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Description of key information

There is a good database for toxicokinetics of D4, which covers absorption, distribution, metabolism and excretion by oral, dermal and inhalation routes, respectively. Therefore, the toxicokinetics of D4 are characterised well for all relevant routes.

In summary, D4 absorption is approximately 0.5% and 8% for the dermal (most of the applied dose evaporates off the skin) and inhalation routes. For the oral route, high percentage (77%) of the administered D4 dose is absorbed (Domoradzkiaet al.,2017a). Most of the recovered dose was found in expired volatiles or was excreted in urine as metabolites. In addition, a high percentage of the recovered D4 dose was eliminated as metabolites in feces. In inhalation studies, higher concentrations of D4 were found in lung tissue and fat than other tissues. Studies in rats indicate that the liver is the site of the first step in the metabolism of D4. Human and rat metabolism of D4 are qualitatively similar with at least eight metabolites (dimethylsilanediol and methylsilanetriol were two major metabolites) identified in urine. In a human volunteer study there was one urinary metabolite tentatively identified as trimethyldisiloxane-1,3,3-triol, which has not been identified in rats. D4 itself is not excreted in urine. Elimination of inhaled D4 is rapid (most within 24 hours). Following oral ingestion most D4 is excreted in faeces. A high proportion of D4 is also exhaled.

Based on the several acute and repeated dose toxicity studies and the PBPK modelling, it can be concluded that D4 has no tendency to accumulate after repeated dosing. Absence of a potential for bioaccumulation is also indicated by an absence of an increase in D4 tissue concentrations in the log-term study. While D4 is very lipophilic with partitioning to fat, it is eliminated by exhalation or by biotransformation to polar metabolites. Furthermore, the overall data demonstrated a varying degree of uptake and absorption of D4 depending on route of administration, however what is absorbed is rapidly eliminated through rapid metabolism and excretion, indicative of no bioaccumulation potential.

In conclusion, results from pharmacokinetic studies and PBPK modelling indicate that dermal absorption of D4 is limited, due to its high volatility and, if absorbed via dermal, oral or inhalation exposure, the majority of D4 is rapidly cleared from the body, indicating that D4 has no tendency for bioaccumulation due to rapid elimination. Therefore, no bioaccumulation potential is anticipated based on the assessment.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
28
Absorption rate - dermal (%):
0.5
Absorption rate - inhalation (%):
8

Additional information

Absorption

Oral

In a key oral ADME study (Domoradzki et al.,2017a), D4 was assessed in female and male Fischer 344 rats following a single oral gavage administration of 30 mg [14C]D4/kg bw in a RLD vehicle. The mean percentage of the administered dose recovered was 87.01% and 85.86% in female and male rats, respectively. The percentage absorbed was 77.2% and 72.5% in females and males, respectively. Cmax, AUCs and the terminal half-lives of elimination for either parent D4 or14C-activity were similar between females and males.

Parent D4 was distributed to all tissues (except in fat ) with the Cmaxin most tissues at 2 hours post-dosing. The Cmax of parent D4 in blood was lower than Cmax levels in tissues. Terminal half-lives of elimination (t1/2) of parent D4 were fastest in blood; 20 and 18.7 h for females and males, respectively. Slower half-lives of elimination in fat were: 233.6 and 166.8 h for females and males, respectively.

The percentage of the total radioactivity attributed to metabolites in tissues and blood from females ranged from 9.51% to 83.29% with blood (83.29%) and liver (61.53%) with the greatest percentage of metabolites, and fat (9.51%) with the least percentage of metabolites. Metabolites found in urine and feces were dimethylsilanediol (51 - 65%), methylsilanetriol (16- 27%) and dimethyldisiloxane-1, 3, 3, 3-tetrol (9 - 13.1%). Hexamethyltrisiloxane-1, 5-diol was measured in females only at 0-12 and 12-24 hour collections.

The study showed that a high percentage (72% in female rats and 77% in male rats) of the administered D4 dose is absorbed following oral gavage administration. Most of the recovered dose was found in expired volatiles or was excreted in urine as metabolites. In addition, a high percentage of the recovered D4 dose was eliminated as metabolites in feces. The data demonstrated a fast uptake of D4 from the GI tract and high absorption, resulting in rapid metabolism and excretion, indicative of no bioaccumulation potential.

In a supporting study, absorption was studied in female Fischer rats following a single oral dose of 300 mg/kg14C‑D4 in corn oil, Simethicone fluid or undiluted. Absorption of radioactivity, expressed as percentage of total recovered radioactivity from urine, carcass, expired volatiles and expired CO2 was 52%, 12% and 28% with14C-D4 in corn oil, Simethicone or neat, respectively. The area under the curve (AUC) generated from blood data also indicated D4 was most readily absorbed when delivered in corn oil and least available in Simethicone fluid. Comparison of blood radioactivity AUC with parent D4 AUC indicated that parent D4 is absorbed, however, the majority of the radioactivity can be attributed to metabolites. The major excretory pathway, for the recovered radioactivity regardless of carrier, was the feces. The distribution of radioactivity to the tissues of female rats and transit time through the GI tract was investigated qualitatively by whole-body autoradiography at 1, 6, 12, 24, 48, and 96 hours and compared to neat D4 (Dow Corning Corporation, 1998a). This study shows that D4 is most readily absorbed following oral administration in corn oil (as compared with other vehicles).

 

Dermal

Dermal absorption of D4 has been assessed in in vitro and in in vivo studies with humans.

