Batch equilibrium experiments and modeling reveal weak temperature dependence of cyclic volatile methylsiloxane sorption in soil/sediment organic carbon-water systems.

The organic carbon normalized partition coefficient, KOC, describes the equilibrium distribution of a chemical between water and organic carbon in soil or sediment. It is a key parameter in evaluating chemical persistence, mass distribution, and transport using multimedia fate and transport models. Considerable uncertainty remains about the KOC values of cyclic volatile methylsiloxane (cVMS) compounds, and in particular the dependence of KOC on temperature. In this study, we used a batch equilibrium (BE) method to measure KOC values and their temperature dependence between ∼5 and 25 °C for octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) with soil and sediments. Approximate log KOC values at 25 °C were 4.5-5.0 for D4 and 5.5-6.1 for D5 with different sorbents, and decreased by 0.3 log units or less at 4-5 °C. Enthalpies of sorption, ΔHOC, obtained for the different sorbents ranged from +7.2 to +16 kJ mol-1, with average values of +7.9 and +13 kJ mol-1 for D4 and D5, respectively. These values differ in magnitude and direction from those reported elsewhere based on KOC values determined by a novel dynamic purge-and-trap (PnT) method, but are consistent with predictions based on their solvation properties. A new fugacity-based multimedia model incorporating sorption/desorption kinetics was developed and used to predict concentrations in the phases of BE and PnT systems during desorption of cVMS under different experimental and ideal conditions. Model simulations suggested that KOC values for cVMS compounds derived from the PnT systems could be influenced by sorption disequilibrium between water and solids controlled by desorption rates from the particle phase to water, and subsequent losses due to volatilization and degradation. This has the potential to result in overestimation of KOC values when fitting the experimental data of cVMS mass remaining in a PnT system over time, which could explain the observed differences between the methods.

Low Dietary Uptake Efficiencies and Biotransformation Prevent Biomagnification of Octamethylcyclotetrasiloxane (D4) and Decamethylcyclopentasiloxane (D5) in Rainbow Trout.

With octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) being considered for evaluation under the UN Stockholm Convention on Persistent Organic Pollutants, which specifically acknowledges risks of biomagnification of persistent organic pollutants in traditional foods, a study into the mechanism of the biomagnification process of D4 and D5 in Rainbow trout was conducted by combining the absorption-distribution-metabolism-excretion for bioaccumulation (ADME-B) approach to determine intestinal and somatic biotransformation rates and radiochemical analyses to identify metabolite formation. High rates of intestinal biotransformation of D4 and D5 (i.e., 2.1 (0.70 SE) and 0.88 (0.67 SE) day-1, respectively) and metabolite formation [i.e., 52.0 (17 SD)% of D4 and 56.5% (8.2 SD)% of D5 were metabolized] were observed that caused low dietary uptake efficiencies of D4 and D5 in fish of 15.5 (2.9 SE)% and 21.0 (6.5 SE)% and biomagnification factors of 0.44 (0.08 SE) for D4 and 0.78 (0.24 SE) kg-lipid·kg-lipid-1 for D5. Bioaccumulation profiles indicated little effect of growth dilution on the bioaccumulation of D4 and D5 in fish and were substantially different from those of PCB153. The study highlights the importance of intestinal biotransformation in negating biomagnification of substances in organisms and explains differences between laboratory tests and field observations of bioaccumulation of D4 and D5.

Seasonal and latitudinal variability in the atmospheric concentrations of cyclic volatile methyl siloxanes in the Northern Hemisphere.

