7

Trimethoxysilane and Tetramethoxysilane1

Acute Exposure Guideline Levels

PREFACE

Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows:

AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could

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1This document was prepared by the AEGL Development Team composed of Dana Glass (Oak Ridge National Laboratory), Mark Follansbee and Julie Klotzbach (SRC, Inc.), Chemical Manager Robert Benson (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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7 Trimethoxysilane and Tetramethoxysilane1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could 1 This document was prepared by the AEGL Development Team composed of Dana Glass (Oak Ridge National Laboratory), Mark Follansbee and Julie Klotzbach (SRC, Inc.), Chemical Manager Robert Benson (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Envi- ronmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are sci- entifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 202

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Trimethoxysilane and Tetramethoxysilane 203 experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic re- sponses, could experience the effects described at concentrations below the cor- responding AEGL. SUMMARY Trimethoxysilane and tetramethoxysilane are colorless liquids with ester- like odors. They are structural analogs and are in the organic silane family. Both chemicals have similar toxicologic effects in the lung and eye. Little relevant data on the toxicity of the chemicals in either humans or laboratory animals are available. AEGL-1 values were not recommended for trimethoxysilane because of inadequate data. Data were also inadequate to derive AEGL-2 values, so values were derived by taking one-third of the AEGL-3 values. The Standing Operating Procedure for determining AEGL values (NRC 2001) specifies that AEGL-2 values can be derived by this method when a chemical has a steep dose-response curve. AEGL-3 values for trimethoxysilane were determined on the basis of mortality data from 1- and 4-h LC50 (lethal concentration, 50% lethality) inhala- tion studies in rats (Nachreiner and Dodd 1988). Points of departure were the calculated LC01 (lethal concentration, 1% lethality) values of 263 ppm for 10 min, 123 ppm for 30 min, 76.3 ppm for 1 h, 29.3 ppm for 4 h, and 18.2 ppm for 8 h. A total uncertainty factor of 30 was used. A factor of 3 was applied for in- terspecies differences, because similar effects were observed in rats, mice, and hamsters exposed at the same concentration in a 5-day inhalation study (Dow Corning Corp. 1981). The default value of 10 was used for intraspecies variabil-

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204 Acute Exposure Guideline Levels ity, because no data were available to estimate human variability and it was not clear that trimethoxysilane acts as a simple chemical irritant in the lungs (NRC 2001). Time scaling was performed using the concentration-time relationship equation Cn × t = k, where C = concentration, t = time, k is a constant, and n generally ranges from 0.8 to 3.5 (ten Berge et al. 1986). An empirical value for n of 1.45 was calculated for trimethoxysilane. AEGL values for trimethoxysilane are presented in Table 7-1. AEGL-1 values were not recommended for tetramethoxysilane because of inadequate data. AEGL-2 values for tetramethoxysilane were derived from an inhalation study in which rats were exposed to tetramethoxysilane at concentra- tions up to 45 ppm for 6 h/day, 5 days/week for 28 days (Kolesar et al. 1989). No deaths or effects on the respiratory or ocular epithelium were observed at 0, 5, and 10 ppm. At 15 ppm, nasal changes indicative of minimal acute inflamma- tion were found in two of 20 rats and acute keratitis of cornea was observed in four of 20 rats, indicating a no-effect level for irreversible effects. At 30 and 45 ppm, lesions more severe than defined by AEGL-2 and deaths were observed, respectively. Therefore, 15 ppm was used as the point of departure for calculat- ing AEGL-2 values. Extrapolation to different exposure durations was per- formed using the equation Cn × t = k (ten Berge et al. 1986), where n = 3 for extrapolation to 30 min, 1 h, and 4 h, and n = 1 for extrapolation to 8 h. The 30- min value was adopted as the 10-min value because extrapolating from dura- tions of more than 4 h to 10 min is not recommended (NRC 2001). A total un- certainty factor of 30 was used. A factor of 3 was applied for interspecies differ- ences because in a 5-day inhalation study with trimethoxysilane, a structural analog, effects were similar in rats, mice, and hamsters (Dow Corning Corp. 1981). A default value of 10 was used for the intraspecies variability because there were no data to estimate human variability and it was not clear that tetramethoxysilane acts as a simple chemical irritant in the lungs (NRC 2001). AEGL-3 values for tetramethoxysilane were derived from a 4-h LC50 inha- lation study in rats (Dow Corning Corp. 1992). The data were analyzed with EPA’s Benchmark Dose Calculation Software, version 1.3.2 (EPA 2005), and values were calculated using log-probit analysis. A BMCL05 (benchmark con- centration, 95% lower confidence limit with 5% response) of 26 ppm was used as the basis for determining AEGL-3 values. For completeness, a BMC01 (benchmark concentration with 1% response) of 30 ppm was also derived, but the lower BMCL05 value was used. Extrapolation to different exposure durations was performed using the equation Cn × t = k (ten Berge et al. 1986), where n = 3 for extrapolation to 30 min and 1 h and n = 1 for extrapolation to 8 h. The 30- min value was adopted as the 10-min value because extrapolating from 4 h to 10 min is not recommended (NRC 2001). A total uncertainty factor of 30 was used. An uncertainty factor of 3 was used for interspecies differences because in a 5- day inhalation study with trimethoxysilane, a structural analog of tetramethox- ysilane, effects were similar in rats, mice, and hamsters (Dow Corning Corp. 1981). A default value of 10 was used for intraspecies variability because there were no data to estimate human variability and it was not clear that tetramethox-

