Potassium methylsilanetriolate

Endpoint summary

Description of key information

An oral OECD 422 screening test (Dow Corning Corporation, 2005) in rats is available for the read across substance substance trimethoxy(methyl)silane. The NOAEL for systemic effects was determined to be 50 mg/kg/day, based on findings in a number of organs including the liver and thymus gland. 
The key study (Dow Corning Corporation, 2007) for repeated dose toxicity via the inhalation route, is a 90-day whole-body inhalation study, in which trimethoxy(methyl)silane was administered to rats six hours per day, five days per week. The NOAEC of 100 ppm  (560 mg/m3) was based on an increased incidence of grossly observed urinary bladder calculi along with kidney dilation at the 400 ppm exposure concentration. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subacute

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

560 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

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

No data on the repeated dose toxicity of potassium methylsilanetriolate are available, so good quality data for the surrogate substance trimethoxy(methyl)silane (CAS 1185-55-3) have been used to assess the systemic toxicity of potassium methylsilanetriolate. This is discussed further below and additional information is given in supporting reports (PFA, 2013a and PFA, 2015t). An in vitro cytogenicity assay (OECD 473) is being conducted with potassium methylsilanetriolate. When the results of this test are available, depending on the outcome of the study, read across from trimethoxy(methyl)silane may be reconsidered.

The key study for repeated dose via the oral route was a combined repeated dose toxicity and reproductive/developmental screening study conducted according to OECD TG 422 and in compliance with GLP. This study found that exposure to trimethoxy(methyl)silane 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 (Dow Corning Corporation 2005). 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 the toxicity phase of the study of 50 mg/kg bw/day.

The key study for repeated dose toxicity via the inhalation route is a 90-day repeated dose toxicity study conducted according to OECD TG 413 and in compliance with GLP. In this study, the reported the NOAEC is 100 ppm (560 mg/m³) (Dow Corning Corporation 2007). Test article-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 article-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 anmals. 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 article-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 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 (8900 mg/m³) 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 (8900 mg/m³). 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.

READ-ACROSS JUSTIFICATION

It is not considered to be either ethical or technically feasible to perform repeated dose toxicity testing with potassium methylsilanetriolate by any route of exposure due to its high pH and consequent likely corrosive properties. Following repeated oral dosing, the corrosive nature of the product could affect the lining of the stomach, giving rise to hyperplasia and a subsequent reduced food intake. All of this would make the interpretation of any systemic findings difficult. A guideline-compliant repeated-dose inhalation study should elicit systemic toxicity at the highest test concentration. Since the local corrosive effects of potassium methylsilanetriolate would be significant a valid inhalation study according to the relevant guidelines is technically not feasible to do. It is also unlikely that any systemic effects would be seen at dose levels made sufficiently low to prevent the known corrosive effects and/or distress in the test species. Similarly with regard to the dermal route, due to the high pH and likely corrosive effects a study according to the relevant guidelines is technically not feasible.

To reduce animal testing REACH recommends to make use of a read-across approach where appropriate based on the high accordance in properties relevant for the specific endpoint. In the case of repeated dose toxicity and reproductive toxicity relevant properties are structural similarity as well as physicochemical and basic toxicological parameters in the same range. In the following paragraphs the read-across approach for potassium methylsilanetriolate is evaluated point by point.

Read-across hypothesis

Read-across is based on the production by the surrogate substance of a silicon-containing hydrolysis product that is the non-ionised form of methylsilanetriolate.

Potassium methylsilanetriolate is a mono-constituent ionic substance of 35-55% w/w potassium methylsilanetriolate in aqueous solution that has a very alkaline pH of >12. Potassium methylsilanetriolate dissociates completely into potassium and methylsilanetriolate ions in aqueous solution.

Due to the high pH, the substance is classified as Corrosive (Cat. 1A), so repeated dose toxicity testing with the substance itself would have to be performed at a very low, non-irritant/corrosive doses, where no relevant systemic toxicity is expected.

In more dilute aqueous solution the pH of the substance will be reduced dependent on concentration. As the pH is reduced, the concentration of the non-ionised form of methylsilanetriolate (methylsilanetriol) increases. At pH <9.0, the substance is no longer in the ionised form; methylsilanetriol is the predominant species at low concentrations, with dimers and oligomers of methylsilanetriol forming at higher concentrations. Under comparable conditions of concentration and pH, methylsilanetriolate is equivalent to methylsilanetriol.