Field data from two latitudinal transects in Europe and Canada were gathered to better characterize the atmospheric fate of three cyclic methylsiloxanes (cVMSs), i.e., octamethyl-cyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5) and dodecamethylcyclohexasiloxane (D6). During a year-long, seasonally resolved outdoor air sampling campaign, passive samplers with an ultra-clean sorbent were deployed at 15 sampling sites covering latitudes ranging from the source regions (43.7-50.7 °N) to the Arctic (79-82.5 °N). For each site, one of two passive samplers and one of two field blanks were separately extracted and analyzed for the cVMSs at two different laboratories using gas-chromatography-mass spectrometry. Whereas the use of a particular batch of sorbent and the applied cleaning procedure to a large extent controlled the levels of cVMS in field blanks, and therefore also the method detection and quantification limits, minor site-specific differences in field blank contamination were apparent. Excellent agreement between duplicates was obtained, with 95% of the concentrations reported by the two laboratories falling within a factor of 1.6 of each other. Nearly all data show a monotonic relationship between the concentration and distance from the major source regions. Concentrations in source regions were comparatively constant throughout the year, while the concentration gradient towards remote regions became steeper during summer when removal via OH radicals is at its maximum. Concentrations of the different cVMS oligomers were highly correlated within a given transect. Changes in relative abundance of cVMS oligomers along the transect were in agreement with relative atmospheric degradation rates via OH radicals.

Comparative pharmacokinetic studies of 14C-octamethylcyclotetrasiloxane (14C-D4) in Fischer 344 and Sprague Dawley CD rats after single and repeated inhalation exposure.

Octamethylcyclotetrasiloxane (D4) is a high production volume chemical that has been subject to thorough toxicological investigations. Animal studies with the substance were conducted with either Fischer 344 or Sprague Dawley CD rats. While the pharmacokinetic fate of D4 in Fischer rats is well understood, little information exists on Sprague Dawley CD rats, where reproductive effects have been demonstrated. The objective of this study was to explore the pharmacokinetic behavior in both rats, and to identify potential strain-specific differences. Fischer and Sprague Dawley CD rats were exposed for six hours to 700 ppm of 14C-D4 vapor either with or without preceding 14-day exposure to non-radiolabeled D4. Time-course data in blood, tissues and excreta were obtained through 168 h post-exposure and analyzed for both total radioactivity and parent D4. The data confirm that repeated exposure results in increased metabolism in both rat strains, confirming the findings of earlier studies of auto-induction of CYP2B1/2 by D4. The results also indicate that D4 is subject to strain-specific pharmacokinetic behavior, and that Fischer rats appear to metabolize D4 to a greater extent than Sprague Dawley CD rats.

Basic considerations to minimize bias in collection and analysis of volatile methyl siloxanes in environmental samples.

Monitoring studies that aim to quantify volatile methyl siloxanes (VMS) in environmental matrices may encounter a multitude of issues, most of which relate to the unique combination of physical-chemical characteristics of VMS that distinguish them from other classes of organic compounds. These properties, which are critical to their function in various applications, also control their fate and distribution in the environment, as well as the analytical chemistry of their measurement. Polycondensation and rearrangement reactions of VMS oligomers are possible during sample storage and analysis. Thus, care should be exercised to suppress these types of reactions by avoiding any catalytic substances or surfaces in sample collection and analysis equipment. Another factor complicating sample integrity in the analysis of trace levels of VMS, is their ubiquitous presence in many common products and components of instrumentation in the laboratory. For example, some gas chromatography columns and inlet septa have been identified as sources of VMS due to surface-catalyzed transformation of silicones to VMS promoted by moisture under high temperature in some silicone-based GC columns. Possible chemical transformation of the analytes, contamination from other sources, and potential loss of analytes need to be assessed throughout all aspects of the study, from sample collection through analysis, by establishing a rigorous quality assurance and quality control program. The implementation of such a robust QA/QC program facilitates the identification and minimization of potential analytical biases and ensures the validity and usability of data generated from environmental monitoring campaigns for VMS. The objective of this paper is to focus on aspects of collection, processing, and analysis of environmental samples that may influence the quality of the VMS analytical results. This information should then be employed in the design and implementation of future monitoring studies and can used to assess the validity of analytical results from VMS monitoring studies.

Comment on "Bioaccumulation of Methyl Siloxanes in Common Carp (Cyprinus carpio) and in an Estuarine Food Web in Northeastern China".

We have reviewed a paper titled "Bioaccumulation of Methyl Siloxanes in Common Carp (Cyprinus carpio) and in an Estuarine Food Web in Northeastern China" by Xue et al., which was published in the Archives of Environmental Contamination and Toxicology in 2019. In the paper, the authors presented and discussed the measured bioconcentration factors (BCFs), biomagnification factors (BMFs), and trophic magnification factors (TMFs) of selected volatile methylsiloxanes in Shuangtaizi estuary in China. Although we appreciate their efforts for sample collection and data analysis, we have identified significant errors in calculations of BCFs, TMFs, and BMFs, as well as animal welfare issues and food web trophic level assumptions. Based on the data, we have attempted to correct some of the analysis and offered a more complete and robust interpretation of the related data, when possible. Collectively, these errors would likely lead to very different conclusions than yours in the paper.