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Trimethoxysilane and Tetramethoxysilane 205 ysilane acts as a simple chemical irritant in the lungs (NRC 2001). The AEGL values for tetramethoxysilane are presented in 7-2. 1. INTRODUCTION Trimethoxysilane and tetramethoxysilane are organosilanes (silicon es- ters). Silicon esters are silicon compounds that contain an oxygen bridge from silicon to an organic group (Si-OR). These compounds are classified according to whether the Si-OR bond is expected to remain intact or hydrolyzed in the final application. Trimethoxysilane and tetramethoxysilane are both alkoxysi- lanes and generally have sweet-fruity odors that become less apparent as the molecular weight increases. Both chemicals can be absorbed into the corneal tissue and cause eye damage (Arkles 2000). Tetramethoxysilane is used in the ceramic industry for closing pores, for coating metal surfaces, and as a bonding agent in paints and lacquers. Trimethoxysilane is used as an intermediate for producing silane. Whereas inorganic silanes are oxidized spontaneously on con- tact with oxygen and air, the organosilanes are more stable. TABLE 7-1 Summary of AEGL Values for Trimethoxysilane End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 NR NR NR NR NR (nondisabling) AEGL-2 2.9 ppm 1.4 ppm 0.83 ppm 0.33 ppm 0.20 ppm One-third of (disabling) (15 mg/m3) (7.0 mg/m3) (4.2 mg/m3) (1.7 mg/m3) (1.0 mg/m3) AEGL-3 values AEGL-3 8.8 ppm 4.1 ppm 2.5 ppm 0.98 ppm 0.61 ppm LC01 values (lethality) (44 mg/m3) (21 mg/m3) (13 mg/m3) (5.0 mg/m3) (3.1 mg/m3) (Nachreiner and Dodd 1988) Abbreviations: LC01, lethal concentration, 1% lethality; NR, not recommended. TABLE 7-2 Summary of AEGL Values for Tetramethoxysilane End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 NR NR NR NR NR (nondisabling) AEGL-2 1.1 ppm 1.1 ppm 0.91 ppm 0.57 ppm 0.38 ppm No-effect level (disabling) (6.8 mg/m3) (6.8 mg/m3) (5.6 mg/m3) (3.5 mg/m3) (2.4 mg/m3) for irreversible effects (Kolesar et al. 1989) AEGL-3 1.7 ppm 1.7 ppm 1.4 ppm 0.87 ppm 0.43 ppm Threshold (lethality) (11 mg/m3) (11 mg/m3) (8.7 mg/m3) (5.4 mg/m3) (2.7 mg/m3) for lethality (Dow Corning Corp. 1992) Abbreviations: NR, not recommended

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206 Acute Exposure Guideline Levels Selected chemical and physical properties for trimethoxysilane and tetra- methoxysilane are presented in Table 7-3. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No data were available on the acute lethality of trimethoxysilane or tetramethoxysilane in humans. 2.2. Nonlethal Toxicity No data were available on the toxicity of trimethoxysilane or tetramethox- ysilane in humans. TABLE 7-3 Physical and Chemical Properties of Trimethoxysilane and Tetramethoxysilane Trimethoxysilane Tetramethoxysilane Parameter (AIHA 1997) (AIHA 1998) Synonyms TMS Methyl silicate; tetramethoxyorthosilicate; TMOS CAS registry no. 2487-90-3 681-84-5 Chemical formula C3H10O3Si C4 H12 O4Si Molecular weight 122.22 152.22 Physical state Colorless liquid Clear, colorless liquid Odor Ester odor Faint, ester-like Melting point -114°C 5°C Boiling point 84°C 122°C Flash point 7.2°C (closed cup) 20°C (closed cup) Density (air = 1) 4.2 5.3 Solubility (in water) Reacts slowly; reacts with Reacts, generating methanol water liberating methanol Vapor pressure 57 mm Hg at 20°C 10.1 mm Hg at 20°C Specific gravity 0.95 at 20°C 1.03 g/cc at 20°C Explosive limits Lower limit: 4.3% at 34°C No data available (volume % in air) Upper limit: 40.1% at 62°C Conversion factors 1 ppm = 5.0 mg/m3 1 ppm = 6.2 mg/m3 1 mg/m3 = 0.2 ppm 1 mg/m3 = 0.16 ppm

