender from the recovery group necropsy. Discoloration of the skin, either erythema or ecchymoses, was observed sporadically (more frequently in females) in intermediate and high-dose group rabbits euthanized on day 12, but not observed in the recovery group animals. Lesions indicative or more serious skin irritation, such as ulceration and necrosis (females only), or fissures (both sexes), were noted sporadically in the high-dose group animals euthanized on day 12. Four intermediate dose group females also had fissures and one had ulceration as well.

HISTOPATHOLOGY: NON-NEOPLASTIC
Statistically significant treatment-related microscopic lesions were observed in the treated skin of MDMS-exposed rabbits from all three dose groups of female animals and from the interrnediate and high-dose groups of male animals euthanized immediately following the exposure period. Lesions indicative of treatment-induced irritation of the skin included hyperkeratosis (corresponding to the exfoliation reported grossly), acanthosis, dermal congestion, edema, hemorrhage, epidermitis, ulceration, dermatitis, and dermal fibrosis. The only lesions seen in low-dose group rabbits were hyperkeratosis and dermatitis. Slight dermatitis (lymphocytic infiltrates) was also seen in a few control group rabbits. Acute inflammation in the intermedite and high-dose group animals was often most intense at the epidermal junction, even when the overlying epidermis was intact. Dermal fibrosis was associated with phagocytosed foreign material within macrophages, which appeared as a brown crystalline substance (dermal pigmentation) on H & E-stained sections. Significant residual lesions of treated skin were also present in all high-dose group rabbits euthanized after the 2-week recovery period. Lesions included hyperkeratosis, dermal fibrosis, and granulomatous dermatitis, in which phagocytic giant cells containing pigmented foreign material were prominent.
Scanning electron microscopy of the superficial dermis revealed numerous electron-dense deposits that were proven by elemental analysis to contain silicon. This material is believed to represent a polymer derived from absorbed MDMS or its breakdown products.


Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
171 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no systemic effects observed at the highest dose tested, the only abnormal finding involved the treated skin
Dose descriptor:
LOAEL
Remarks:
local effects
Effect level:
43 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
dermal irritation
Dose descriptor:
LOAEL
Remarks:
local effects
Effect level:
0.051 mg/cm² per day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified

table1: Summary of clinical observations of rabbits

   Males           Females         
 group [mg/kg bw] 0  43  85  171  0  43  85  171

 Treated skin

               
 total number examined  10  5  10  10  10  5  10  10

 Number affected

               
 Exfoliation  0  1  10  10  0  5  10  10
Ecchymoses   0  0  0  3  0  0  3  9
 Ulceration  0  0  0  0  0  0  0  2
 Fissures  0  0  0  8  0  0  4  10
 Necrosis  0  0  0  0  0  0  0  3

table2: Necropsy Findings for rabbits euthanized on day 12

   Males         Females         

 group [mg/kg bw]

 0  43  85  171  0  43  85  171

 treated skin

               
total number examined  5  5  10  5  5  5  10  5

 Number affected

               
 Exfoliation  0  1  9  5  0  5  10  5
 Excoriation  1  0  0  1  0  0  0  0
 Erythema  0  0  1  1  0  0  4  0
 Ecchymoses  0  0  0  1  0  0  2  2
 Ulceration  0  0  0  0  0  0  0  1
 Fissures  0  0  0  2  0  0  4  5
 Necrosis  0  0  0  0  0  0  1  2

table3: Necropsy Findings for rabbits euthanized on day 29

   Males         Females         
 group [mg/kg bw]  0  43  85  171  0  43  85  171
 treated skin                
 total number examined  -  -  5  5  -  -  5
 number affected              
Exfoliation  0  -  -  4  0  -  -  4
 Papule 0  -  -  1  0  -  -  0

table4: Microscopic Findings for rabbits euthanized on day 12

   Males         Females         
 group [mg/kg bw]  0  43  85  171  0  43  85  171

 treated skin

               
 total number examined  5  5  10  5  5  5  10  5
 examined, unremarkable  3  0  0  0  4  0  0  0

 number affected

               
 Hyperkeratosis  0  2  10**  5**  0  5**  10**  5**
 Acanthosis  1  0  10**  5*  0  1  7*  5**
 Congestion  0  0  4  0  0  0  6*  4*
 Epidermitis  0  0  7*  4*  0  0  9**  5**
 Ulceration  1  0  3  2  0  0  3  4*
 Dermal edema  0  0  0  0  0  0  1  3
 Dermal hemorrhage  0  0  4  3  0  0  7*  5**
 Dermatitis  2  5  10*  5  1  4  10**  4
 Dermal fibrosis  0  0  10**  4*  0  0  8**  5**
 Dermal pigmentation  0  0  10**  4*  0  0  9**  5**

