Hexachlorodisilane

Endpoint summary

Description of key information

No data are available for the repeated dose oral toxicity of hexachlorodisilane, therefore good quality data for the hydrolysis product, polysilicic acid (equivalent to SAS) have been read-across to address the potential for systemic toxicity. In a repeat dose 90-day oral toxicity study (Kim et al., 2014) with Sprague-Dawley rats, two forms of synthetic amorphous silica (SAS and NM-202; differing in particle size and specific surface area) were administered (vehicle: water) by oral gavage for 90 consecutive days at a dose of 500, 1000 or 2000 mg/kg bw/day (10 animals/sex/group). The particles were described as either 20 or 100 nm in diameter. Extra animals were included in the control (received water only) and highest dose groups to allow for a two-week post-exposure recovery period. Observations were made according to OECD TG 408. For 20 and 100 nm silica samples the findings were sporadic and without a dose-response, so were concluded by the study authors not to be treatment-related. The NOAEL for both particle sizes was therefore concluded to be ≥2000 mg/kg bw/day. For local effects a good quality study on hydrogen chloride is available. In a 90-day repeated dose inhalation study in rats and mice (Toxigenics, 1983), 31 males and 21 females of each species/strain were exposed to test concentrations of 0, 10, 20 and 50 ppm hydrogen chloride gas (HCl). Treatment was whole-body exposure for six hour per day, 5 days per week. The No Observed Adverse Effect Concentration (NOAEC) for systemic effects was determined to be 20 ppm (approximately 30 mg/m3) based on decreased body weight following exposure to 50 ppm. No NOAEC for local effects was established as irritant/corrosive effects were observed at all dose levels tested. No suitable dermal data are available.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The key study was conducted according to OECD TG 408 and to GLP, without any significant deviations and is therefore the most suitable key study for the repeat dose oral toxicity endpoint.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

15 mg/m³

Study duration:

subchronic

Species:

mouse

Quality of whole database:

The key study was conducted according to OECD TG 413 and to GLP, without any significant deviations and is therefore the most suitable key study for the repeat dose inhalation local toxicity endpoint.

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

There are no adequate long term repeated dose toxicity data on hexachlorodisilane so good quality data for the hydrolysis products polysilicic acid (equivalent to synthetic amorphous silica) and hydrogen chloride have been used to assess the potential for adverse effects following exposure to hexachlorodisilane.

Overview

It is considered not to be either ethical or technically feasible to perform repeated dose toxicity testing with hexachlorodisilane by any route of exposure due to its known corrosive properties, which dominate the toxicity profile of this substance. 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. This would confound the interpretation of any systemically driven effects. A guideline-compliant repeated-dose inhalation study should elicit systemic toxicity at the highest test concentration. Since the local corrosive effects of hexachlorodisilane 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 (<10 ppm) to prevent the known corrosive effects and/or distress in the test species. This has been confirmed in a 28-day inhalation study with another chlorosilane, dichloro(dimethyl)silane (WIL, 2014), in which there were no effects of treatment on clinical signs, body weight or food consumption that would indicate a systemic effect. Furthermore, the histopathology in the study indicated that the local effects in the upper respiratory tract were similar to HCl. It is therefore concluded that local effects caused by HCl will dominate the inhalation toxicity profile of hexachlorodisilane.

With regard to the dermal and inhalation routes, due to the known corrosive effects of hexachlorodisilane, appropriate H-phrases and P-statements are included in the labelling, meaning that repeated skin and inhalation exposure is not expected. Any accidental skin contact or inhalation exposure could cause severe local effects but would be unlikely to cause any systemic effects.

ORAL ROUTE

SYSTEMIC EFFECTS

There are no adequate repeat-dose toxicity data on hexachlorodisilane so good quality data for synthetic amorphous silica (CAS 112926-00-8) have been used to assess the general systemic oral toxicity of hexachlorodisilane. Local effects from the hydrolysis product, hydrogen chloride (HCl) are not addressed by these data (see section on local effects below).