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Trimethoxysilane and Tetramethoxysilane 207 2.2.1. Odor Threshold Inadequate data were available to calculate an odor threshold for trimeth- oxysilane or tetramethoxysilane. 2.2.2. Experimental Studies No data were available on experimental studies in humans with trimethox- ysilane or tetramethoxysilane. 2.2.3. Epidemiologic Studies/Occupational Exposures Secondary sources indicate that both trimethoxysilane (AIHA 1997) and tetramethoxysilane (BIBRA 1988) cause ocular irritation; however, primary sources describing such effects were not available. 2.2.4. Clinical Studies No data were available on clinical studies of trimethoxysilane or tetra- methoxysilane. 2.3. Neurotoxicity No data were available on the neurotoxicity of trimethoxysilane or tetra- methoxysilane in humans. 2.4. Developmental and Reproductive Toxicity No data were available on the developmental and reproductive toxicity of trimethoxysilane or tetramethoxysilane in humans. 2.5. Genotoxicity No data were available on the genotoxicity of trimethoxysilane or tetra- methoxysilane in humans. 2.6. Carcinogenicity No data were available on the chronic toxicity or carcinogenicity of tri- methoxysilane or tetramethoxysilane in humans.

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208 Acute Exposure Guideline Levels 2.7. Summary Very little data were available on human exposure to trimethoxysilane or tetramethoxysilane. 3. ANIMAL TOXICITY DATA: TRIMETHOXYSILANE 3.1. Acute Lethality An LC50 study was conducted using Good Laboratory Practices (GLP) by Union Carbide (Nachreiner and Dodd 1988). Five male and five female Spra- gue-Dawley rats were exposed to trimethoxysilane at concentrations of 19, 39, 71, or 166 ppm for 4 h or at 68, 155, 342, or 643 ppm for 1 h. Liquid trimethox- ysilane was metered from a syringe pump into a heated evaporator and the re- sulting vapor was carried into the chamber by an inlet air stream. A gas chro- matograph equipped with a flame-ionization detector was used to measure chamber concentrations of the trimethoxysilane. Because methanol can be pro- duced from the breakdown of trimethoxysilane with moisture, methanol concen- trations also were measured. The highest methanol vapor concentration was 173 ppm in the 1-h study and 66 ppm in the 4-h study. Methanol production was controlled by limiting the relative humidity of the chamber. The 4-h LC50 (with 95% confidence level) for trimethoxysilane was 81 ppm for males, 42 ppm for females, and 60 ppm for both sexes. The 1-h LC50 (with 95% confidence level) was 161 ppm for males, 146 ppm for females, and 154 ppm for both sexes. Those values were determined by a modified method of Finney (1964) using probit analysis. Mortalities were observed at all of the concentrations except 19 ppm in the 4-h group and 68 ppm in the 1-h group, with all deaths occurring during the 14-day post-exposure observation period. Mortality data are pre- sented in Table 7-4. Clinical signs were observed on the day of exposure in all groups, except for the 68-ppm (1 h) and 19-ppm (4 h) groups, and included: hyperactivity fol- lowed by hypoactivity; respiratory irritation; ocular irritation; and ataxia and slow righting reflex (71 ppm only). The following clinical signs were observed post exposure mostly beginning about day 5: unkempt fur, perinasal encrusta- tion, decreased respiratory rate, body weight loss, and audible respiration. These effects were observed in all groups except for the 68-ppm group (1 h), which only had unkempt hair the last week of the post exposure period and the rats in the 19-ppm group (4 h), which had no clinical signs. The primary gross lesion identified in the animals that died was a red discoloration of the lungs. Rats in the 643-ppm group (1 h) or 166-ppm group (4 h) also had dark purple discolora- tion of the liver and fluid in the trachea. No gross lesions were observed in the animals that died in the 39- or 71-ppm groups. Microscopic examination of the lungs showed lesions that increased in severity and incidence with increasing