Significantly different from control group, *p<0.05, **p<0.01

table5: Microscopic Findings for rabbits euthanized on day 29

   Males         Females         
 group [mg/kg bw]  0  43  85  171  0  43  85  171

treated skin 

               
 total number examined  5  0  0  5  5  0  0  5
 examined, unremarkable  4  -  -  0  1  -  -  0

 number affected

 
 Hyperkeratosis  0  -  -  5**  0  -  -  5**
 Acanthosis  0  -  -  0  0  -  -  2
 Ulceration  0  -  -  0  1  -  -  0
 Dermal hemorrhage  0  -  -  0  1  -  -  1
 Dermatitis  1  -  -  5* 3  -  -  4
 Granulomatous dermatitis  0  -  -  4*  0  -  -  5**
 Dermal fibrosis  0  -  -  2  0  -  -  5**
 Dermal pigmentation  0  -  -  5**  0  -  -  5**

Significantly different from control group, *p<0.05, **p<0.01

Conclusions:
Repeated dermal application of the test substance did not result in systemic toxicity. The only abnormal findings involved the treated skin.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
0.051 mg/cm²
Study duration:
subacute
Species:
rabbit
Quality of whole database:
The study was well documented and meets generally accepted scientific principles, but was not conducted in compliance with GLP.

Additional information

Studies were chosen as key when the available study was of relevance and of sufficient quality for classification, labelling and for risk assessment.

No adequate repeated-dose toxicity data are available for dimethoxymethylsilane, therefore good quality oral and inhalation data on the closest structurally related substances trimethoxymethylsilane (CAS 1185-55-3) have been used as an interim measure to conduct hazard and risk assessment for the registered substance. Both substances share a common hydrolysis product, methylsilanetriol, with the other hydrolysis product being methanol. Since methanol would not contribute to general systemic toxicity effects in rodents at the dose levels tested, it is considered that the observed toxicological effects are due to the action of the methylsilantriol moiety, although the specific toxicological mechanism cannot be determined from the available information. Both substances have log Kow in the range that is favourable for absorption across the respiratory tract (dimethoxy log Kow= 0.8 and trimethoxy log Kow= 0.73).

Acute oral and dermal LD50 values for both substances in rats are >2000 mg/kg. Furthermore, reliable acute inhalation toxicity studies in the rat are available for both the registration substance and the analogue substance. In both cases, the LC50 value is in excess of 4.6 mg/l following a single dose for 4 to 6 hours. It is therefore considered valid to read-across the results for the trimethoxy analogue to fill data gap for the registered substance. The molecular weight difference between target and source chemical is 106/136 = 0.78.  

Oral

For the oral route, a reliable key OECD 422 combined repeated dose/reproductive and developmental screening study in compliance with GLP is available for trimethoxymethylsilane (CAS 1185-55-3) (Dow Corning Corporation, 2005). This study is a valid investigation of the toxicological effects resulting from repeated oral-gavage administration of the test item to male and female rats for at least 28 days. The test item was administered in corn oil as vehicle at dosages of 50, 250, and 1000 mg/kg body weight/day, and controls received the vehicle only. There were two unscheduled deaths (one female each at 0 and 50 mg/kg bw/day), both were related to dosing errors. Clinical signs included transient inactivity or salivation following dosing. Statistically significant decreases in body weight gain and food consumption were noted for 1000 mg/kg bw/day group males. Increased liver weight was observed for male and female animals at 250 and 1000 mg/kg bw/day. Exposure to trimethoxymethylsilane was associated with organ weight and/or histomorphological changes in males (liver, thymus, thyroid, duodenum, jejunum) and females (liver, thyroid, duodenum, jejunum and adrenal gland) at dose levels at or above 250 mg/kg bw/day. A marked increase in prothrombin time was observed for males at 250 and 1000 mg/kg bw/day, whereas females were unaffected. Exposure was also associated with increased blood platelet concentration for males and females at 1000 mg/kg bw/day. The NOAEL for systemic toxicity was 50 mg/kg bw/day (Dow Corning, 2005). The NOAEL for the target chemical is 39 mg/kg bw/day.  

