Trimethoxypropylsilane

Endpoint summary

Description of key information

In order to fulfil the standard information requirements, a GLP-compliant 90-day repeated dose toxicity study in rats via the inhalation route following OECD 413 is proposed according to Annex IX, Column 1, Section 8.6.2. In the interim, read-across to the structural analogue substance trimethoxy(methyl)silane (CAS 1185-55-3) has been used to assess the systemic toxicity of trimethoxy(propyl)silane.

Studies on trimethoxy(methyl)silane (CAS 1185-55-3):

Inhalation, subchronic (OECD 413 in rats): NOAEC = 560 mg/m³ (100 ppm)

Oral, subacute (OECD 422 in rats): NOAEL = 50 mg/kg bw/day

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

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

See attached interim read-across justification.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

organ weights and organ / body weight ratios

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

250 mg/kg bw/day (nominal)

System:

other: hepatobiliary; gastrointestinal; endocrine; immune system

Organ:

adrenal glands

duodenum

jejunum

liver

thymus

thyroid gland

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Conclusions:

In the key Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test on the structural analogue substance trimethoxy(methyl)silane (CAS 1185-55-3), conducted according to OECD Test Guideline 422 and in compliance with GLP, the NOAEL for systemic effects was concluded to be 50 mg/kg bw/day based on 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. In addition, a marked increase in prothrombin time was observed for males at 250 and 1000 mg/kg bw/day whereas females were unaffected, and exposure was associated with increased blood platelet concentration for males and females at 1000 mg/kg bw/day.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

50 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 VIII, 8.6, of Regulation (EC) No 1907/2006.

System:

other: hepatobiliary; gastrointestinal; endocrine; immune system

Organ:

adrenal glands

duodenum

jejunum

liver

thymus

thyroid gland

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study planned

Study period:

The test will be conducted after a decision on the requirement to carry out the proposed test has been taken according to the procedure laid down in Regulation (EC) 1907/2006 and a deadline to submit the information required has been set by the Agency.

Justification for type of information:

TESTING PROPOSAL ON VERTEBRATE ANIMALS
NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out: Trimethoxy(propyl)silane (CAS 1067-25-0)

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- Available GLP studies: There are no GLP-compliant studies available on subchronic repeated dose toxicity with the registered substance.
- Available non-GLP studies: There are no non-GLP-compliant studies available on subchronic repeated dose toxicity with the registered substance.
- Historical human data: Not available.
- QSAR: (Q)SAR methods are not applicable to assess the full scope of subchronic repeated dose toxicity.
- In vitro methods: No validated or regulatory accepted alternative methods are available for replacing animal testing with respect to subchronic repeated dose toxicity.
- Weight of evidence: There is no information (QSAR, in vitro data, developmental toxicity or fertility data) available which is suitable to assess subchronic repeated dose toxicity in a weight of evidence approach.
- Grouping and read-across: Subchronic repeated dose toxicity data on suitable structural analogue substances is not available.

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- In order to fulfil the standard information requirements, a GLP-compliant subchronic toxicity study (90-day) in rats via the inhalation route following OECD guideline 413 is proposed according to Annex IX, Column 1, Section 8.6.2.
- Column 2 adaptation possibilities at the Annex IX, Section 8.6.2 level were considered and do not apply: There is no short-term toxicity data available for trimethoxy(propyl)silane that shows severe effects meeting the criteria for STOT RE 1 or 2 classification. Furthermore, no chronic toxicity study is available or proposed and there is not sufficient data on the hydrolysis product propylsilanetriol available. In addition, the substance cannot be regarded as unreactive, insoluble and not inhalable; there is evidence of absorption and toxicity.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed: a subchronic toxicity study (90-day) in rats via the inhalation route following OECD guideline 413 including fertility parameter is proposed with trimethoxy(propyl)silane. The inhalation route is selected as the vapour pressure of the registered substance (1.9 kPa) indicates that it has a moderate volatility, and therefore inhalation as a vapour may occur.

Qualifier:

according to guideline

Guideline:

OECD Guideline 413 (90-Day (Subchronic) Inhalation Toxicity Study

Version / remarks:

2018

Deviations:

yes

Remarks:

additional reproductive endpoints will be covered. These could include but are not limited to "Examination of reproductive organs, sperm parameters, and oestrus cycle".

Principles of method if other than guideline:

There are no data available on the repeated dose toxicity of trimethoxy(propyl)silane.
In order to fulfil the standard information requirements, a GLP-compliant subchronic toxicity study (90-day) in rats via the inhalation route following OECD guideline 413 is proposed according to Annex IX, Column 1, Section 8.6.2.

Species:

rat

Route of administration:

inhalation

Reference 2

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:

See attached interim read-across justification.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

LOAEL

Effect level:

2.2 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Key result

Dose descriptor:

NOAEL

Effect level:

0.56 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

gross pathology

histopathology: non-neoplastic

mortality

organ weights and organ / body weight ratios

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

2.2 mg/L air (analytical)

System:

urinary

Organ:

bladder

kidney

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Conclusions:

In the 90-day inhalation repeated dose toxicity study, conducted according to OECD Test Guideline 413 and in compliance with GLP, the NOAEL for systemic effects for the structural analogue substance trimethoxy(methyl)silane (CAS 1185-55-3) vapor administered six hours per day, five days per week via whole-body inhalation exposure to male and female Sprague-Dawley rats, was 100 ppm (equivalent to 0.56 mg/L) based on the increased incidence of grossly observed urinary bladder calculi along with the kidney dilation at the 400 ppm exposure level.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

560 mg/m³

Study duration:

subchronic

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 VIII-IX, 8.6, of Regulation (EC) No 1907/2006.

