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BIO Trimethvlsilanol â¢ Harold L. Kaplan, Ph.D., Martin E. Coleman, Ph.D., and John T. James, Ph.D. Johnson Space Center Toxicology Group Biomedical Operations and Research Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Trimethylsilanol (TMS) is a volatile liquid with the following properties (Rouviere, 1973): Synonym: Trimethylhydroxysilane Formula: (CH3) 3Si-OH CAS number: 1066-40-6 Molecular weight: 90.2 Liquid density: 0.81 Boiling point: 98.6-99Â°C Conversion factors at 25Â°C, 1 atm: 1 ppm = 3.69 mg/m 3 1 mg/m 3 = 0.27 ppm. OCCURRENCE AND USE TMS is commonly seen as an off-gassed product in spacecraft atmo- spheres and from individual flight articles (Coleman, 1991). Concentra- tions measured during a number of shuttle missions ranged from 0.004 to 0.018 mg/m3 (Coleman, 1991). TMS is released largely from the break- down of silicone polymers in various types of lubricants, fluids, adhesives, and plastics. 177
178 SMACS FOR SELECTED AIRBORNE CONTAMINANTS PHARMACOKINETICS AND METABOLISM There is no information on the pharmacokinetics of TMS vapor because, to our knowledge, inhalation studies with this compound have not been conducted in animals or humans. However, analyses of urine, blood, and tissues indicate that TMS administered orally to the rat is absorbed from the gastrointestinal tract into the systemic circulation and is eliminated within 48 h from the body (Dow Corning Corp., 1972). In a study in which TMS was administered orally to rats at doses of 33 and 100 mg/kg/d for 31 d, there was no evidence of TMS or organosoluble silicon metabo- lites in blood, liver, or kidneys or of silicon in urine beyond 48 h following the last dosing (Dow Corning Corp., 1972). TOXICITY SUMMARY Acute and Short-Term Studies Inhalation studies of the toxicity of TMS have not been conducted in animals or humans (Dow Corning Corp., 1991), and published animal studies of TMS by other routes of administration are rare. The available studies do not provide much relevant information. The most useful infor- mation for establishing SMAC values for TMS are in internal research reports, abstracts of which were provided by Dow Corning Corp. of Midland, Michigan. On the basis of these reports, TMS is a central nervous system (CNS) depressant, producing states of sedation, hypnosis, or general anesthesia in the rat, guinea pig, and rabbit, depending on the dose and route of administration (Dow Corning Corp., 1991). Depression of the CNS was the only effect observed grossly in studies in which TMS (in a 2% solution in saline) was administered by oral, subcutaneous (sc), intramuscular (im), intraperitoneal (ip), or intravenous (iv) routes. This effect was reversible. Qualitatively, it was the same as that of a carbon analog, tert-butyl alcohol, but TMS appeared to be more potent. In a Russian study of the tranquilizing activity of several silicon com- pounds, the silating agent, TMS, at doses of 6.25-25 mg/kg (route not specified in English abstract) did not produce a tranquilizing effect in mice nor did it alter neuromediator (GABA, dopamine) turnover in the brain (Tsareva et al., 1982).
TRIMETHYLSILANOL 179 Intraperitoneal or intravenous administration of TMS to the rat, guinea pig, and rabbit in doses of 100-200 mg/kg produced light-to-moderate anesthesia, persisting for 10 to 60 min (Dow Corning Corp., 1991). The lowest reported lethal ip dose of a lithium derivative of TMS in the mouse is 125 mg/kg (DHHS, 1988). However, this report is not relevant to SMAC values for TMS because of possible interactive effects of lithium with CNS depressants. A Dow Corning Corp. internal report stated that the initial data suggest that rapid attainment of a blood level of 1 mg/mL of TMS is necessary to produce a state of light anesthesia (Dow Corning Corp., 1991). The statement most likely was intended to indicate that ip or iv administration of 100-200 mg/kg of TMS results in rapid absorption of TMS and blood levels of 1 mg/mL necessary for light anesthesia. Subchronic and Chronic Studies In a study in which TMS was administered by gavage once daily for 5 d/w for 2 w to four groups of male Sprague-Dawley rats (number unspeci- fied) at doses of 0, 250, 500, or 750 mg/kg/d, no significant toxic or adverse effects, including behavioral changes, gross pathological changes, or effects on food consumption or body or organ weights, were observed at the lowest TMS dose of 250 mg/kg/d (Dow Corning Corp., 1983). At doses of 500 and 750 mg/kg/d, CNS depressant effects were observed, consisting of ataxia, decreased locomotor activity, dyspnea, irregular respiration, weakness of hind-leg muscles, and loss of consciousness. At both doses there were significant reductions in total body-weight gains, but there were no significant dose-related pathological changes or effects on food consumption or organ weights. There was one death at the 750- mg/kg/d dose (Dow Corning Corp., 1983). In a 31-d study in which TMS was administered to rats in single daily oral doses of 33 and 100 mg/kg, there were no deaths or significant alter- ations in hematology or body and organ weight ratios of the liver, kidneys, adrenals, heart, or gonads (Dow Corning Corp, 1972). There also were no histopathological changes or significant alterations in clinical blood chemistry parameters (uric acid, cholesterol, triglycerides, total lipid, creatinine, bilirubin, LOH, SGOT, AP, albumin, total protein). Analyses for total silicon in urine and for organosoluble silicon in blood, liver, and kidneys indicated the absence of TMS in blood, tissues, and urine at 48 h following the last dose.