Long-range transport potential and atmospheric persistence of cyclic volatile methylsiloxanes based on global measurements.

This study investigates persistence (P) and long-range transport potential (LRTP) of cyclic volatile methylsiloxanes (cVMS) based on the field measurements in the Northern Hemisphere. The field data consisted of published outdoor air concentrations of octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5) and dodecamethylcyclohexasiloxane (D6) at urban, suburban, rural and remote locations excluding the point sources. Three major trends were observed. First, D4 and D6 concentrations were correlated with measured concentrations for D5 at the same times and locations in the majority of the datasets, reflecting the common sources and similar removal mechanism(s) for these compounds. Second, as the sampling sites changed from the source to remote locations along a south-to-north transect, average cVMS concentrations in air decreased in an exponential manner. The empirical characteristic travel distances (eCTD) extracted from these spatial patterns were smaller than model estimated values and differed in order among individual compounds (D4 ∼ D5 < D6). Finally, D5/D6 concentration ratios were also found to decrease exponentially along the same spatial gradient, contrary to model predictions of an increase based on current knowledge of mechanisms controlling atmospheric cVMS degradation. These findings suggest that there may be additional removal process(es) for airborne cVMS, currently not accounted for, that requires further elucidation.

Bioaccumulation and trophic transfer of cyclic volatile methylsiloxanes (cVMS) in the aquatic marine food webs of the Oslofjord, Norway.

The trophic transfer of cyclic methylsiloxanes (cVMS) in aquatic ecosystems is an important criterion for assessing bioaccumulation and ecological risk. Bioaccumulation and trophic transfer of cVMS, specifically octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), and dodecamethylcyclohexasiloxane (D6), were evaluated for the marine food webs of the Inner and Outer Oslofjord, Norway. The sampled food webs included zooplankton, benthic macroinvertebrates, shellfish, and finfish species. Zooplankton, benthic macroinvertebrates, and shellfish occupied the lowest trophic levels (TL ≈2 to 3); northern shrimp (Pandalus borealis) and Atlantic herring (Clupea harengus) occupied the middle trophic levels (TL ≈3 to 4), and Atlantic cod (Gadus morhua) occupied the highest tropic level (TL>4.0). Trophic dynamics in the Oslofjord were best described as a compressed food web defined by demersal and pelagic components that were confounded by a diversity in prey organisms and feeding relationships. Lipid-normalized concentrations of D4, D5, and D6 were greatest in the lowest trophic levels and significantly decreased up the food web, with the lowest concentrations being observed in the highest trophic level species. Trophic magnification factors (TMF) for D4, D5, and D6 were <1.0 (range 0.3 to 0.9) and were consistent between the Inner and Outer Oslofjord, indicating that exposure did not impact TMF across the marine food web. There was no evidence to suggest biomagnification of cVMS in the Oslofjord. Rather, results indicated that trophic dilution of cVMS, not trophic magnification, occurred across the sampled food webs.

Development of collection, storage and analysis procedures for the quantification of cyclic volatile methylsiloxanes in wastewater treatment plant effluent and influent.

A reliable and accurate method for collection and analysis of octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), and dodecamethylcyclohexasiloxane (D6) in wastewater treatment plant influent, effluent and surface waters was developed. Due to the use of cyclic volatile methylsiloxanes (cVMS) in industrial and consumer products including some personal care products, the wastewater stream represents a potential post-use disposal route and cVMS may subsequently enter the environment through wastewater treatment plant effluents. cVMS in the environment has come under increased regulatory scrutiny with regard to their potential for persistence, bioaccumulation and toxicity indicating a need for monitoring programs with reliable analytical methods. The developed method is unique in that it utilizes low density polyethylene (LDPE) to inhibit loss of cVMS during sampling and transport to the laboratory. The samples are then processed with a simple solvent extraction and analyzed by gas chromatography mass spectrometry with stable isotope internal standard calibration. This method utilizes readily available laboratory supplies and requires minimal field processing, reducing contamination potential. Method detection limits of 17 ng/L, 57 ng/L, and 20 ng/L were obtained for D4, D5, and D6, respectively. Additionally a robust quality control program was employed to ensure sample integrity. The method described herein can readily be adopted for use in monitoring studies where the amount of cVMS in water samples will be quantified.