Hexachlorodisilane, like all inorganic chlorosilanes, is a severely corrosive substance that is decomposed by water. The reaction is highly exothermic (Merck, 2013). Hydrolysis half-life is estimated to be less than 5s at 25°C and pH 4, 7 and 9. The estimated half-lives of the substance at 25ºC and pH 4, 7 and 9 are approximately 5 seconds, producing hexahydroxydisilane and hydrogen chloride. Further hydrolysis of the Si-Si bonds in hexahydroxydisilane is expected to happen rapidly and produces monosilicic acid.

 

Monosilicic acid condenses to insoluble polysilicic acid [equivalent to synthetic amorphous silica (SAS)] at concentrations higher than 100-150 mg/l ‘SiO₂ equivalent’ in water (Holleman-Wiberg, 2001). At very high concentration, polysilicic acid can condense to silicon dioxide (SiO₂). Hexahydroxydisilane is also likely to form condensation products (polyhydroxy-polysilanes) at similar concentrations (in terms of SiO₂ equivalents). The structure and predicted properties of the Si-Si containing hydrolysis products (polyhydroxy-polysilanes) and (poly)silicic acid are very similar, and distinguishing between them would be very difficult analytically. The hydrolysis products of hydrochloric acid and (poly)silicic acid are significant for the chemical safety assessment (CSR).

 

Monosilicic acid and polysilicic acid are naturally occurring substances which are ubiquitous in the environment. Soluble monosilicic acid is the major bioavailable form of silicon and plays an important role in the biogeochemical cycle of silicon (ECETOC, 2006). Typical background concentrations of monosilicic acid in the environment are up to 75 mg/l ‘SiO₂equivalent’ in river water and up to 14 mg/l ‘SiO₂equivalent’ in seawater (Iler, 1979).

 

The literature gives various values for the solubility of silicic acid, determined indirectly as ‘SiO₂ equivalent’ because the soluble species cannot be directly measured:

 

The solubility of monosilicic acid according to Alexander et al. (1954) at 25 °C:

• 150 mg/l ‘SiO₂ equivalent’ at pH 2.0 and pH 3.0
• 130 mg/l ‘SiO₂ equivalent’ at pH 4.2
• 110 mg/l ‘SiO₂ equivalent’ at pH 5.7
• 100 mg/l ‘SiO₂ equivalent’ at pH 7.7
• 490 mg/l ‘SiO₂ equivalent’ at pH 10.3
• 1120 mg/l ‘SiO₂ equivalent’ at pH 10.6

 

The solubility of monosilicic acid according to Goto and Okura (1953) at 25 °C:

• 120 mg/l ‘SiO₂ equivalent’ at pH 2.0
• 150 mg/l ‘SiO₂ equivalent’ at pH 7.0

 

The solubility of monosilicic acid according to Elmer and Nordberg (1958) at neutral pH:

• 170 mg/l ‘SiO₂ equivalent’ at 35 °C
• 270 mg/l ‘SiO₂ equivalent’ at 65 °C
• 465 mg/l ‘SiO₂ equivalent’ at 95 °C

 

With the described properties of hexachlorodisilane in mind it is not possible to conduct 90-day repeated dose toxicity studies in experimental animals due to the corrosive nature of this substance. Nor can the hydrolysis product, monosilicic acid, be tested as it is not possible to isolate this substance. However, we know from physicochemical properties that following ingestion of hexachlorodisilane, the conditions in the stomach are such that following an initial rapid hydrolysis to soluble monosilicic acid, this monomer will start to condense to form insoluble polysilicic acid (equivalent to SAS). This condensation will start to occur once the concentration of monosilicic acid reaches approximately 150 mg/l in the gastric juices.

Monosilicic acid (soluble silica) undergoes condensation reactions in solution at about 100-150 mg/l ‘SiO₂ equivalent’. The solubility of monosilicic acid in water is 150 mg/l ‘SiO₂ equivalent'.

Following dosing by oral gavage, partitioning will occur between the dose vehicle and the aqueous environment in the stomach.

