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EC number: 219-785-8 | CAS number: 2530-85-0
There are several reliable studies that investigated the potential for formation of laryngeal granulomas following inhalation of aerosols of aqueous solution of 3-trimethoxysilylpropyl methacrylate. These studies exposed rats for 28 or 90 days. In addition, there is one nine day study. These studies on the aerosol tested several concentrations, solution strengths and durations, making interpretation of results complex. Following a weight-of-evidence approach it was concluded that the overall NOAEC for granuloma formation is 15 mg/m3 and this is a local effect.
Granulomas were not observed in a nine day vapour inhalation study.
The nine-day studies were assigned reliability 4 since they were of insufficient duration to meet current criteria for repeated dose toxicity testing. The results, however, are useful for weight of evidence.
The only consistently significant finding relating to general systemic toxicity was a reduction in body weight gains. The overall NOAEC for this effect appears to be between 50 and 100 mg/m3 for a 1 or 2% solution. As a worst-case interpretation, it is assumed that the body weight effects are not linked to granuloma formation and the lowest available systemic NOAEC of 50 mg/m3 is used as a starting point for risk characterisation purposes.
Chamber Concentrations. Particle Size Analyses. Temperature, and Relative Humidity:
The following table presents data for the nominal and gravimetric exposure concentrations obtained for the study:
Target Concentration (mg/m3)
Nominal Concentration of test substance solution (mg/m3)
Corrected* Nominal Concentration (mg/m3)
Gravimetric Concentration (mg/m3)
Equivalent(a) test substance Concentration (mg/m3)
*Corrected Nominal Concentration = Nominal Concentration x 0.01 for 1% solutions
**Two chambers had to be used for this group because of the large number of animals.
(a)Equivalent test substance concentration = Gravimetric Concentration + 0.7217
The following table summarizes the particle size data collected during the study:
Target Conc. (mg/m3)
CMAD = Count Median Aerodynamic Diameter
MMAD = Mass Median Aerodynamic Diameter
sg = Geometric Standard Deviation
The means of the daily mean chamber temperature and relative humidity ranged from 21.2 to 23.8°C and from 40-56%,
Discussion of study author regarding formation of laryngeal granuloma
The formulation of generated solution had no biological significance; rats from all three groups exposed to approximately 70 mg/m3 of 3-(trimethoxysilyl)propyl methacrylate developed laryngeal granulomas after 2 and/or 4 weeks of exposure. The granulomas from rats exposed to aerosols of the 1%, pH5 solution (Group III) were smaller than those observed for both groups exposed to aerosols of the 15%, pH3 solution. However, no qualitative difference in the IR spectra was observed in samples obtained from the chamber atmosphere of Groups III and IV to explain these slight differences in granuloma incidence (at 2 weeks) and size (at both 2 and 4 weeks). Similarly, no difference was observed in the appearance of the material in the granuloma, or the morphological and cytological characteristics of the granuloma itself, to account for these changes. The incidence and severity of the lesion was very similar in both groups exposed to the 15%, pH3 solution (Groups IV and V). Therefore, the recirculation of the 15% solution (Group IV) produced no apparent biological differences from the non-recirculated solution (Group V).
The mechanism whereby the laryngeal granuloma is produced remains unknown. The reasons for the unusual location of the lesion (larynx) and the presence of particles (of approximately 2 microns) in the submucosa under the intact epithelium are not apparent. Some factors that could relate to the site of the lesion may be an unusual sensitivity of these cells to 3-(trimethoxysilyl)propyl methacrylate toxicity, or an increased deposition and/or decreased clearance of particles in this area. Possible explanations for the appearance of spherical siliceous particles in the submucosa include the transport of particles across the epithelium or an initial necrosis and ulceration of the epithelium, followed by particulate deposition, with reepithelialization of the ulcerated site(s). However, there was no evidence of focal necrosis, reepithelialization, or a prominent change in cell type was observed in this study. An additional explanation, which gains support from the fact that the material was determined not to be a solid particulate in the chamber atmosphere, is that the 3-(trimethoxysilyl)propyl methacrylate is inhaled as a liquid aerosol. It then somehow crosses the intact epithelium to the submucosa, where it eventually polymerizes into a solid particulate.
All of the exposure atmosphere concentrations described in this discussion (as stated in the study reports) relate to corrected concentrations of parent test material, calculated according to:
Equivalent MPTMS Concentration = Measured Concentration / 0.7217
where the resulting silicone formed on the dried filter paper used for gravimetric analysis represents approximately 72.17% of the test atmosphere.