Metabolism of 14C-octamethylcyclotetrasiloxane ([14C]D4) or 14C-decamethylcyclopentasiloxane ([14C]D5) orally gavaged in rainbow trout (Oncorhynchus mykiss).

Critical factors (uptake, distribution, metabolism and elimination) for understanding the bioaccumulation/biomagnification potential of Octamethylcyclotetrasiloxane (D4) and Decamethylcyclopentasiloxane (D5) siloxanes in fish were investigated to address whether these chemicals meet the "B" criteria of the Persistent, Bioaccumulative, and Toxic (PBT) classification. A metabolism study was conducted in rainbow trout whereby a 15mg [14C]D4/kg bw or [14C]D5/kg bw as a single bolus oral dose was administered via gavage. Of the administered dose, 79% (D4) and 78% (D5) was recovered by the end of the study (96-h). Eighty-two percent and 25% of the recovered dose was absorbed based on the percentage of recovered dose in carcass (69% and 17%), tissues, bile and blood (12% and 8%) and urine (1%) for D4 and D5, respectively. A significant portion of the recovered dose (i.e. 18% for D4 and 75% for D5) was eliminated in feces. Maximum blood concentrations were 1.6 and 1.4µg D4 or D5/g blood at 24h post-dosing, with elimination half-lives of 39h (D4) and 70h (D5). Modeling of parent and metabolite blood concentrations resulted in estimated metabolism rate constants (km(blood)) of 0.15 (D4) and 0.17day-1(D5). Metabolites in tissues, bile, blood, and urine totaled a minimum of 2% (D4) and 14% (D5) of the absorbed dose. The highest concentration of 14C-activity in the fish following D4 administration was in mesenteric fat followed by bile, but the opposite was true for D5. Metabolites were not detected in fat, only parent chemical. In bile, 94% (D4) and 99% (D5) of the 14C-activity was due to metabolites. Metabolites were also detected in the digestive tract, liver and gonads. Approximately 40% of the 14C-activity detected in the liver was due to the presence of metabolites. Urinary elimination represented a minor pathway, but all the 14C-activity in the urine was associated with metabolites. Clearance may occur via enterohepatic circulation of metabolic products in bile with excretion via the digestive tract and urinary clearance of polar metabolites.

Determination of soil-water sorption coefficients of volatile methylsiloxanes.

The sorption behaviors of 4 cyclic and linear volatile methyl siloxane (VMS) compounds between water and organic matter in 3 United Kingdom soils were studied by a batch equilibrium method using(13)C-enriched sorbates. Sorption and desorption kinetics and isotherms were determined for octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), octamethyltrisiloxane (L3), and decamethyltetrasiloxane (L4). Concentrations of [(13)C]-VMS in the soil and aqueous phases were measured directly by extraction and gas chromatography-mass spectrometry techniques. All VMS compounds were sorbed rapidly, reaching constant distributions in all soils by 24 h. Desorption kinetics were very rapid, with reattainment of equilibrium within 1 h. In the main, linear isotherms were observed for aqueous concentrations at or below 4% of the solubility limits. The average sorption organic carbon partition coefficient (logK(OC)) values across soils were 4.23 for D4, 5.17 for D5, 4.32 for L3, and 5.13 for L4, with standard deviations of 0.09 to 0.34. Desorption K(OC) values were systematically greater by 0.1 log units to 0.3 log units. The linear isotherms and low variation in K(OC) values across soils suggested partitioning-dominated sorption of the VMS. Compared with traditional hydrophobic organic compounds, K(OC) values for the VMS compounds were significantly lower than expected on the basis of their octanol-water partition coefficients. A linear free energy relationship analysis showed that these differences could be rationalized quantitatively in terms of the inherent characteristics of the VMS compounds, combined with the differences in solvation properties of organic matter and octanol.