180 SMACS FOR SELECTED AIRBORNE CONTAMINANTS Genotoxicity Results of in vivo bone marrow cytogenic assays indicate that TMS is not genotoxic at doses of 100-500 mg/kg administered ip to rats (Isquith et al., 1988). The lack of significant clastogenic potential of TMS also was evident in a rodent dominant lethal test in which oral doses of 20-200 mg/kg/d, 5 d/w for 8 w had no effect on fertility index, pre-implantation loss, or fetal resorptions in the rat (Isquith et al., 1988). No data are available on the carcinogenicity of TMS by any route of administration.
TABLE 10-1 Toxicity Summary Exposure Concentration Duration Species Effects Reference 6.25-25 mg/kg N.S. Mouse No tranquilizing effect or effect on neuromediator Tsareva et al., 1982 (route N.S.a) turnover in brain. 20,100, or 200 5 d/wfor 8 w Rath No genetic treatment-related effects in dominant lethal Isquith et al., 1988 mg/kg/d (oral) study; transient sedation at unspecified dose. 33 or 100 mg/kg/d 31 d Rat No effects on organ weight ratios, hematology, clinical Dow Coming Corp., (oral) blood chemistry, pathology. 1972 100 to 200 mg/kg (ip 1 time Rat, guinea Light to moderate anesthesia, persisting for 10 to 60 Dow Coming Corp., or iv) pig; rabbit min. 1991 100,200,or420 1d Rat No significant treatment-related chromosomal damage Isquith et al., 1988 mg/kg/d (ip) in bone marrow cytogenic tests at 48 h. 300,400, or 500 1d Rat No significant treatment-related chromosomal damage Isquith et al., 1988 mg/kg/d (ip) in repeat bone marrow cytogenic tests at 48 h. 125 mg/kg (ip) 1 time Mouse Lowest reported lethal dose of lithium derivative of DHHS, 1988 TMS. 250 mg/kg/d (oral) 5d/wfor2w Rat No adverse effects on mortality, behavior, growth, Dow Coming Corp., food consumption, organ weights, pathology. 1983 500 or 750 mg/kg/d 5 d/w for2 w Rat CNS depressant effects, decreased body weight gain; Dow Coming Corp., (oral) one death at 750 mg/kg. 1983 ~N.S. =not specified. Rats in all the studies were Sprague-Dawley. ~ QO ~
182 SMACS FOR SELECTED AIRBORNE CONTAMINANTS EXPOSURE LIMITS No exposure limits have been set for TMS by any other organizations. TABLE 10-2 Spacecraft Maximum Allowable Concentrations Duration ppm mg/m3 Target Toxicity lb 150 555 CNS 24h 20 0.74 CNS 7d 10 37 CNS 30d 10 37 CNS 180 d 10 37 CNS RATIONALE Inhalation toxicity data are not available on TMS; however, it is clear from studies u:;ing other routes of administration that the primary acute effect is on the CNS. The information available to the authors was in abstract form from private communications; hence, the details of the experiments could not be reviewed. From oral dosing studies at 250, 500, and 750 mg/kg/d, 5 d/w for 2 w, a no-observed-adverse-effect level (NOAEL) for CNS effects, and all other measured effects, was 250 mg/kg/d (Dow Corning Corp., 1983). A more sensitive NOAEL comes from ip and iv studies in which single injections of 100 or 200 mg/kg induced light or moderate anesthesia (Dow Corning Corp, 1991). Light anesthesia was associated with blood concentrations of 1 mg/mL, and the effects disappeared in 10 to 60 min. The dose of 100 mg/kg was a lowest- observed-adverse-effect level (LOAEL), and the NOAEL was calculated by using the proportion (100/200) that caused a change from moderate-to- light anesthesia as the proportion that would convert light anesthesia to no anesthesia. The NOAEL for anesthesia was calculated to be 50 mg/kg by injection in rats. This injection dosage might be converted to an equivalent dosage in humans by using the species extrapolation factor of 10. The equivalent inhalation dosage was calculated assuming a moderate breathing volume of