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Trimethoxysilane and Tetramethoxysilane 209 TABLE 7-4 Summary of Mortality in Rats Exposed to Trimethoxysilane by Inhalation Concentration (ppm) Sex Mortality Day of death (post exposure) 1-h exposure 68 Male 0/5 Not applicable Female 0/5 Not applicable 155 Male 2/5 Days 5 and 9 Female 3/5 Two deaths on day 7, one on day 8 342 Male 5/5 One on day 7, and twp on days 8 and 9 Female 5/5 One on day 6, 7, and 9; two on day 10 643 Male 5/5 1 on days 1, 2, and 9 and 2 on day 8 Females 5/5 1 on days 7, 9, and 13 and 2 on day 8 4-h exposure 19 Male 0/5 Not applicable Female 0/5 Not applicable 39 Male 0/5 0/5 Female 1/5 One on day 14 71 Male 2/5 One on days 13 and 14 Female 5/5 One on days 6, 7, 9; two on day 13 166 Male 5/5 One on days 5, 7, and 10; two on day 6 Female 5/5 One on days 6, 8, and 10; two on day 7 Source: Nachreiner and Dodd 1988. concentration and exposure duration; however, statistical analysis was not per- formed. The study author and the pathologist for the study both concluded that pulmonary lesions increased in severity with increasing concentration and expo- sure duration with animal death caused by lung dysfunction. Pathologic findings in the lungs of the rats exposed to trimethoxysilane for 1 h included:  643 ppm: four males and four females; marked to severe necrotic bronchiolitis in all lungs, squamous metaplasia of bronchiolar epithelium in three lungs, and marked to severe vascular changes (congestion, edema) in all lungs.  342 ppm: one male and three females; vascular changes in all lungs, and some degree of bronchial epithelial changes and submucosal fibrosis in all lungs.

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210 Acute Exposure Guideline Levels  155 ppm: four males and three females; necrotic bronchiolitis in some lungs, severe atelectasis in one lung, and most vascular and inflammatory le- sions were of at least moderate severity.  68 ppm: three males and three females; all survived; mild to moderate vascular and inflammatory changes, and considerable variation in severity of lung reaction. Pathologic findings in the lungs of rats exposed to trimethoxysilane for 4 h included:  166 ppm: three males and four females; marked to severe necrotic bronchiolitis in all lungs, and moderate to marked vascular/inflammatory changes in all lungs.  71 ppm: one male; necrotic bronchiolitis, congestion, and edema.  39 ppm: three males and three females; all rats survived until day 14; necrotic bronchiolitis in four lungs, atelectasis in two lungs, and considerable variability in vascular/inflammatory lesions.  19 ppm: three males and three females; all survived; two females had mild inflammatory cells; two males had moderate bronchiolar epithelial cell degeneration. In this same study, Nachreiner and Dodd (1988) conducted static expo- sures. Five rats per sex were exposed for 10 or 60 min to a near saturated vapor atmosphere of trimethoxysilane. In the 1-h static exposure, the chamber concen- tration of trimethoxysilane decreased from 60,000 ppm to 3,000 ppm within the first 22 min while the methanol concentration increased to 111,000 ppm. During the 10-min static exposure, the concentration of trimethoxysilane decreased from 56,000 ppm to 47,000 ppm, and methanol increased to 69,000 ppm. All animals died during or within 2 h post exposure. Clinical signs in these animals included tremors and respiratory difficulty; gross examination showed red dis- coloration of the lungs and fluid in the trachea. 3.2. Acute Nonlethal Ocular and dermal irritation studies of trimethoxysilane were conducted in rabbits (Union Carbide 1988). A 4-h application of 0.5 mL of trimethoxysilane to occluded rabbit skin caused moderate to severe erythema, severe edema, and necrosis in all six rabbits tested. Edema was gone by day 14 and erythema by day 7; however, the chemical was given an overall rating of severe irritant be- cause ulceration, scabs, and alopecia remained through day 14. Two of the rab- bits were found dead at day 12 but it was unclear if their deaths were related to treatment. Trimethoxysilane (0.1 mL) placed in the eyes of six rabbits resulted in corneal opacity in three rabbits and iritis and moderate to severe conjunctival