Mass dosed (in mg/day) = Body weight (in kg) x dose level (in mg/kg bw/day)

 

Dose concentration (in mg/l) = mass dosed (in mg/day) ÷ volume (in l)

So, the dose level (mg/kg bw/day) required to reach the dose concentration of 150 mg/l 'SiO₂ equivalent', the estimated (conservative) maximum concentration of silicic acid that can occur in the stomach before condensation to insoluble polysilicic acid (equivalent to SAS) begins is calculated as follows:

Body weight of rat = 0.3 kg

Dose level = X                                                        

Estimated aqueous volume = 0.0015 l                                                                      

Dose concentration = 150 mg/l

150 mg/l = 0.3 kg x dose level (mg/kg bw/day) ÷ 0.0015l

Dose level = 0.75 mg/kg bw/day 'SiO₂ equivalent'

Therefore based on a condensation limit of 150 mg/l, the maximum dose level that could be used in practice to ensure exposure mainly to monosilicic acid in the stomach of experimental animals is approximately 0.75 mg/kg bw/day or less of 'SiO₂ equivalent'.

A correction for molecular weight gives a maximum dose level for hexachlorodisilane:

Mr [hexachlorodisilane]               =             268.89 g/mol

Mr [silicon dioxide]                         =             60.08 g/mol

Dose level [hexachlorodisilane]        =            [Dose level [silicon dioxide]  x  Mr [hexachlorodisilane]]

                                                                                                         Mr [silicon dioxide]

 

                                                            =            (0.75 mg/kg bw/day) x (268.89 g/mol)

                                                                                                         (60.08 g/mol)

 

                                                            =             3.36 mg/kg bw/day

Therefore based on a condensation limit of 150 mg/l the maximum dose level of hexachlorodisilane that could theoretically be dosed to ensure exposure mainly to monosilicic acid is approximately 3 mg/kg bw/day.

For comparison purposes, using the above calculation, the following shows the dose concentrations for the dose levels typically used in experimental animal studies (100, 300 and 1000 mg/kg bw/day).

Body weight                                = 0.3 kg

Total amount dosed                     = 30 mg

Estimated aqueous volume           = 1.5 ml

Dose concentration                      = 20,000 mg/l

Body weight                                = 0.3 kg

Total amount dosed                     = 90 mg

Estimated aqueous volume           = 1.5 ml

Dose concentration                     =  60,000 mg/l

Body weight                                 = 0.3 kg

Total amount dosed                      = 300 mg

Estimated aqueous volume           = 1.5 ml

Dose concentration                       = 200,000 mg/l

Therefore dosing at these dose levels clearly gives a dose concentration in the stomach that far exceeds the dose at which condensation to polysilicic acid (equivalent to SAS) starts to occur. Consequently, the majority of the dose in the stomach will be present as insoluble polysilicic acid (equivalent to SAS). In all cases only approximately 150 mg/l will be present as soluble monosilicic acid.

Overall, it can be concluded that gavaging hexachlorodisilane at doses unlikely to cause local corrosive effects and at doses that give mainly soluble monosilicic acid (2 mg/kg bw/day or less) would be unethical based on animal usage. However, because the vast majority of a gavaged dose will rapidly condense to insoluble polysilicic acid it is appropriate to use toxicology data on SAS to address the potential for oral toxicity of hexachlorodisilane.

The key study is a repeated dose 90-day oral toxicity study in rats (Kim et al., 2014) conducted according to OECD test guideline 408 and in compliance with GLP. In this study two forms of synthetic amorphous silica (described as SAS and NM-202; differing in particle size and specific surface area) were administered (vehicle: water) by oral gavage for 90 consecutive days at a dose of 500, 1000 or 2000 mg/kg bw/day (10 animals/sex/group). A number of control and high dose group animals were used for a two-week post-exposure recovery group follow-up. All findings were sporadic and without a dose-response, so were concluded by the study authors not to be treatment-related. The NOAEL for SAS was therefore concluded to be ≥2000 mg/kg bw/day.

 

INHALATION ROUTE

LOCAL EFFECTS

As has already been described above, hexachlorodisilane is a severely corrosive substance that is decomposed by water, producing silicic acid and HCl. For local effects it is appropriate to read across results of a 90-day inhalation toxicity study on HCl, which demonstrates the severe corrosive effects of HCl in the respiratory tract.

