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Description of key information

There is a good database for toxicokinetics of D5, which covers absorption, distribution, metabolism and excretion by various routes.

In summary, D5 dermal absorption is less than 1%, and the majority of an applied dose evaporates from the skin surface. The proportion of an oral dose that is absorbed depends on the vehicle; however, the majority is not absorbed and is excreted in faeces. When applied in corn oil or rodent liquid diet (RLD) to rats, absorption of D5 was approximately 20% and 17%. Following oral administration, D5 appears to enter the blood via the lymphatics within the lipid core of chylomicrons and other lipoproteins, which is in a form different from that for inhalation or dermal routes of exposure. The organs with the greatest concentrations of D5 were the liver, lungs, fat and adrenal glands. D5 was distributed to fat, with elimination of parent and radioactivity occurring slower than observed for plasma and other tissues. Two major metabolites (dimethylsilanediol and methylsilanetriol) and five minor metabolites of D5 have been identified in urine. Parent D5 is not excreted in urine. The majority of inhaled and orally ingested D5 that is absorbed is expired as volatiles. The rest is then excreted as metabolites in urine.

Based on the several acute and repeated dose toxicity studies and the PBTK modelling, it can be concluded that D5 has no tendency to accumulate after repeated dosing. Absence of a potential for bioaccumulation is also indicated by an absence of an increase in D5 tissue concentrations after a 6-month inhalation exposure performed as a segment of the chronic bioassay. While D5 is very lipophilic with fat: blood partition coefficients between 500 and 1,000, it is readily eliminated by exhalation or by biotransformation to polar metabolites. No genotoxicity was detected in any in vitro mutagenicity tests in absence or presence of metabolising enzymes or in any in vivo tests and no indication of the importance of the metabolism of the registered substance was obtained from these studies.

Conclusion: no bioaccumulation potential is anticipated based on the assessment.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
17.2
Absorption rate - dermal (%):
1

Additional information

Absorption

The absorption of D5 is well characterized. Studies covering both single and repeated inhalation exposures to D5, and following dermal application and oral administration have been performed in experimental animals. In addition, human data on extent of dermal absorption of D5 and the disposition of systemically available D5 have been generated.

In a key oral ADME study (Domoradzki et al., 2017a;Dow Corning Corporation, 2012), D5 was assessed in female and male rats. Following single gavage administration of14C-D5 at 100 mg/kg bw, the percentages absorbed were 17.4% and 16.9% (average: 17.2%) in females and males, respectively. Calculated AUCs from the blood time-course data (D5 low) indicated that14C-activity was absorbed (AUC inμg14C-equivalents D5×hr/g of blood) and were similar, no statistically significant difference, between females and males; AUCs for parent D5 were also similar between sexes.

 

In a supporting study (Dow Corning Corporation, 2003b), following oral administration to rats, the majority of administered dose, regardless of sex or carrier, was excreted in faeces and not absorbed. Approximately 20% of14C-D5 delivered in corn oil appeared to be absorbed after a single oral administration in Fischer 344 rats. The study indicated that oral absorption of D5 could be significantly influenced by the carrier used to deliver D5. Blood kinetics data indicated that D5 was most readily absorbed when delivered in corn oil and least available for absorption when carried in simethicone fluid (Dow Corning Corporation, 2003b). The maximum concentration of D5 in blood was achieved at 6 hours after dosing for both males and females. The maximum concentration was 51.15 µg D5/ g of blood in males and 46.94 µg D5/ g of blood in females based on total radioactivity, and 62.49 µg D5/g in males and 52.12 µg D5/g in females based on D5 parent analysis. Radioactivity and parent D5 distribution half-lives were 9.88 hours and 6.78 hours for males, respectively and 12.05 hours and 8.15 hours for females, respectively. Radioactivity and parent D5 elimination half-lives were 81.15 hours and 166.80 hours for males, respectively, and 240.36 hours and 160.91 hours for females, respectively.