Positive vs. false detection: a comparison of analytical methods and performance for analysis of cyclic volatile methylsiloxanes (cVMS) in environmental samples from remote regions.

Contamination and analytical variation can significantly hinder trace analysis of cyclic methyl volatile siloxanes (cVMS); potentially resulting in the report of false positives at concentrations approaching detection limits. To assess detection and variation associated with trace cVMS analysis in environmental matrices, a co-operative laboratory comparison for the analysis of octametylcyclotetrasiloxane (D4), decamethylcylcopentasiloxane (D5), and dodecametylcyclohexasiloxane (D6) in sediment and biota from the Svalbard Archipelago was conducted. Two definitions of detection limits were evaluated in this study; method detection limits (MDL, matrix defined) and limits of detection (LOD, solvent defined). D5 was the only cVMS detected above both LOD (0.08-0.81ngg(-1)ww) and MDL (0.47-2.36ngg(-1)ww) within sediment by all laboratories where concentrations ranged from 0.55 to 3.91ngg(-1)ww. The percentage of positive detects for D5 decreased by 80% when MDL was defined as the detection limit. D5 was also detected at the highest frequency among all laboratories in fish liver with concentrations ranging from 0.72 to 345ngg(-1)ww. Similar to sediment, percentage of positive detects for D5 decreased by 60% across all laboratories for fish livers when using MDL (0.68-3.49ngg(-1)ww). Similar observations were seen with both D4 and D6, indicating that sample matrix significantly contributes to analytical response variation. Despite differences in analytical methods used between laboratories, good agreement was obtained when using MDL to define detection limits. This study shows the importance of incorporating variation introduced by sample matrices into detection limit calculations to insure data accuracy of cVMS at low concentrations.

Determination of the dietary biomagnification of octamethylcyclotetrasiloxane and decamethylcyclopentasiloxane with the rainbow trout (Oncorhynchus mykiss).

Separate 77-d fish feeding studies were conducted on the cyclic volatile methylsiloxane (cVMS) chemicals octamethylcyclotetrasiloxane and decamethylcyclopentasiloxane with the rainbow trout, Oncorhynchus mykiss, with the determination of biomagnification factor (BMF) and lipid-adjusted BMF (BMF(L)) values as the final experimental metrics. The studies used fish food concentrations of ∼500µgg(-1) for exposure periods of 35d, followed by a depuration period of 42d with clean food. The fish tissue concentrations of D4 and D5 achieved empirical steady-state by day 21 in each study. By day 7 of exposure, total (14)C activity of both compounds had moved from the fish gastrointestinal (GI) tract into surrounding tissue. An absence of significant fish growth during the initial depuration phase allowed for measurement of empirical depuration rate constants (k2) independent of growth dilution for D4 and D5 of 0.035 and 0.040d(-1), respectively, corresponding to elimination half-lives of approximately 20d. These rate constants indicated that ∼70-75% of steady-state was achieved during exposure in both studies, resulting in empirical steady-state BMF and BMF(L) values of 0.28 and 0.66 for D4, respectively, and 0.32 and 0.85 for D5, respectively. Kinetic modeling using simple first-order uptake and depuration dynamics produced good agreement with experimental data, with D4 and D5 assimilation efficiencies of 40% and 44%, respectively. Growth-corrected depuration rate constants modeled over the entire study data set indicated slower elimination kinetics for D4 (k2 of 0.007d(-1) or half-life of 100d) compared to D5 (k2 of 0.010d(-1) or elimination half-life of 69d). Kinetic BMFk values (i.e., k1/k2) for D4 and D5 were 1.7 and 1.3, respectively, with lipid-adjusted BMFk(L) values of 4.0 and 3.4, respectively.

Assessing inter-laboratory comparability and limits of determination for the analysis of cyclic volatile methyl siloxanes in whole Rainbow Trout (Oncorhynchus mykiss).