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Trimethoxysilane and Tetramethoxysilane 211 irritation in all rabbits. All lesions resolved by day 7. After 0.01 mL of trimeth- oxysilane was placed in the eye, five of six rabbits had minor to moderate cor- neal opacity, and all rabbits had iritis and moderate to severe conjunctival irrita- tion. No corneal lesions were reported when 0.005 mL was tested, but irisitis was observed in four of six rabbits. 3.3. Repeat Exposure Studies 3.3.1. Rats In a study using GLP, 10 Sprague-Dawley rats per sex were exposed 7 h/day, 5 days/week for 4 weeks to trimethoxysilane at concentrations of 0.5, 5.0, or 10.0 ppm (Breckenridge et al. 1980). Animals were exposed whole body in four 400-L volume chambers. Air flow through the chambers was maintained at 45 L/min. Rats were not provided food or water during exposure. Chamber tem- perature, humidity, and concentration were measured continually during the exposure. The chamber concentrations were measured hourly by an infrared-gas analyzer. The concentrations were achieved after a 30-min equilibration period. Controls were exposed to filtered room air. During weeks 2 and 3 of treatment, 60% of the high-concentration animals died and 40% of the mid-concentration animals died by the end of the fourth week. No mortalities occurred in the con- trol- or low-concentration groups. Exposure in the high-concentration group was terminated at day 21 and the survivors immediately sacrificed due to the high mortality rate. High- and mid-concentration animals exhibited lung congestion, generalized weakness, and a statistically significant decrease in body weight and food consumption. The low-concentration group was comparable to controls and showed no clinical signs. Histopathologic examination was performed on the control, low-concentration, and high-concentration animals only. All 20 rats in the 10-ppm group had bronchitis and bronchiolitis, whereas none of the rats in the 0.5-ppm and control groups exhibited these effects. Hematology results showed a concentration-dependent increase in red blood cells, hemoglobin, and hematocrit in the mid- and high-concentration animals and a concentration- dependent decrease in the white blood cells in most of the treated animals. In a study by Union Carbide (1991), Fisher 344 rats were exposed to trimethoxysilane vapor at 0 (control), 0.2 ± 0.05 (standard deviation), 0.9 ± 0.12 (1 ppm), or 4.9 ± 0.34 (5 ppm) for 6 h/day. The rats were exposed for a total of nine exposures over an 11-day period. Ten rats of each sex were tested in the 0.2- and 1-ppm groups, and 15 of each sex in the control- and 5-ppm group. The additional five animals in the latter two groups were to be kept for a post- exposure recovery period; however, mortality was too high in the 5-ppm group (14/15 males and 12/15 females died between days 8 and 12) to allow for a post- exposure observation period. Table 7-5 presents observations at each concentra- tion.

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212 Acute Exposure Guideline Levels 3.3.2. Rats, Mice, Hamsters, and Rabbits In a repeat exposure study, Sprague-Dawley (BR) rats, (ICR) BR mice, LVG (SYR) hamsters, and New Zealand White rabbits were exposed to trimeth- oxysilane at concentrations of 0, 10, 25, or 50 ppm for 7 h/day for 5 consecutive days, with a 14-day observation period post exposure (Dow Corning Corp. 1981). Five animals per sex were used in the studies with rats, mice, and ham- sters, and two animals per sex were used in the study with rabbits. Table 7-6 presents the mortality data for this study. The investigators calculated 5-day LC50 values of 13, 14, 72, and 1 ppm for the rats, mice, hamsters, and rabbits, respectively. The report stated that the rabbits could have had a preexisting viral condition that was exacerbated under study conditions, thus resulting in high mortality. The laboratory had experienced this scenario in other studies with rabbits from the same supplier. All animals had similar clinical signs of gasping, depression, and nasal discharge (see Table 7-7). In the animals that died, lung congestion, atelectosis, and hemorrhage were observed; however, raw data were not provided. The study author reported that the animals killed at the end of the observation period had the same effects, but they were less severe. TABLE 7-5 Observations in the Union Carbide (1991) Study of Rats Exposed to Trimethoxysilane 0 0.2 ppm 1 ppm 5 ppm No clinical Laryngitis in Weight loss; increased lung 87% mortality; severe signs 1/10 males, weight; bronchopneumonia irritation (labored breathing, 2/10 females (10/10 males; 10/10 females); gasping); weight loss; lymphoid tissue depletion decreased organ weight (lymph nodes) (spleen, liver, kidney); increased erythrocytes, hemoglobin,, and hematocrit; lymphocytopenia; lymphoid depletion; bronchopneumonia (1/1 male and 2/3 female survivors; 11/14 males and 12/12 females that died) TABLE 7-6 Mortality Results in Dow Corning Corp. (1981) Study of Trimethoxysilane Concentration (ppm) Rats Mice Hamsters Rabbits 0 0/10 0/10 0/10 0/2 10 3/10 5/10 0/10 2/2 25 9/10 4/10 3/10 2/2 50 10/10 10/10 3/10 2/2