For all of the available aerosol inhalation studies, the test atmosphere was generated by first preparing an aqueous solution of 3-trimethoxysilylpropyl methacrylate, adjusting to pH 4 or 5 (or in some cases pH3) and stirring for a period of 30 minutes or until solutions were clear, prior to aerosolisation. The starting concentration of parent material was generally 1, 2, 5 or 15% but since the parent test substance is hydrolytically unstable (measured half-life 1.87 hours at pH 7, expected to be faster at pH 3, 4 or 5), a significant amount of hydrolysis would have occurred prior to exposure, generating 3-trimethoxysilylpropyl methacrylate and methanol. Furthermore, at the relatively high aqueous concentrations of the solutions used to generate the aerosol atmospheres (approximately 10, 20 or 150 g/l), significant condensation or polymerisation of the silanol hydrolysis product would have taken place. Hydrolysis and condensation are discussed further in Sections 1.3 and 4.1. Gravimetric analysis of the chamber atmosphere confirmed that the test animals were exposed to approximately 72% silicone products of condensation; the remaining 28% would therefore have consisted of parent substance.
Analysis of the methanol concentration in the test chambers (e.g. in BRRC, 1994) does not allow the relative proportions of parent and hydrolysis product to be determined. The measured methanol concentration in the 100 mg/m3 test chamber exceeded the maximum theoretical concentration that could be generated from 100 mg/m3 parent substance, since additional methanol would also have been generated during the stirring period. Methanol concentrations levelled out during the exposure period, indicating that further hydrolysis was not occurring.
The most significant effect observed in the aerosol inhalation studies was the formation of laryngeal granulomas, which is considered to be a local effect on the respiratory system. It is not possible to determine definitively if the effects seen in these studies were caused by exposure to condensate, hydrolysis product or parent material, or a combination of these, although the study author of BRRC, 1989b postulates that granuloma formation is initiated by deposition and polymerisation of liquid test material. The formation of laryngeal granulomas is therefore apparently linked specifically to aerosol exposure, which is supported by the absence of these effects in a 9-day vapour inhalation study. Several observations can be made from the available aerosol studies:
1) Solution concentrations of 15% caused larger granulomas than 1% with the same aerosol concentration;
2) Granulomas have been observed after 2 days exposure (BRRC, 1989b), so it can be assumed that the effect is not exposure duration dependent; and
3) Granulomas produced with a 90-day inhalation of 100 mg/m3 (2% solution) did not change/reverse/progress after a 1-year post-exposure period, i.e. no change in frequency of occurrence or severity during the recovery period, and there was no evidence of laryngeal carcinomas (BRRC, 1994).
Due to the choice of dose levels and examinations performed, a NOAEC for effects on the larynx was not determined in all of the available studies. In addition, laryngeal granuloma formation was not observed at any concentration up to 50 mg/m3 in one of the 14-week studies (BRRC, 1989a). Clear evidence of effects at this level were seen in another 14 -week study (BRRC, 1984). An overall NOAEC of 15 mg/m3 was established for effects on the larynx in a 4-week study (BRRC, 1986), also supported by the absence of granulomas in the 90-day study (BRRC, 1989a), and since there was no apparent duration dependency seen between 9-day, 4-week and 14-week study duration, this result can be considered as a subchronic NOAEC value.
End use of 3-trimethoxysilylpropyl methacrylate relates typically to aqueous-based products containing 1-5% parent substance in the formulation. Partial curing of the parent material prior to use is to be expected, and thus the mixture of parent, hydrolysis product and condensate tested in the available aerosol inhalation studies is considered to be representative of the exposure atmosphere experienced by workers, professionals or consumers in situations where aerosol formation is possible. Use of the NOAEC established for A-174 hydrolysate mixture is therefore suitable for risk characterisation purposes in these scenarios.
For applications where there is no potential for aerosol formation, the laryngeal granuloma effect is not relevant. Laryngeal granuloma formation was not observed in a vapour inhalation study with parent 3-trimethoxysilylpropyl methacrylate, and the only effects seen at the maximum attainable concentration of 42 ppm (approximately 426 mg/m3) were minor organ weight and relative organ weight changes (Bushy Run Research Center, 1982). It is therefore necessary to determine a separate NOAEC for systemic toxicity. There were very few clinical signs of toxicity in any of the available repeated dose toxicity studies. The only consistently significant finding was a reduction in body weight gains. The overall NOAEC for this effect appears to be between 50 and 100 mg/m3 for a 1 or 2% solution. However, in the absence of granuloma formation the effects on body weight were not observed (Bushy Run Research Centre, 1989a), thus there might be a link between these two adverse effects in the other studies. There was no apparent duration-dependent increase in severity of clinical effects. As a worst-case interpretation, it is assumed that the body weight effects are not linked to granuloma formation and the lowest available systemic NOAEC of 50 mg/m3 is used as a starting point for risk characterisation purposes.
Based on the available data 3-trimethoxysilylpropyl methacrylate does not require classification for repeated dose toxicity according to Regulation (EC) No 1272/2008.
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