18
Trimethylsilanol

John T. James, Ph.D., D.A.B.T.

Toxicology Group

Habitability and Environmental Factors Division

Johnson Space Center

National Aeronautics and Space Administration

Houston, Texas

BACKGROUND AND SUMMARY OF ORIGINAL APPROACH

No inhalation toxicity data were available on trimethylsilanol (TMS) at the time the original spacecraft maximum allowable concentrations (SMACs) were set; however, there were limited data from oral, intraperitoneal, and intravenous doses administered primarily to rodent species (Kaplan et al. 1994). The longest study was an oral dominant lethal study in Sprague-Dawley (S-D) rats given TMS doses of 20, 100, or 200 milligrams per kilogram of body weight per day (mg/kg/d), 5 d/wk for 8 wk (Isquith et al. 1988). The SMACs were based on various limited studies in which central nervous system (CNS) depression was an observed clinical sign in the dosed animals. Abstract data on the disposition of TMS (absence of silicon compounds in the urine) suggest that rodents eliminate it within 48 h (Dow Corning Corp. 1972). Further factors considered in setting the SMACs included an interspecies extrapolation factor of 10, the uptake efficiency of TMS in the respiratory system (50%), and the minute volume of a crewmember over the putative exposure period. The details for each SMAC calculation are given below and the SMAC values are presented in Table 18-1.

An intravenous study in rats showed that TMS caused mild anesthesia at 100 mg/kg and moderate anesthesia at 200 mg/kg (A.J. Isquith, Dow Corning Corp., unpublished material, 1991). From these data, it was estimated that 50 mg/kg would be a no-observed-adverse-effect level (NOAEL). It was further assumed that the inhalation uptake was 50% in a human breathing 0.02 m3/min and weighing 70 kg. The calculation, which used a 10-fold species-extrapolation factor, was as follows:



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18 Trimethylsilanol John T. James, Ph.D., D.A.B.T. Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas BACKGROUND AND SUMMARY OF ORIGINAL APPROACH No inhalation toxicity data were available on trimethylsilanol (TMS) at the time the original spacecraft maximum allowable concentrations (SMACs) were set; however, there were limited data from oral, intraperitoneal, and intravenous doses administered primarily to rodent species (Kaplan et al. 1994). The longest study was an oral dominant lethal study in Sprague-Dawley (S-D) rats given TMS doses of 20, 100, or 200 milligrams per kilogram of body weight per day (mg/kg/d), 5 d/wk for 8 wk (Isquith et al. 1988). The SMACs were based on various limited studies in which central nervous system (CNS) depression was an observed clinical sign in the dosed animals. Abstract data on the disposition of TMS (absence of silicon compounds in the urine) suggest that rodents elimi- nate it within 48 h (Dow Corning Corp. 1972). Further factors considered in setting the SMACs included an interspecies extrapolation factor of 10, the up- take efficiency of TMS in the respiratory system (50%), and the minute volume of a crewmember over the putative exposure period. The details for each SMAC calculation are given below and the SMAC values are presented in Table 18-1. An intravenous study in rats showed that TMS caused mild anesthesia at 100 mg/kg and moderate anesthesia at 200 mg/kg (A.J. Isquith, Dow Corning Corp., unpublished material, 1991). From these data, it was estimated that 50 mg/kg would be a no-observed-adverse-effect level (NOAEL). It was further assumed that the inhalation uptake was 50% in a human breathing 0.02 m3/min and weighing 70 kg. The calculation, which used a 10-fold species-extrapolation factor, was as follows: AC (CNS) = 50 mg/kg (NOAEL) × 1/10 (species) × [70 kg/(0.5 × 0.02 m3/min × 60 min)] (inhalation uptake) = 580 mg/m3 348