During dermal exposures to decamethylcyclopentasiloxane (D5), this chemical is rapidly absorbed into the outer layers of skin, but it evaporates back out of the skin before significant systemic absorption can occur. In an in vivo dermal absorption study in rats after 24 hours of exposure most of a topically applied dose of14C-D5 had evaporated from the skin surface of the female Fisher 344 rats. Radioactivity in expired volatile traps (charcoal tubes) was attributed to the leakage from the dosing chamber and was excluded from the total absorption. The portion of D5 that remained in the skin after 24 hours of exposure, and could be considered part of the absorbed dose, actually migrated to the skin surface and continued to evaporate, significantly decreasing the apparent absorption of D5 from 0.243% to 0.089% of applied dose (Dow Corning Corporation, 2003a). The results of rat or human (Dow Corning Corporation, 2003a; University of Rochester, 2002) in vivo dermal absorption studies are also consistent with human in vitro dermal absorption studies (Dow Corning Corporation, 1999a). Using human cadaver abdominal skin, only a small amount of the D5 applied to the skin is actually absorbed (approximately 0.04%). In the human in vivo study (University of Rochester, 2002) plasma and blood levels of D5 after dermal application were quite low, i. e., less than 2.0 ng/gm blood or plasma.

 

Distribution

In a key oral ADME study (Domoradzki et al., 2017;Dow Corning Corporation, 2012), following single gavage administration of14C-D5 at 100 mg/kg bw, parent D5 was detected in all tissues with the Cmax in tissues typically observed at 2, 4 or 6 hours postdosing, except in brown fat and perirenal fat where the highest concentrations were observed at 12 and 48 hours post-dosing. Radioactivity was detected in key model tissues with the highest concentrations at 2, 4, or 6 hours post-dosing, except in brown fat and perirenal fat where the highest concentrations were observed at 12 and 48 hours post-dosing. The study (Dow Corning Corporation, 2012) further demonstrated the disposition of D5 in tissues, faeces, urine, expired volatiles, expired CO2, and remaining carcass (including pelt) between female and male Fischer 344 rats was similar except for expired volatiles. Females expired 2.01% and males expired 1.26% as volatiles. Parent D5 was detected in all tissues with the highest concentration in tissues at 2, 4 or 6 h post-dosing, except in brown fat, perirenal fat, ovaries, uterus, testes and adrenals (female only), where the highest concentrations were observed at 12, 24 or 48 h post-dosing. The Cmax of parent D5 and of radioactivity was found in adrenals of female rats, and adrenals and gastrointestinal tract of males, respectively. The half-lives of D5 in blood (72 h, females; 19 h males) were shorter than the half-lives of radioactivity (96 h, females; 93 h, males).

 

In another oral study (Dow Corning Corporation, 2003b), following administration of D5, qualitative assessment of tissue distribution (WBA) showed that the radioactivity was systemically available and distributed to major organs such as bone marrow, liver kidney and fat.

 

The disposition of D5 in male and female Fischer 344 rats following single (Batelle, 2001a) or multiple (Dow Corning Corporation, 2007 inhalation exposures was evaluated. Animals were administered a single 6 hour nose-only exposure to 7 or 160 ppm14C-D5 or fourteen 6-hour nose-only exposures to unlabelled D5 followed on the 15th day by a 6-hour exposure to 14C-D5. Subgroups of exposed animals were established to evaluate body burden, distribution, and elimination. Samples of plasma, fat, liver, lung, faeces and expired air were also processed for parent D5 analysis. Retention of D5 following single exposures was relatively low (2% of inhaled D5). Following multiple doses approximately 8-9% of the achieved dose of 14C-D5 was associated with the whole animal at the time of sacrifice.

Following repeated exposures by inhalation (Dow Corning Corporation, 2007), approximately 44% of this retained dose was attributed to deposition on the fur for males and 70% for the females. (This finding was supported by results of a single-exposure study (Batelle, 2001b) in which approximately 3% of the dose was absorbed but 50 -80% for males and 60 -70% for females was shown to be retained on the pelt). Parent and radioactivity was widely distributed to tissues of both males and females, with maximum concentrations observed in the majority of the tissues by 3 hours post-exposure. The organs with the greatest concentrations of D5 were the liver, lungs, fat and adrenal glands. D5 was distributed to fat, with elimination of parent and radioactivity occurring slower than observed for plasma and other tissues.