Cyclic volatile methyl siloxanes (cVMS) are high volume production chemicals used in a wide range of industrial and consumer products. Three cVMS compounds (D4, D5, and D6) have and are undergoing environmental risk evaluations in several countries and have been proposed for legal regulation in Canada. As interest in monitoring concentrations of these chemicals in the environment increase, there is a need to evaluate the analytical procedures for cVMS in biological matrices in order to assess the quality of data produced. The purpose of this study was to determine laboratory testing performance for measuring residues of D4, D5, and D6 in a standard set of fish homogenate samples and to estimate limits of determination for each substance. The samples sent to each laboratory consisted of homogenized whole body tissues of hatchery raised rainbow trout which were fed food fortified with D4, D5, and D6 (dosed) and trout that were fed standard food rations (control). The participants analyzed each sample using their analytical method of choice using their own standards and procedures for quantification and quality control. With a few exceptions, participating laboratories generated comparable results for D4, D5, and D6 in both the dosed and control samples having z-scores between 2 and -2. Method detection limits for the whole fish matrix were on average 2.4 ng g(-1) ww for D4, 2.3 ng g(-1) ww for D5, and 1.8 ng g(-1) ww for D6.

Disposition of decamethylcyclopentasiloxane in Fischer 344 rats following single or repeated inhalation exposure to 14C-decamethylcyclopentasiloxane (14C-D5).

The disposition of decamethylcyclopentasiloxane (D5) in male and female Fischer 344 rats following single or repeated inhalation exposures was evaluated. Animals were administered a single 6-h nose-only exposure to 7 or 160 ppm 14C-D5 or fourteen 6-h nose-only exposures to unlabeled D5 followed on day 15 by a 6-h exposure to 14C-D5. Subgroups of exposed animals were used to evaluate body burden, distribution, elimination, and deposition on the fur. Retention of radioactivity following single and repeated exposures was relatively low (approximately 1-2% of inhaled D5). Radioactivity and parent D5 were widely distributed to tissues of both male and female rats, with the maximum concentration of radioactivity observed in most tissues by 3 h postexposure. Fat was a depot for D5, with elimination occurring much slower than observed for plasma and other tissues. In all groups, the primary route for elimination of radioactivity was through expired air. Analyses for parent D5 indicated that essentially all the radioactivity in the expired volatiles was unchanged D5. Repeated exposure gave rise to higher levels of parent D5 in the lung and fat of both sexes and in female liver relative to the single exposure. In fat, immediately after sacrifice approximately 50% of the radioactivity was attributed to parent. Five polar metabolites of D5 were identified in urine, with no parent D5 detected. Radiochromatograms demonstrated two peaks in feces. One corresponded to the retention time for D5. The second has been putatively identified as hydroxylated D5.

Closed-chamber inhalation pharmacokinetic studies with hexamethyldisiloxane in the rat.

Gas uptake methods together with physiologically based pharmacokinetic (PBPK) modeling have been used to assess metabolic parameters and oral absorption rates for a wide variety of volatile organic compounds. We applied these techniques to study the in vivo metabolism of hexamethyldisiloxane (HMDS), a volatile siloxane with low blood/air (partition coefficient PB approximately 1.00) and high fat/blood partitioning (partition coefficient PF approximately 300). In contrast to other classes of metabolized volatiles, metabolic parameters could only be estimated from closed-chamber results with confidence by evaluating both closed-chamber disappearance curves and constant concentration inhalation studies. The constant-concentration inhalation results refine the estimate of the blood/air partition coefficient and constrain model structure for storage of the lipophilic compound in blood and tissues. The gas uptake results, from Fischer 344 rats (male, 8-9 wk old) exposed to initial HMDS air concentrations from 500 to 5000 ppm, were modeled with a 5-tissue PBPK model. Excellent fits were obtained with diffusion-limited uptake of HMDS in fat and a lipid storage pool in the blood. Metabolism, restricted to the liver, was described as a single saturable process (V(max) = 113.6 micro mol/h/kg; K(m) = 42.6 micro mol/L) and was affected by inhibitors (diethyldithiocarbamate) or inducers (phenobarbital) of cytochrome P-450s. Exhalation kinetics of HMDS after oral/intraperitoneal administration showed low bioavailability and significant lag times, also quite different from results of other classes of volatile hydrocarbons. In general, estimates of metabolic clearance by gas uptake studies were improved by simultaneous examination of time-course results from constant concentration inhalation studies. This conclusion is likely to hold for any volatile lipophilic compound with low blood/air partitioning.