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349 Trimethylsilanol 580 mg/m3 × (0.27 ppm / 1 mg/m3) (conversion) = 156.6 ppm, rounded to 150 ppm where AC is the acceptable concentration and ppm is parts per million. The 24-h SMAC was set with the same starting point except that it was as- sumed that 50% of the TMS was eliminated in 24 h and the average breathing rate was lower (0.015 m3/min) because of sleep periods. The calculation was as follows: 24-h AC (CNS) = 50 mg/kg (NOAEL) × 1/10 (species) × [70 kg/(0.5 × 0.5 × 0.015 m3/min × 1,440 min)] (inhalation uptake) = 65 mg/m3 65 mg/m3 × (0.27 ppm / 1 mg/m3)(conversion) = 17.6 ppm, rounded to 20 ppm The long-term SMACs were set from the oral CNS-depression NOAEL of 100 mg/kg observed in rats given doses over 31 d (Dow Corning Corp. 1972). The calculation was as follows: 7-, 30-, 180-, and 1,000-d AC (CNS) = 100 mg/kg (NOAEL) × 1/10 (species) × [70 kg/(0.015 m3/min × 1,440 min/d)] (inhalation uptake) = 32 mg/m3 32 mg/m3 × (0.27 ppm / 1 mg/m3) (conversion) = 8.6 ppm, rounded to 10 ppm Because the relative uptake of an oral and an inhalation dose was un- known, no factor was used to relate the oral and inhalation routes. Basically, it was assumed that the two routes of exposure have comparable uptakes. Experience with samples of air obtained in the International Space Station shows that the concentration of TMS is typically about 0.1 mg/m3 (0.03 ppm) or less, with occasional excursions up to 0.3 mg/m3 (1.1 ppm) and one excursion to 0.65 mg/m3 (2.4 ppm). The most likely source is silicone lubricants, which would have in episodic entry into the atmosphere. TMS is commonly found in off-gas tests of flight hardware, presumably from lubricants in hardware joints or from off-gassing from silicone-based seals. TABLE 18-1 Previously Set SMACs for TMS Duration of exposure SMAC, ppm Target toxicity to prevent 1h 150 CNS depression 24 h 20 CNS depression 7d 10 CNS depression 30 d 10 CNS depression 180 d 10 CNS depression Source: Data from Kaplan et al. 1994.

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350 SMACs for Selected Airborne Contaminants CHANGES IN ORIGINAL APPROACH The studies upon which the SMACs were based were reported in abstract form by Dow Corning Corp. 1972. As noted in the section on new risk assess- ment approaches, a structure-activity comparison with the CNS effects of t- butanol is considered. RELEVANT NEW DATA SINCE 1991 No new data were found as a result of a search of the open literature. Dow Corning was contacted and reported that they have not developed any new data since 1991 (M. Andriot, Dow Corning Corp., personal communication). How- ever, an industry consortium, the Silicon Environmental Safety and Health Council, expects to initiate a research effort in 2008 to build the database on TMS toxicity. NEW RISK ASSESSMENT APPROACHES The limited data on TMS toxicity, available primarily in abstract form, consist of nonquantitative clinical observations of the anesthetic effects of orally or intravenously administered TMS. Such nonquantitative data are not suitable for benchmark dose analysis because a dose-response relationship is not re- ported. One important observation not considered in the original assessment was that “the CNS effect is qualitatively the same as noted for similar carbon ana- logs, e.g. t-butanol; however, quantitatively TMS appears to be more potent” (A.J. Isquith, Dow Corning Corp., unpublished material, 1991). To avoid CNS effects, the AC for t-butanol has been set at 50 ppm; thus, one must expect that the SMACs for TMS ought to be lower than 50 ppm. RATIONALE FOR REVISIONS TO THE PREVIOUS APPROACHES The previous SMACs have four critical weaknesses. They were based on a noninhalation route of administration, there were no prolonged exposures even approaching a subchronic study, the data were reported mostly in the form of company abstracts, and the means of assessment of CNS effects was insensitive. There is potential for considerable bias in the reporting of data under these con- ditions. On the basis of these considerations, a factor should be applied to com- pensate for the uncertainty these weaknesses cause. A factor of 10 is proposed for this uncertainty. Thus, each of the original SMACs has been reduced by a factor of 10 because of these database limitations. STRUCTURE-ACTIVITY RELATIONSHIP AND LIPOPHILICITY An approach using structure-activity relationships was considered. Unfor-