 

Metabolism

In a key oral ADME study (Domoradzki et al., 2017a;Dow Corning Corporation, 2012), following single gavage administration of14C-D5 at 100 mg/kg bw, the radioactivity eliminated in the urine consisted entirely of polar metabolites of D5. The mean percentage of radioactivity that was attributed to individual metabolites from urine at 012 and 1224, hours following oral administration D5 in the low dose study. Dimethylsilanediol represented the greatest percentage of total urinary radioactivity followed by methylsilanetriol. The percentages for dimethylsilanediol for the two collection intervals ranged from 53 to 58% in female animals and 50 to 53% in male animals and the percentages for methylsilanetriol for the three collection intervals ranged from 35 to 36% in female rats and 38 to 42% in male rats. Dimethyldisiloxane-1,3,3,3-tetrol as a percentage of urinary activity for the two collection intervals ranged from 1 to 2% in females and 2% in male animals. The average sum of de-methylated peak percentages ranged from 39 to 41% for females and 44 to 47% for males. In faecal extracts, hydroxylated D5 metabolite (D4DOH) was observed by GC/MS; however, peak assignment in the radiochemical profile was inconclusive.

 

The metabolic profile of D5 in rats was obtained using a high-pressure liquid chromatography (HPLC) system equipped with a radioisotope detector. The HPLC chromatogram revealed two major metabolites and five minor metabolites in the urine of female rats administered 14C-D5 orally. The two major metabolites were dimethylsilanediol [Me2Si(OH)2] and methylsilanetriol [MeSi(OH)3]. No parent D5 was found in the urine. The minor metabolites were identified as: [MeSi(OH)2-O-Si(OH)3], [MeSi(OH)2-O-Si(OH)2Me], [MeSi(OH)2-O-Si(OH) Me2], [Me2Si(OH) -O-Si(OH) Me2], and [Me2Si(OH) -OSiMe2-OSi(OH) Me2]. In addition, the presence of D4D’OH and D4D’CH2OH also were detected in the urine using GC-MS (D4 is octamethylcyclotetrasiloxane). The formation of D4D’OH and MeSi(OH)3 clearly shows demethylation at the silicon-methyl bonds (Dow Corning Corporation, 1999b).The metabolite structures suggest that D5 is initially oxidized to a hydroxylated derivative, presumably by cytochrome P450. This initial metabolite appears to rearrange and downstream products are degraded by hydrolysis to the short-chain siloxanes, which are excreted.

Elimination

In a key oral ADME study (Domoradzki et al.,2017a; Dow Corning Corporation, 2012), following single gavage administration of14C-D5 at 100 mg/kg bw in a RLD vehicle, radioactivity was measurable through 168 h in faeces, expired volatiles, urine, and as14CO2. Totals of 2.0 and 1.3% of the recovered dose were accounted for in expired volatiles in females and males, respectively. A total of 83% of recovered radioactivity was found in faeces. Terminal half-lives of elimination for radioactivity were shorter in male animals for expired volatiles, urine, faeces, and CO2. Half-lives ranged from 28.36 to 69.77 hours in females and 25.72 to 49.39 hours in males. The AUC for total radioactivity is composed of both parent D5 and labelled metabolites. No parent D5 was found in urine samples; only metabolites were present. The percentage of the total radioactivity attributed to metabolites in excreta from females following administration was urine (100.00%) and in males it was faeces (19.40%) and urine (100.00%).

 

The elimination of D5 from male and female Fischer 344 rats following single and multiple inhalation exposures was evaluated. Elimination of retained radioactivity was similar in urine (~12%) and faeces (~16%) of both sexes following all exposures. Expired air was similar for both sexes following multiple exposures and females following single exposure (~45%) with significantly higher amounts for the males following a single exposure (~72%). In the plasma, liver and lung, the majority of radioactivity immediately following exposure could be attributed to parent, with this decreasing over time to a small fraction attributable to parent from 24 to 168 hours post exposure. In the urine samples, several peaks were present, but none corresponded to the retention time of parent D5. In contrast, the major peak for the faeces corresponded to the retention time for parent D5 (Batelle, 2001a; Dow Corning Corporation, 2007). Elimination half-lives were determined for both parent and14C-labeled D5. For14C-labeled D5 the longest half-lives for males and females were found in the adrenal glands, fat and lungs. The values for males and females were 88.9 and 142.9 for adrenals, 102.0 and 227.1 for fat and 273.2 and 201.4 for lungs. The longest half-lives determined for parent D5 were in the lung, liver and fat. The values for males and females were 160.1 and 135.3 for lung, 96.9 and 124.1 for liver and 130.4 and 120.5 for fat. The data demonstrates that the fat has the longest half-lives of all the tissues, which is due to the lipophilicity of D5.