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Trimethoxysilane and Tetramethoxysilane 231 APPENDIX C DERIVATION OF AEGL VALUES FOR TETRAMETHOXYSILANE Derivation of AEGL-1 Values Inadequate data exist for deriving AEGL-1 values for tetramethoxysilane. Derivation of AEGL-2 Values Key study: Kolesar, G.B., W.H. Siddiqui, R.G. Geil, R.M. Malczewski, and E.J. Hobbs. 1989. Subchronic inhalation toxicity of tetramethoxysilane in rats. Fundam. Appl. Toxicol. 13(2):285-295. Toxicity end point: No-effect level for irreversible effects of 15 ppm Time scaling: Cn × t = k n = 3 for extrapolating to 30 min, 1 h, and 4 h (15 ppm)3 × 6 h = 20,250 ppm n = 1 for extrapolating to 8-h (15 ppm)1 × 6 h = 90 ppm Uncertainty factors: 3 for interspecies differences 10 for intraspecies variability 10-min AEGL-2: 1.1 ppm (6.8 mg/m3) Set equivalent to 30-min AEGL-2 value because extrapolating from 4 h to 10 min is not recommended (NRC 2001) 30-min AEGL-2: C3 × 0.5 h = 20,250 ppm-h C3 = 40,500 ppm C = 34.34 34.34 ÷ 30 = 1.1 ppm (6.8 mg/m3) 1-h AEGL-2: C3 × 1 h = 20,250 ppm-h C3 = 20,250 ppm C = 27.26 ppm 27.26 ppm ÷ 30 = 0.91 ppm (5.6 mg/m3)

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232 Acute Exposure Guideline Levels 4-h AEGL-2: C3 × 4 h = 20,250 ppm-h C3 = 5,062.5 ppm C = 17.17 17.17 ppm ÷ 30 = 0.57 ppm (3.5 mg/m3) 8-h AEGL-2: C1 × 8 h = 90 ppm-h C1 = 11.25 ppm 11.25 ppm ÷ 30 = 0.38 ppm (2.4 mg/m3) Derivation of AEGL-3 Values Key study: Dow Corning Corp. 1992. Initial Submission: The Acute Vapor Inhalation Toxicity of Tetramethoxysilane and Trimethoxysilane with Rats (Final Report) with Cover Letter Dated 040992. Document ID No. 88920001842; Microfiche No. OTS0539103. Toxicity end point: 4-h LC50 rat data; a BMCL05 of 26 ppm was used as the point of departure for AEGL-3 values (EPA Benchmark Calculation Dose Software, Version 1.3.2) Time scaling: Cn × t = k n = 3 for extrapolating to 30-min and 1-h (26 ppm)3 × 4 h = 70,000 ppm n = 1 for extrapolating to 8-h (26 ppm)1 × 4 h = 104 ppm Uncertainty factors: 3 for interspecies differences 10 for intraspecies variability 10-min AEGL-3: 1.7 ppm (11 mg/m3) Set equivalent to 30-min AEGL-3 value because extrapolating from 4 h to 10 min is not recommended (NRC 2001) 30-min AEGL-3: C3 × 0.5 h = 70,000 ppm-h C3 = 140,000 ppm C = 52 52 ÷ 30 = 1.7 ppm (11 mg/m3)

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Trimethoxysilane and Tetramethoxysilane 233 1-h AEGL-3: C3 × 1 h = 70,000 ppm-h C3 = 70,000 ppm C = 41 ppm 41 ppm ÷ 30 = 1.4 ppm (8.7 mg/m3) 4-h AEGL-3: C = 26 ppm 26 ppm ÷ 30 = 0.87 ppm (5.4 mg/m3) 8-h AEGL-3: C1 × 8 h = 104 ppm-h C1 = 13 ppm C = 13 ppm 13 ppm ÷ 30 = 0.43 ppm (2.7 mg/m3)