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351 Trimethylsilanol tunately, there are few toxicity data on structurally similar compounds. No use- ful data on dimethylsilanol could be found except that it does not appear to be a CNS depressant like TMS (Bennett and Statt 1973). A study designed to charac- terize the antimicrobial activity of trialkylsilanol compounds compared the an- timicrobial activity of TMS, t-butanol, and triethylsilanol (TES) in two bacterial strains (Kim et al. 2006). The structures are presented in Figure 18-1. The average antimicrobial activity in the bacterial strains was inversely re- lated to the octanol-water partition coefficient as shown in Table 18-2. Kim et al. (2006) speculate that the increased antimicrobial activity of si- lanols is due to the higher lipophilicity of the silanols compared with the alco- hol. This was especially true for the larger, more lipophilic silanol, TES. The most important observation from Table 18-2 is that t-butanol is approximately 5- fold less toxic than TMS, which is reasonably consistent with the observation that TMS is roughly 3 times as potent as t-butanol in inducing CNS depression, a phenomenon known to depend on lipophilicity. The relationship between lipo- philicity and anesthetic potency, called the Meyer-Overton correlation, has been known for more than a century. At least for small compounds such as those con- sidered here, the mechanism of action is basically that the compounds act by partitioning into the lipid bilayer of membranes and crossing the blood-brain barrier. The differences in potency are due to the degree of lipophilicity. Once the 10-fold factor has been applied for database weaknesses, the TMS SMACs are much lower than the t-butanol SMACs, which is consistent with the observation that t-butanol is approximately 3-fold less potent than TMS in inducing CNS depression (A.J. Isquith, Dow Corning Corp., unpublished ma- terial, 1991) and 5-fold less potent in antimicrobial activity (Kim et al. 2006). t-butanol TMS TES FIGURE 18-1 Structures of compounds tested by Kim et al. (2006). Abbreviation: TES, triethylsilanol; TMS, trimethylsilanol. Source: Data from Kim et al. 2006. TABLE 18-2 Lipophilicity (Octanol-Water Partition Coefficient) of Three Compounds Compared with Their Antimicrobial Activity in Two Strains of Bacteria Minimum lethal concentration, % Compound/parameter Log OWPC TES 2.62 0.2 TMS 1.14 2.5 t-butanol 0.73 12.5 Abbreviation: OWPC, octanol-water partition coefficient; TES, triethylsilanol; TMS, trimethylsilanol. Source: Kim et al. 2006.

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352 SMACs for Selected Airborne Contaminants RATIONALE FOR THE 1,000-D SMAC With the addition of a factor of 10 for the limited nature of the database, the 7- to 180-d SMAC was reduced from 10 to 1 ppm. Given the demonstration that this compound does not accumulate and that no pathological effects have been found in rats repeatedly exposed to the compound by gavage (Dow Corn- ing Corp. 1972), there is no need to reduce the limit further for 1,000 d of expo- sure. COMPARISON OF SMACS WITH OTHER AIR-QUALITY LIMITS The state of Michigan has set an initial threshold screening level (ITSL) based on analysis by the Air Quality Division of the Department of Environ- mental Quality. The value was set at 0.065 mg/m3. The starting point was the NOAEL of 100 mg/kg from a 31-d gavage study (Dow Corning Corp. 1972, M.L. Hultin, Michigan Department of Natural Resources, personal communica- tion, 1993). A safety factor of 15 was used (10 for the short duration of the study, plus 5 for the lack of controls in the study). The calculation was as fol- lows: ITSL = 100 mg/kg (NOAEL) × 0.97 (inhalation rate conversion) × 1/15 (safety factors) × 1/100 = 0.065 mg/m3 ~ 0.02 ppm where 0.97 is the conversion factor for inhalation rate per kg of body weight (rats to humans), and a default value of 1 was used for unknown relative absorp- tion efficiency. The genesis of the factor of 100 is unclear but is probably for inter- and intraspecies differences. The U.S. Department of Energy (DOE) has declared temporary emergency exposure limits (TEELs) for TMS. Table 18-3 compares the TEELs for TMS and t-butanol (DOE 2005). As indicated in Table 18-3, the method used to derive the TEELs for TMS was the structure-activity relationship. The specific method for t-butanol, how- ever, was not provided. It is apparent from the footnote material that TEELs are a work in progress and that they are default values with minimal expert judg- ment used to derive the values. No rational explanation was given as to why TMS should be 2,000 (300/0.15) times as toxic as t-butanol based on a Si atom in place of a C atom. In Table 18-4, the new SMACs are presented in comparison to the previ- ous SMACs. The proposed long-term SMACs for TMS are generally above ei- ther the Michigan ITSL or the DOE TEEL-0. There is good consistency between the TEEL-1 of 1.5 ppm and the 24-h SMAC of 2 ppm. Both are set to avoid any- thing more than mild transient effects. If the factor of 100 were dropped from the ITSL, the value would be 2 ppm, which is close to the long-term SMAC of 1 ppm. The application of this