Following oral administration both sexes showed similar patterns of disposition with the majority of absorbed dose excreted in expired volatiles and urine (Dow Corning Corporation, 2003b).

Radioactivity recovered in faeces accounted for 82.5 and 83.0% of the recovered dose in females and males, respectively with the majority of this activity eliminated in the first 24 h. Faeces consisted of mostly parent D5 and in the 0-24 h collection interval, parent represented 93.4% and 91.2% of the radioactivity, in females and males, respectively. The percentage of radioactivity from systemically absorbed 14C-D5 was eliminated in the urine (8.2%, females and 9.0%, males), in expired volatiles (2.01%, females and 1.26%, males) and in CO(1.25%, females and 1.38%, males) following a single oral administration to male and female Fischer 344 rats. Elimination half-lives were determined for both D5 and radioactivity.The longest half-lives of elimination for D5 were in the digestive tract: 441.20 and 538.00 h for females and males, respectively. The longest half-lives of elimination for radioactivity were in the digestive tract (386.17 h) and perirenal fat (341.32 h) for females and males, respectively(Domoradzki et al.,2017a; Dow Corning Corporation, 2012).

The toxicokinetics of D5 after inhalation exposure were also studied in human subjects (three males and two females) after inhalation of D5 at a single concentration of 10 ppm for one hour using a mouthpiece exposure system under a mixed rest/exercise scheme (Dow Corning Corporation, 2004). During exposure, D5 concentrations in exhaled air rapidly reached a steady state between 7 and 10 ppm; after the end of the exposures, D5 levels in exhaled air rapidly declined and reached concentrations of less than 1 ppm within 20 min in most of the subjects. Concentrations of D5 in plasma increased from a baseline level of 3.3 mg/L to between 31 and 70 mg/L at the end of the inhalation exposure and rapidly declined after the end of the exposure to reach the basal levels within 24 h after the termination of the inhalation exposure (Dow Corning Corporation, 2004).

The kinetics of D5 following inhalation and dermal exposure are similar and therefore comparable and allow for the development of physiologically based pharmacokinetic models that enable accurate predictions of human exposure by these routes (discussed below). Following oral administration, D5 appears to enter the blood via the lymphatics within the lipid core of chylomicrons and other lipoproteins, which is in a form different from that for inhalation or dermal routes of exposure.

Physiologically Based Toxicokinetics (PBTK) modelling:

The toxicokinetic data obtained in studies after D5 inhalation or after dermal application were used as a basis to develop and evaluate PBTK. The lipophilicity and volatility of D5 have a major influence on the toxicokinetics. The high lipophilicity results in high lipid partitioning and in retention of D5 in blood lipids. This is the cause of the differences in kinetic behaviour after inhalation and dermal administration as compared to oral dosing. Due to the high volatility, D5 is rapidly cleared from blood by exhalation. Hepatic clearance by biotransformation of D5 to polar metabolites also occurs.

Inhalation and dermal administration result in a similar pharmacokinetic profile, presumably due to diffusion of D5 molecules through membranes. At the onset of inhalation, blood levels of D5 climb rapidly and equilibrium between inhalation and exhalation of unchanged D5 is rapidly reached. Only a relatively small amount of the inhaled D5 is retained. In blood, D5 may exist in a free pool available for exhalation and biotransformation and a sequestered pool associated with blood lipids. During dermal exposures, D5 is rapidly absorbed into the outer layers of skin, but readily evaporates before significant systemic absorption occurs. PBTK modelling of the percutaneous absorption data from the human dermal absorption study predicts the dermal absorption of D5 as 0.05% (Reddy et al., 2007). Due to the efficient clearance of D5 by exhalation, approximately 90% of the D5 systemically available after dermal application is exhaled.