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234 Acute Exposure Guideline Levels APPENDIX D ACUTE EXPOSURE GUIDELINE LEVELS FOR TETRAMETHOXYSILANE Derivation Summary for Tetramethoxysilane AEGL-1 VALUES Inadequate data exist for deriving AEGL-1 values for tetramethoxysilane. Absence of AEGL-1 values does not indicate that exposure below AEGL-2 val- ues is safe. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 1.1 ppm 1.1 ppm 0.91 ppm 0.57 ppm 0.38 ppm Key reference: Kolesar, G.B., W.H. Siddiqui, R.G. Geil, R.M. Malczewski, and E.J. Hobbs. 1989. Subchronic inhalation toxicity of tetramethoxysilane in rats. Fundam. Appl. Toxicol. 13(2):285-295. Test species/Strain/Number: Rat, Sprague-Dawley, 10 males and 10 females per concentration Exposure route/Concentrations/Durations: Inhalation; 0, 1, 5, or 10 ppm (Phase 1) and 0, 15, 30, or 45 ppm (Phase 2); 6 h/day, 5 days/week for 28 days Effects: 45 ppm: mortality (20/20) 30 ppm: ulceration in nasal cavity (18/20), squamous lung metaplasia (15/20), bilateral corneal desquamation of epithelium. 15 ppm: no lung lesions, minimal acute keratitis in corneal epithelium. ≤ 10 ppm: no lesions. End point/Concentration/Rationale: 15 ppm was the no-effect level for irreversible effects Uncertainty factors/Rationale: Interspecies: 3, rats, mice, and hamsters had similar clinical signs and the rate of mortality was similar among rats and mice in a subchronic study of trimethoxysilane, a structural analog of tetramethoxysilane (Dow Corning Corp. 1981). Intraspecies: 10, no data were available to estimate human variability and it was not clear that tetramethoxysilane acts as a simple chemical irritant in the lungs (NRC 2001). Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applicable

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Trimethoxysilane and Tetramethoxysilane 235 Time scaling: Cn × t = k (ten Berge et al. 1986), where n = 3 for extrapolation to 30 min, 1 h, and 4 h and n = 1 for extrapolation to 8 h. The 30-min AEGL-2 value was adopted as the 10-min value because extrapolating from 4 h to 10 min is not recommended (NRC 2001). Data adequacy: Adequate for deriving AEGL-2 values AEGL-3 VALUES 10 min 30 min 1h 4h 8h 1.7 ppm 1.7 ppm 1.4 ppm 0.87 ppm 0.43 ppm Key reference: Dow Corning Corp. 1992. Initial Submission: The Acute Vapor Inhalation Toxicity of Tetramethoxysilane and Trimethoxysilane with Rats (Final Report) with Cover Letter Dated 040992. Document ID No. 88-920001842; Microfiche No. OTS0539103. Test species/Strain/Number: Rat; Sprague-Dawley; 10 males per concentration Exposure route/Concentrations/Durations: Inhalation; 31, 50, or 88 ppm for 4 h Effects: 31 ppm: no deaths or no clinical signs. 50 ppm: 3/10 deaths, gasping/coughing post exposure, lung damage. 88 ppm: 9/10 deaths, gasping/coughing post exposure, more wide-spread lung damage. End point/Concentration/Rationale: Lethality; BMCL05 of 26 ppm determined using EPA Benchmark Database Software Uncertainty factors/Rationale: Interspecies: 3, rats, mice, and hamsters had similar clinical signs and the rate of mortality was similar among rats and mice in a subchronic study of trimethoxysilane, a structural analog of tetramethoxysilane (Dow Corning Corp. 1981). Intraspecies: 10, no data were available to estimate human variability and it was not clear that tetramethoxysilane acts as a simple chemical irritant in the lungs (NRC 2001). Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applicable Time scaling: Cn × t = k (ten Berge et al. 1986), where n = 3 for extrapolation to 30 min and 1 h and n = 1 for extrapolation to 8 h. The 30-min AEGL-3 value is adopted as the 10-min value because extrapolating from 4 h to 10 min is not recommended (NRC 2001). Data adequacy: Adequate for deriving AEGL-3 values

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236 Acute Exposure Guideline Levels APPENDIX E TIME SCALING FOR TRIMETHOXYSILANE The relationship between dose and time for any given chemical is a func- tion of the physical and chemical properties of the substance and its toxicologic and pharmacologic properties. Historically, the relationship according to Haber (1924), commonly called Haber’s Law (NRC 1993) or Haber’s Rule (C × t = k, where C = exposure concentration, t = exposure duration, and k = a constant) has been used to relate exposure concentration and duration to effect (Rinehart and Hatch 1964). According to this concept, exposure concentration and expo- sure duration may be reciprocally adjusted to maintain a cumulative exposure constant (k) and this cumulative exposure constant will always reflect a specific quantitative and qualitative response. This inverse relationship of concentration and time may be valid when the toxic response to a chemical is dependent equally on the concentration and the exposure duration. However, an assessment by ten Berge et al. (1986) of LC50 data for certain chemicals revealed chemical-specific relationships between exposure concentra- tion and exposure duration that were often exponential. The relationship can be expressed by the equation Cn × t = k, where n represents a chemical-specific, and even a toxic-end-point specific, exponent. The relationship described by this equation is basically the form of a linear regression analysis of the log-log trans- formation of a plot of C vs. t. ten Berge et al. (1986) examined the airborne con- centration (C) and short-term exposure duration (t) relationship relative to death for approximately 20 chemicals and found that the empirically derived value of n ranged from 0.8 to 3.5 among this group of chemicals. Hence, the value of the exponent (n) in the equation Cn × t = k quantitatively defines the relationship FIGURE E-1 Regression Plot of LC50 Values in Rats from Study by Nachreiner and Dodd (1988).