Hydrogen chloride

In a 90-day repeated dose inhalation study in rats and mice (Toxigenics, 1983), 31 males and 21 females of each species/strain were exposed to test concentrations of 0, 10, 20 and 50 ppm hydrogen chloride gas (HCl). Treatment was whole-body exposure for six hour per day, 5 days per week. Fifteen males and 10 females from each group were sacrificed after four exposures and the nasal turbinates, trachea, lung and gross lesions were examined microscopically. In general, all animals in the high dose group showed adverse findings after 4-days exposure. One female high dose mouse was found dead on study day 12, and four low dose male mice were found dead on study day 92. In addition, one high dose female mouse was sacrificed in extremis on study day 20. One high dose female Sprague-Dawley rat was found dead on study day 4. However, the study authors noted that the deaths did not appear to be related to exposure to HCl. Clinical signs were consistent with the irritant/corrosive properties of HCl (appendage, tail or lip injury in the form of toe missing/swollen/open/gelatinous, scabbed/deformed/lesion, crusty nose, tissue mass, mouth injury, scabbed nose, crusty muzzle, red stained fur, nasal discharge, crusty eye, poor coat quality); some of the observed injuries may have been mechanical and not related to test material exposure.

 

Ninety days exposure to 50 ppm HCl resulted in decreased body weights in all four strains after four exposures. Following 90 days of exposure B6C3F1 male and female mice and male Sprague-Dawley rats exposed to 50 ppm had biologically significant decreases in body weight. After four days of exposure there were statistically significant decreases in food consumption for high dose male Sprague-Dawley rats and male Fischer 344 rats. After 90 days high dose mice had the largest reduction in food consumption. The rats did not show a consistent reduction in food consumption that could be deemed exposure-related. There were no treatment-related effects on the haematology, clinical chemistry or urinalysis parameters that were examined. Decreased liver weights were observed in high dose male and female mice and Fischer 344 female rats. The authors noted that this might have been due to the overall reduced body weights.

 

Animals exposed to all concentrations of HCl had minimal to mild rhinitis, which occurred in the anterior portion of the nasal cavity and was dose and time related. Mice also developed varying degrees of cheilitis with accumulations of haemosiderin-laden macrophages involving the perioral tissues at 50 ppm. At all exposure concentrations mice developed oesinophilic globules in epithelial cells lining the nasal turbinates after 90 days of exposure. The No Observed Adverse Effect Concentration (NOAEC) for systemic effects was determined to be 20 ppm (approximately 30 mg/m³) based on decreased body weight following exposure to 50 ppm. No NOAEC for local effects was established as irritant/corrosive effects were observed at all dose levels tested.

References

Alexander G.B., Heston W.M. and Iler R.K. (1954) J. Phys. Chem., 58, 453.

Cotton F.A. and Wilkinson G. (1999) Advanced Inorganic Chemistry, 6^thEdition, p271

ECETOC (2006) Synthetic Amorphous Silica (CAS No. 7631 -86 -9), JACC REPORT No. 51

Elmer and Nordberg (1958) J. Am.Chem. Soc., 41, 517

Goto K. and Okura T. (1953) Kagaku, 23, 426.

Holleman-Wiberg, (2001) Inorganic Chemistry, Academic Press, p. 865

Iler, Ralph K. (1979) The Chemistry of Silica: Solubility, Polymerization, Colloid and Surface Properties and Biochemistry of Silica, Wiley, p. 13.

Jones, R. G., Wataru, A., and Chojnowski, J. (2000) Silicon-Containing Polymers: The Science and Technology of Their Synthesis, Kluwer Academic Press pp168-169

Merck Index (2013) Monograph Number. 8639 (15th Ed)

Justification for classification or non-classification

Based on the available read-across data from the hydrolysis products insoluble polysilicic acid [equivalent to synthetic amorphous silica (SAS)] and hydrogen chloride, hexachlorodisilane does not require classification for specific organ toxicity following repeated administration according to Regulation (EC) No. 1272/2008.