The surrogate substance, trimethoxy(methyl) silane (MTMS), hydrolyses in contact with water (half-life ca. 2 hours at pH 7), producing methanol and methylsilanetriol. Under acidic conditions, such as in the stomach following oral ingestion, hydrolysis is very rapid (half-life estimated as approximately 5 seconds at pH 2 and 37°C).

Since potassium ions will not contribute to any systemic toxicity effect, and methanol does not contribute any significant repeated dose toxicity to rodents at the dose levels tested, it is considered appropriate to read across the available data on MTMS.

Analogue approach justification

(a) Structural similarity

Methylsilanetriol is both the non-ionised form of the registered substance, potassium methylsilanetriolate, and the hydrolysis product of read-across substance trimethoxy(methyl) silane.

(b) Toxicokinetics

Oral exposure: Potassium methylsilanetriolate, at gastric pH, will be neutralised and therefore exposure via the gastric route will be to methylsilanetriol. The read-across substance, trimethoxy(methyl)silane, will hydrolyse very rapidly to methylsilanetriol. Therefore systemic exposure subsequent to oral dosing will be to the substance most relevant to the registered substance. Inhalation exposure: Due to the high pH of the registered substance as sold, high doses via the inhalation route would be expected to lead to local effects, therefore lower doses are relevant to the systemic hazard assessment of the substance. At lower doses, the lower physiological pH and the dilution that will occur in the interior of the lungs will mean that exposure will be to methylsilanetriol. Inhalation exposure to the read-across substance will result in formation of methylsilanetriol (half-life approximately 0.8 hours at pH7 and 37.5°C), therefore exposure of the test animal to methylsilanetriol is expected to be significant in inhalation studies performed with MTMS.

Following oral exposure, should it occur, as methylsilanetriol has properties in the favourable range for oral absorption (molecular weight below 200 and high water solubility) then so significant systemic exposure would be expected. Methylsilanetriol also has properties in the favourable range for absorption across the respiratory tract. However, although the water solubility is favourable for absorption, the log Kow values are not, so it is considered too hydrophilic to cross the lipid-rich stratum corneum and dermal uptake is likely minimal. Distribution into the main body compartments is predicted to be minimal for both and as their soluble fraction in blood is predicted to be high it will be effectively eliminated via the kidneys in urine and accumulation will not occur.

(c) Methanol

The repeated dose toxicity of the non-silanol hydrolysis product of the read across substance (trimethoxy(methyl) silane), methanol, has been extensively studied. It is beyond the scope of this assessment to review all of the available data in detail. However, the key findings from the disseminated REACH dossiers and OECD SIAR reports (OECD, 2004) are reported here to support read-across arguments.

The majority of repeated dose toxicity information for methanol comes from inhalation studies in rats and monkeys.

Generally effects noted include nasal irritation in rats (but not monkeys), CNS depression, effects on body and organ weight and in some cases effects on clinical chemistry parameters. Studies were conducted up to significant doses and generally effects when noted, are considered adverse only at upper end of the dose ranges studied e. g 650 mg/m³ in monkeys, 13 000 mg/m³ in rats. Therefore any effects noted in studies with read-across substance trimethoxy(methyl)silane are considered not to be attributable to methanol.

Methanol is not classified for repeated dose toxicity in Annex VI of Regulation (EC) No 1272/2008.

Conclusion

As methylsilanetriol is representative of the registered substance and also the hydrolysis product of the read-across substance, it is considered appropriate to read across long-term mammalian toxicity data for trimethoxy(methyl)silane to potassium methylsilanetriolate in order to minimise the number of animal tests performed.

OECD (2004): SIDS Initial Assessment Report for SIAM 19, Berlin, Germany, 18-20 October 2004, Methanol, CAS 67-56-1.

PFA (2013a). Peter Fisk Associates, Application of Category - Analogue - QSAR for Reconsile, PFA.300.006.014

PFA, (2015t). Peter Fisk Associates, Analogue report – mammalian toxicity of alkyl alkoxysilanes, PFA.404.002.002.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study was conducted in accordance with an appropriate OECD test guideline and in compliance with GLP.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The study was conducted in accordance with an appropriate OECD test guideline and in compliance with GLP.

Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: other; digestive: duodenum; digestive: jejunum; digestive: liver; glandular: thyroids

Repeated dose toxicity: inhalation - systemic effects (target organ) urogenital: kidneys; urogenital: prostate; urogenital: urinary bladder

Justification for classification or non-classification

Based on the available read-across data, potassium methylsilanetriolate does not require classification for repeated dose toxicity according to Regulation (EC) No. 1272/2008.