Inhalation

In an acceptable key repeated inhalation toxicity study according to the OECD TG 413 and GLP (Dow Corning Corporation, 2008), the test item (CAS 1185-55-3) was administered to Sprague-Dawley rats (10 per sex and dose) by whole body exposure at concentrations of 25, 100, 400 and 1600 ppm, corresponding to 140, 560, 2200 and 8900 mg/m³ for 6 hours per day, 5 days/week for a total of 90 days followed by a 28 day recovery period for the control and high dose groups. Two animals were found dead (one male (2200 mg/m³) on study day 25; one male (8900 mg/m³) on study day 72) and one animal (control group male on study day 65) was sacrificed moribund prior to terminal sacrifice. There were no abnormal clinical or gross pathological findings for the 2200 mg/m³ male. Test article-related clinical signs for the 8900 mg/m³ male included decreased activity, soiling around muzzle, abdomen and urogenital regions with gross pathological findings including dilation of kidneys and urinary bladder with calculus in bladder. Test article-related clinical signs reported for all surviving animals were limited to 2200 mg/m³ and higher exposed animals and primarily included soiling of the urogenital and abdominal regions of both sexes. Test article-related gross necropsy findings were primarily limited to the 2200 and 8900 mg/m³ animals and included moderate dilation of the kidney, and calculi in the urinary bladder. Histomorphologic changes included minimal to moderate urinary bladder hyperplasia and inflammation in all 8900 mg/m³ males and 9/10 females. Kidney changes were characterized by hyperplasia of the pelvic epithelium and/or granulomatous inflammation. Following the 28-day recovery period, calculi were observed in the 8900 mg/m³ males only. Minimal to moderate hyperplasia of urinary bladder epithelium persisted in most rats, and exposure-related urinary bladder calculi were observed in several. Chronic or granulomatous inflammation in the renal pelvis was observed in several female rats. In male rats, there was no histomorphological evidence of a residual effect on the kidneys after the recovery period. In females, the incidence of pelvic epithelial hyperplasia and inflammation was modestly increased over controls. Based on the increased incidence of grossly observed urinary bladder calculi along with the kidney dilation at the 2200 mg/m³ exposure level, the NOAEC for trimethoxymethylsilane vapour administered six hours per day, five days per week for a 90-day interval via whole-body inhalation exposure to male and female Sprague-Dawley rats, was 100 ppm (corresponding to 560 mg/m³) the LOAEC was 400 ppm (corresponding to 2200 mg/m³) (Dow Corning Corporation, 2008). The NOAEC and LOAEC for the target chemical are 436.8 mg/m³ and 1716 mg/m³, respectively.

Dermal

In the available key dermal repeated dose toxicity study (Losco P. E. et al., 1996), which meets generally accepted scientific principles, but was not conducted according to an appropriate OECD TG and without GLP, New Zealand White rabbits of both sexes were exposed to dimethoxymethylsilane (CAS 16881-77-9) under occlusive conditions for 9 doses over a time of 11 days. The animals received the test item at doses of 43, 85, and 171 mg/kg bw. At the end of exposure period the animals were euthanised. 5 animals from high-dose and control group were kept as satellite groups for 2 weeks of recovery. Observations were made for clinical effects, gross and microscopic lesions, haematology, clinical chemistry and urinanalysis. Repeated dermal application of the test substance did not result in systemic toxicity. The only abnormal findings involved the treated skin. Clinical observations included mild to moderate irritation of the treated skin, affecting mainly high dose group animals euthanized immediately after the exposure period, with females being sligthly more sensitive. Significant gross and microscopic lesions were seen in the treated skin of animals recieving 85 mg/kg bw/day and higher. Gross lesions consisted of erythema, ecchymoses, exfoliation, excoriation, fissures, ulceration and necrosis. Microscopic lesions included hyperkeratosis, acanthosis, congestion, haemorrhage, epidermitis, dermatitis and ulceration. Dermal fibrosis and prominent granulomatous inflammation, associated with pigmented granular foreign material, was found in the superficial dermis. After the 2 week recovery period, exfoliation was the only gross skin lesion found in high dose group animals. Microscopic skin lesions consisted of marked granulomatous dermatitis and a fibrotic reaction associated with the foreign material, as well as residual lesions of surface irritation. Based on the outcome of the study, the NOAEL for systemic toxicity was set at 171 mg/kg bw. Due to skin irritating effects seen in this study already at the low dose level of 43 mg/kg bw/day, the LOAEL for local effects was set at 0.051 mg/cm².

Justification for classification or non-classification

The available data on repeated dose toxicity of the structural analogue substance trimethoxymethylsilane (CAS 1185-55-3) do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and is therefore conclusive but not sufficient for classification of the registered substance.