The distribution and kinetics of D5 after oral dosing differed significantly from the predictions of the PBTK model that adequately described the inhalation and dermal exposure routes (Reddy et al., 2007, 2008). The differences in toxicokinetics after oral administration as compared to inhalation or skin contact suggest that D5 is transferred from the gastrointestinal tract to the blood by different mechanisms as compared to those that operate after inhalation or dermal administration. The oral route may deliver microemulsions of D5 that do not readily dissolve in plasma and blood and are distributed as such. Uptake may be more associated with lipid transport, such as chylomicron formation and thus D5 may not be completely available for tissue interactions. The microemulsions may be removed from the circulation by the reticuloendothelial system in liver and spleen.

The oral dosing studies suggested a much higher persistence of D5 in blood compared to inhalation and dermal dosing. However, this apparent persistence after oral dosing is most likely due to the fact that a fraction of D5 is present in a pool that is unavailable to interact with tissues. These differences in toxicokinetics indicate that results from toxicity studies with D5 using oral dosing in oil vehicles likely have little relevance for assessing human health risks of D5 after inhalation and dermal exposures.

Conclusion:

D5 is a highly lipophilic and volatile compound with a particular kinetic behaviour after oral administration (predicted uptake and distribution in the form of microemulsions).

In contrast, absorption of these compounds after inhalation and dermal contact, two exposure routes considered most relevant to humans, occurs by their molecules diffusing through cell membranes. Therefore, only inhalation and dermal toxicity studies will provide useful information on their hazard properties potentially relevant to humans. Studies have identified that D4 and D5 are not extensively absorbed by the oral route including dietary exposure (Plotzke et al., 1994; Reddy et al., 2007; Campbell et al. (2017).

Due to the very low permeability of D5 through human skin and the rapid evaporation of this compound when applied to skin, dermal uptake is expected to be of low significance with regard to the generation of sufficient plasma concentrations to produce potential systemic toxicity. Moreover, due to the volatility and the surface spreading characteristics, repeated dose dermal studies cannot be conducted with reasonable confidence. In contrast, after inhalation, D5 is absorbed through the lungs and inhalation therefore is the only reasonable route of exposure resulting with a potentially important contribution to systemic availability. Recently an integrated D5 multi-route model(McMullin et al., 2016)was developed and kinetics behaviour following inhalation and dermal exposures have been found to be similar.

As other volatile lipophilic molecules, absorbed D5 is preferentially distributed to lipid-rich tissues. However, due to its high volatility, exhalation of unchanged D5 is the major route of elimination of absorbed D5. Due to this rapid elimination by inhalation, a bioaccumulation of D5 in lipid-rich tissues is not expected and due to the increased metabolism, high tissue levels were not observed after repeated inhalation for 6 months.

 

References:

Campbell JL, M.E. Andersen, C. Van Landinghman, R. Gentry, E. Jensen, J.Y. Domoradzki, H.I. Clewell. Refinement of the oral exposure description in the cyclic siloxane PBPK model for rats and humans: implications for exposure assessment Toxicol. Lett. (2017)

 

McMullin, TS, Y. Yang, J. Campbell, H.J. Clewell, K. Plotzke, M.E.AndersenDevelopment of an integrated multi-species and multi-dose route PBPK model for volatile methyl siloxanes – D4 and D5

Regul. Toxicol. Pharm., 74 (Supplement) (2016), pp. S1-S13

 

Plotzke, KP, J.M. McMahon, B.G. Hubbell, R.G. Meeks, R.W. MastDermal absorption of 14C-decamethylcyclopentasiloxane (D5) in rats Toxicologist, 14 (1994), p. 434 Abstract 1720

 

Reddy MB, Dobrev ID, McNett DA, et al. (2008) Inhalation dosimetry modeling with decamethylcyclopentasiloxane in rats and humans. Toxicological Sciences: An Official Journal of the Society of Toxicology 105: 275–285.

 

Reddy MB, Looney RJ, Utell MJ, et al. (2007) Modeling of human dermal absorption of octamethylcyclotetrasiloxane (D(4)) and decamethylcyclopentasiloxane (D(5)). Toxicological Sciences : An Official Journal of the Society of Toxicology 99: 422–431.