System:

urinary

Organ:

bladder

kidney

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:

See attached interim read-across justification.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

LOAEL

Effect level:

2.2 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Key result

Dose descriptor:

NOAEL

Effect level:

0.56 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

gross pathology

histopathology: non-neoplastic

mortality

organ weights and organ / body weight ratios

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

2.2 mg/L air (analytical)

System:

urinary

Organ:

bladder

kidney

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Conclusions:

In the 90-day inhalation repeated dose toxicity study, conducted according to OECD Test Guideline 413 and in compliance with GLP, the NOAEL for systemic effects for the structural analogue substance trimethoxy(methyl)silane (CAS 1185-55-3) vapor administered six hours per day, five days per week via whole-body inhalation exposure to male and female Sprague-Dawley rats, was 100 ppm (equivalent to 0.56 mg/L) based on the increased incidence of grossly observed urinary bladder calculi along with the kidney dilation at the 400 ppm exposure level.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

subchronic

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 VIII-IX, 8.6, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In order to fulfil the standard information requirements, a GLP-compliant 90-day repeated dose toxicity study in rats via the inhalation route following OECD 413 is proposed according to Annex IX, Column 1, Section 8.6.2. In the interim, read-across to the structural analogue substance trimethoxy(methyl)silane (CAS 1185-55-3) has been used to assess the repeated dose toxicity of trimethoxy(propyl)silane (see the interim analogue justification in the respective target endpoint study record).

 

In the key Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test, conducted according to OECD 422 and in compliance with GLP (Dow Corning Corporation, 2005), the structural analogue substance trimethoxy(methyl)silane was administered by oral gavage to 10 male and 10 female rats per group at dose levels of 0, 50, 250 and 1000 mg/kg bw/day for at least 28 days. Clinical signs included transient inactivity or salivation following dosing. The dose levels were based on the results of a dose range-finding study (Dow Corning Corporation, 2004). There were two unscheduled deaths (one female each at 0 and 50 mg/kg bw/day); both were related to dosing errors. Statistically significant decreases in body weight gain and food consumption were noted for 1000 mg/kg bw/day group males. 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, and increased red blood cell concentration in males at 1000 mg/kg bw/day. Increased liver weight was observed for male and female animals at 250 and 1000 mg/kg bw/day. Histomorphological changes were observed in males in liver, thymus, thyroid, duodenum, jejunum and females in liver, thyroid, duodenum, jejunum, and adrenal gland at dose levels at or above 250 mg/kg bw/day. Based on the findings of this study, the NOAEL for systemic effects was concluded to be 50 mg/kg bw/day.

 

In the key 90-day inhalation repeated dose toxicity study, conducted according to OECD 413 and in compliance with GLP (Dow Corning Corporation, 2008), the structural analogue substance trimethoxy(methyl)silane vapor concentrations of 0, 0.14, 0.56, 2.2 and 8.9 mg/L (0, 25, 100, 400, 1600 ppm) were administered for six hours per day, five days per week via whole-body inhalation exposure to male and female Sprague-Dawley rats for 90 days, followed by a 28-day recovery period for control and high dose animals. The concentration levels were based on the results of a dose range-finding study (Dow Corning Corporation, 2007).

Test material-related clinical signs 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 material-related clinical signs included soiling of the urogenital and abdominal regions of both sexes.

Mean body weights trended lower than controls over the exposure period for test animals. This difference persisted through the completion of exposures and into week one of the post exposure recovery period. There were no differences in food consumption for either sex, in any of the 90-day exposure groups.

Test material-related gross necropsy included moderate dilation of the kidney, decreased soft testes, and calculi in the urinary bladder. Histomorphologic changes included minimal to moderate urinary bladder hyperplasia and inflammation. Kidney changes were characterized by hyperplasia of the pelvic epithelium and/or granulomatous inflammation. One male animal found dead on study day 72, demonstrated an apparent urinary obstruction possibly leading to acute uraemia, with calcification of the aorta and pulmonary haemorrhagic edema as secondary effects. Additional changes included prostatic inflammation in moderate or severe degrees in two 1600 ppm exposure group rats.

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 but without histological correlate and the finding was not present in males or in recovery group females. In males, increases in kidney weight were observed.

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 to be common spontaneous findings in young Sprague-Dawley rats and not test material-related. There were no test material-related changes in clinical pathology or serum chemistry.

Based on these findings, the NOAEL for systemic effects for trimethoxy(methyl)silane vapor administered six hours per day, five days per week via whole-body inhalation exposure to male and female Sprague-Dawley rats, was 100 ppm (equivalent to 0.56 mg/L).

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) No. 1272/2008, and are therefore conclusive but not sufficient for classification of the registered substance.