TRIMETHYLSILANOL 183 20 L/min and a body weight of 70 kg. Additional assumptions were that the uptake was 50% from the inspired air and that there was no clearance of TMS from blood during a 1-h exposure. A 50% uptake is typical of many organic vapors (Dahl et al., 1991). The computation was as follows: C = 50 mg/kg X 1/10 x 70 kg + (50% x 20 L/min x 60 min) 3 = 580mg/m = 157 ppm. The 1-h SMAC was set at 150 ppm to protect against CNS effects. The 24-h SMAC was set using the same starting point except the aver- age breathing volume was 15 L/min and it was assumed that at least 50% of inhaled TMS was cleared from the blood in a 24-h period. This latter assumption was based on the fact that no trace of TMS could be found 48 h after administration (Dow Corning Corp, 1972) and clinical anesthesia disappeared quickly after rats were injected with TMS (Dow Corning Corp., 1991). The computation was as follows: C = 50 mg/kg x 1/ 10 x 70 kg + (50% X 50% X 15 L/min x 1440 min) = 18 ppm. The 24-h SMAC was rounded to 20 ppm. The long-term SMACs were based on the NOAEL from 31 d of oral dosing of rats with 100 mg/kg/d (Dow Corning Corp., 1972). Since the CNS appears to be the target of TMS, there should be a threshold below which no effects occur even in prolonged exposure. That threshold was determined from the rat oral data, assuming a species factor of 10, a body weight of 70 kg, and a breathing volume of 15 L/min. The concentration was C = 100 mg/kg/d X 1/10 X 70 kg + (15 L/min x 1440 min/d) 3 = 32 mg/m = 9 ppm. Therefore, the 7-d, 30-d, and 180-d SMACs were set at 10 ppm by round- ing of the value above. It should be noted that factors for uptake from the respiratory system and elimination were not used because the comparative uptake and elimination using the oral and inhalation routes are unknown.
184 SMACS FOR SELECTED AIRBORNE CONTAMINANTS Since there is no evidence that spaceflight-induced physiological changes would sensitize astronauts to anesthetics, no factor was applied to the values derived above. REFERENCES Coleman, M. 1991. Summary Report of Postflight Atmospheric Analysis for STS-26 to STS-36, SD4-91-430. National Aeronautics and Space Administration, Washington, D.C. Dahl, A.R., M.B. Snipes, and P. Gerde. 1991. Sites for uptake of inhaled vapors in Beagle dogs. Toxicol. Appl. Pharmacol. 109:263- 275. Dow Corning Corp. 1972. A toxicological evaluation of trimethylsilanol and dimethylsilanediol in the rat. Dow Corning Internal Research Report Abstract. Dow Corning Corp., Midland, Mich. Dow Corning Corp. 1983. A two-week maximum tolerated dose study of trimethylsilanol in the rat. Dow Corning Internal Research Report Abstract. Dow Corning Corp., Midland, Mich. Dow Corning Corp. 1991. Trimethylsilanol. Dow Corning Internal Research Report Summary. Dow Corning Corp., Midland, Mich. Isquith, A., R. Slesinski, and D. Matheson. 1988. Genotoxicity studies on selected organosilicon compounds: In vivo assays. Fd. Chem. Toxic. 26:263-266. Rouviere, J., V. Tabacik, and G. Fleury. 1973. Vibrational spectra of trimethylsilanol. Part A. Spectrochim. Acta 29:229-242. Tsareva, T.A., E.P. Kramarova, and A.M. Zharkovskii. 1982. Phar- macological characteristics of the silyl derivatives of alpha-pyrrolidine [English abstract]. Farmakol. Toksikol. 45:20-23. DHHS. 1988. No. 77713, Silanol, trimethyl-, lithium derivative. In Registry of Toxic Effects of Chemical Substances. 1985-86 Edition. U.S. Department of Health and Human Services, Washington, D.C.