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Trimethoxysilane and Tetramethoxysilane 237 between exposure concentration and exposure duration for a given chemical and for a specific health-effect end point. Haber's Rule is the special case where n = 1. As the value of n increases, the plot of C vs. t yields a progressive decrease in the slope of the curve. To calculate n for trimethoxysilane, a regression plot of LC50 values was derived using the concentration specific 60- and 240-min LC50 values in rats reported by Nachreiner and Dodd (1988). The LC50 values were analyzed using a linear regression analysis of the log-log transformation of a plot of C vs. t to derive a value of n for trimethoxysilane (see Figure E-1). The value of n for trimethoxysilane is 1.45.

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238 Acute Exposure Guideline Levels APPENDIX F CATEGORY PLOTS FOR TRIMETHOXYSILANE AND TETRAMETHOXYSILANE Chemical Toxicity - TSD Animal Data Trimethoxysilane 1000 No Effe c t 100 Dis c om fort ppm Dis a bl i n g 10 Som e L eth al i ty L eth al AEGL -3 1 AEGL AEGL-2 0 0 60 120 180 240 300 360 420 480 Minutes FIGURE F-1 Category plot of toxicity data and AEGL values for trimethoxysilane. Chemical Toxicity - TSD Animal Data Tetramethoxysilane 100 No Effe c t 10 Dis c om fort ppm Dis a bl i n g Som e L eth al i ty AEGL -3 1 L eth al AEGL -2 AEGL 0 0 60 120 180 240 300 360 420 480 Minutes FIGURE F-2 Category plot of toxicity data and AEGL values for tetramethoxysilane.

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Trimethoxysilane and Tetramethoxysilane 239 APPENDIX G BENCHMARK CALCULATIONS FOR TETRAMETHOXYSILANE The benchmark calculations for tetramethoxysilane are based on a 4-h acute LC50 inhalation study (Dow Corning Corp. 1992). For the derivation of AEGL-3, the BMCL05 of 26 ppm was used. BMCL05 = 26 ppm BMC01 = 30 ppm Probit Model $Revision: 2.1 $ $Date: 2000/02/26 03:38:53 $ Input Data File: C:\BMDS\DATA\TETRAMETHOXYSILANE.(d) Gnuplot Plotting File: C:\BMDS\DATA\TETRAMETHOXYSILANE.plt Thu Jan 12 10:41:03 2006 BMDS MODEL RUN The form of the probability function is: P[response] = Background + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)) where, CumNorm(.) is the cumulative normal distribution function Dependent variable = COLUMN3 Independent variable = COLUMN1 Slope parameter is not restricted Total number of observations: 3 Total number of records with missing values: 0 Maximum number of iterations: 250 Relative Function Convergence has been set to: 1E-008 Parameter Convergence has been set to: 1E-008 User has chosen the log transformed model Default Initial (and Specified) Parameter Values Background = 0 Intercept = -11.5792 Slope = 2.85911

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240 Acute Exposure Guideline Levels Asymptotic Correlation Matrix of Parameter Estimates Intercept Slope Intercept 1 -1 Slope -1 1 (***The model parameter(s) background has been estimated at a boundary point, or has been specified by the user, and do not appear in the correlation matrix). Parameter Estimates Variable Estimate Standard error Background 0 NA Intercept -14.29 4.18256 Slope 3.49447 1.02457 NA: indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error. Analysis of Deviance Table Model Log (likelihood) Deviance Test DF P-value Full model -9.35947 Fitted model -9.50533 0.291706 1 0.5891 Reduced model -20.1904 21.6618 2 <0.0001 AIC: 23.0107 Goodness of Fit Scaled Estimated Dose probability Expected Observed Size Residual 31.0000 0.0110 0.110 0 10 -0.3337 50.0000 0.2678 2.678 3 10 0.23 88.0000 0.9124 9.124 9 10 -0.1392 Chi-square = 0.18; DF = 1; P-value = 0.6683 Benchmark Dose Computation Specified effect = 0.05 Risk Type = Extra risk Confidence level = 0.95 BMD = 37.2855 BMDL = 25.9763

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Trimethoxysilane and Tetramethoxysilane 241 Probit Model with 0.95 Confidence Level Probit 1 0.8 Fraction Affected 0.6 0.4 0.2 0 BMDL BMD 20 30 40 50 60 70 80 90 dose 08:15 01/13 2006