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353 Trimethylsilanol factor of 100 seems excessive as TMS does not accumulate, the intravenous study is likely to exaggerate any CNS effects when compared with the same dose inhaled over 24 h, and there is no evidence that the compound is metabo- lized, even in the liver. The long-term SMAC is 7 times higher than the TEEL-0 of 0.15 ppm; however, the TEEL-0 seems excessively low compared with the t- butanol TEEL-0 of 300 ppm and the observation that TMS is 3-5 times as potent as t-butanol. This is based on the comparative observations of CNS depression in rats (A.J. Isquith, Dow Corning Corp., unpublished material, 1991) and the relative antimicrobial activity in two strains of bacteria (Kim et al. 2006). RECOMMENDATIONS FOR ADDITIONAL RESEARCH An inhalation database is needed to develop evidence-based exposure standards. It should consist of short-term exposures in animals and perhaps even in humans to determine irritancy and odor thresholds and to more thoroughly characterize CNS effects. Inhalation exposures in animals for at least 13 wk are needed to more precisely develop longer term inhalation standards. TABLE 18-3 Comparison of TEELs for TMS and t-Butanol t-Butanol, TEELa Explanation TMS, ppm ppm 0 The threshold concentration below which most 0.15 300 people will experience no appreciable risk of health effects 1 The maximum concentration in air below which it 1.5 400 is believed nearly all individuals could be exposed without experiencing other than mild transient adverse health effects or perceiving a clearly defined objectionable odor 2 The maximum concentration in air below which it 7.5 5,000 is believed nearly all individuals could be exposed without experiencing or developing irreversible or other serious health effects or symptoms that could impair their abilities to take protective action 3 The maximum concentration in air below which it 15 5,000 is believed nearly all individuals could be exposed without experiencing or developing life- threatening health effects a It is recommended that, for application of TEELs, the concentration at the receptor point of interest be calculated as the peak, 15-min time-weighted average concentration. It should be emphasized that TEELs are default values, following the published methodol- ogy (on Subcommitte on Consequence Assessment and Protective Actions’ web page) explicitly. The only judgment involved is that exercised in extracting data that are entered in the Excel Workbook used to automatically calculate the recommended TEELs (DOE 2007).

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TABLE 18-4 Previous and Revised SMACs for TMS 354 Uncertainty Factors Acceptable Concentrations, ppm Critical weakness NOAEL, in original Effect, exposure route Species / Sex, Reference mg/m3 Species approach a 1 h 24 h 7d 30 d 180 d 1,000 d Original Approach CNS depression, IV Rats/unknown 50 10 N/A 150 — — — — — (A.J. Isquith, unpublished material, 1991) CNS depression , IV Rats/unknown 50 10 N/A — 20 — — — — (A.J. Isquith, unpublished material, 1991) CNS depression, Oral Sprague-Dawley rats/M 100 10 N/A — — 10 10 10 10 100 mg/kg/d and F (Dow Corning 1972) Original SMACs 150 20 10 10 10 10 Revised Approacha CNS depression, IV Rats/unknown 50 10 10 15 — — — — — (A.J. Isquith, unpublished material, 1991) CNS depression , IV Rats/unknown 50 10 10 — 2 — — — — (A.J. Isquith, unpublished material, 1991) CNS depression, Oral Sprague-Dawley rats/M 100 10 10 — — 1 1 1 1 100 mg/kg/d and F (Dow Corning 1972) Revised SMACs 15 2 1 1 1 1 a Because the original SMACs were based on a noninhalation route of administration, a lack of prolonged exposure, data reported in the form of company abstracts, and an insensitive means of assessment of CNS effects, a factor of 10 is applied to compensate for uncertainty. Abbreviations: F, female; IV, intravenous; M, male; N/A, not applicable.

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355 Trimethylsilanol REFERENCES Bennett, D.R., and H. Statt. 1973. Primate absorption and elimination balance studies including pulmonary, urinary, biliary and fecal excretion of t-butanol, trimethylsi- lanol, dimethylsilanol and hexamethyldisiloxane. Toxicol. Appl. Pharmacol. 25:445. DOE (U.S. Department of Energy). 2007. Protective Action Criteria (PAC) with AEGLs, ERPGs, & TEELs: Rev. 23 for Chemicals of Concern. Chemical Safety Program, Office of Health, Safety and Security, U.S. Department of Energy [online]. Avail- able: http://www.hss.energy.gov/HealthSafety/WSHP/chem_safety/teel.html [ac- cessed Jan. 16, 2008]. Dow Corning Corp. 1972. A Toxicological Evaluation of Trimethylsilanol and Dimethyl- silanol in the Rat. Dow Corning Internal Research Report No. 4006. Dow Corning Corp., Midland, MI. Isquith, A.R., R. Slesinski, and D. Matheson. 1988. Genotoxicity studies on selected organosilicon compounds: In vivo assays. Food Chem. Toxicol. 26(3):263-266. Kaplan, H.L., M.E. Coleman, and J.T. James. 1994. Trimethylsilanol. Pp. 177-184 in Spacecraft Maximum Allowable Concentrations for Selected Airborne Contami- nants, Vol. 1. Washington, DC: National Academy Press. Kim, Y.M., S. Farrah, and R.H. Baney. 2006. Silanol—A novel class of antimicrobial agents. Electron. J. Biotechnol. 9(2) [online]. Available: http://www. ejbiotechnology.info/content/vol9/issue2/full/4/index.html [accessed Jan. 15, 2008].