Human volunteers were exposed via the dermal route to a single dose of 14C-D4 applied to the axillae (1.4 g for males and 1.0 g for females) (Dow Corning Corporation, 2000c). Peak blood levels at one hour were less than 10 ng/g of blood or plasma. Peak D4 levels in exhaled air were achieved at one hour – 111 ng/l for females and 30 ng/l for males, the difference was not statistically significant. The authors had no explanation for a poor correlation between the expired air levels and blood and plasma levels.

In vitro absorption studies using human cadaver skin resulted in the absorption of only 0.5% of undiluted D4 (Dow Corning Corporation, 1998b). Duplicate studies showed there were no major differences detected between male and female skin. The majority of the dose (about 90% of the applied dose) volatilised from the skin and was collected in a charcoal basket of the diffusion set-up. Cumulative penetration over 24 hours for neat D4 was 1.23±0.19m/cm2(study 1) or 0.91±0.14m/cm2(study 2). The steady state flux for neat D4 was 0.06 or 0.05m/cm2/hr in studies 1 and 2, respectively. Lag time for the penetration of D4 was approximately 3 hours. After 24 hours, approximately 0.47% of the applied neat D4 remained in the skin.

In vivo human dermal absorption was assessed using a human skin/nude mouse model (Dow Corning Corporation, 2000d). In this study, human skin was grafted onto the backs of nude mice and D4 applied directly to the human skin. This study showed a low degree of D4 dermal absorption amounting to only 1.09% of the applied dose. Very little of the applied material was found to remain in the skin following application (0.02% after 24 hours exposure). Most (94.59±12.28%) of the material volatilised from the dosing site. The mean total recovery was 96.35±12.75%, including the volatilised material. About 42% of the absorbed dose was eliminated in expired air, while 49% was excreted in the urine and faeces. Overall, the data from these absorption studies and the study with human volunteers indicate a low D4 dermal absorption rate for humans. Overall, a value of 0.5% is considered to be reliable.

Inhalation

Single inhalation exposure studies have also been conducted in adult human male and female volunteers (Dow Corning Corporation, 1997d). In these studies, respiratory intake and uptake of D4 were measured on two occasions. The human subjects inhaled 10 ppm D4 (122µg/l) or air during a one-hour exposure via a mouthpiece in a double blind, randomised fashion. The concentration of D4 in inhaled and exhaled air and plasma was continuously measured before, during, and after exposure. The uptake of D4 was measured under steady state conditions during three rest periods of 10, 20, and 10 minutes, respectively which alternated with two 10 minute exercise periods. Mean D4 uptake was about 11 mg and plasma D4 measurements showed a mean peak value of 78 ng/g (or 78 ppb).

In three nose-only inhalation studies, male F344 rats were exposed to14C-D4 at 700 ppm for 6 hours (Dow Corning Corporation, 1996a),male and female F344 rats were exposed to 14C-D4 at 7, 70 or 700 ppm for 3 or 6 hours (Dow Corning Corporation, 1996b),and male and female F344 rats were exposed to unlabelled D4 at 7 or 700 ppm for 14 consecutive days followed by a single 6-hour exposure of14C-D4 at 7 or 700 ppm (Dow Corning Corporation, 1997b). After 6 hours exposure, the percent of 14C-D4 retained by males ranged from 4.99 to 5.47 % and in females from 5.19 to 5.52% of the delivered radioactivity (Dow Corning Corporation, 1996c). Similar retention levels (males: 4.38 -5.96%; females: 4.50 -6.14%) were achieved in males and females exposed to 7 or 700 ppm for 14 consecutive days. When dosed at 700 ppm concentration in plasma was 30 µ eq/ml at time 0 in male and female rats, then it decreased to 0.5 to 1.0 µ eq/ml at 170 hr in male and female rats, respectively. When dosed at 7 ppm plasma concentration was 0.5 µ eq/ml at time 0 in male and female rats, and 0.01 to 0.005 µ eq/ml at170 hr in male and female respectively. The measured half-lives values in plasma at 700 ppm were 70 hr and 89 hr in male and female rats, respectively. At 7 ppm the values were 70 hr and 45 hr in male and female rats, respectively. Plasma values of14C-D4 at the three concentrations (7, 70 and 700 ppm) showed an increase that was approximately proportional to increasing dose. Overall, the data show that approximately 8% of an inhaled D4 dose is absorbed in rats.

In a supporting single dose whole-body inhalation study, the concentration of parent D4 in blood, brain and uterus was determined in female Fischer 344 rats following 3 consecutive days of 16 h whole-body inhalation exposure to 700 ppm (Dow Corning Corporation, 2004). Following exposure, parent D4 concentration levels of blood, brain and uterus averaged 5.73, 115.32 and 70.21 μg/g of respectively.

 

Distribution

In a key oral ADME study (Domoradzki et al.,2017a), parent D4 was detected in all tissues (except in fat) with the Cmax in most tissues at 2 h post-dosing. Parent D4 was measurable in tissues through 168h post-dosing in all animals. The Cmax of parent D4 in blood was lower than Cmax levels in tissues. Terminal half-lives of elimination (t1/2) of parent D4 were fastest in blood; 20 and 18.7 h for females and males, respectively. Slower t1/2s of elimination in fat were: 233.6 and 166.8 h for females and males, respectively.

In the previously summarised single inhalation exposure studies conducted in adult human male and female volunteers (Dow Corning Corporation, 1997d) the estimated t1/2of parent D4in these human subjects was about 20 hours.

D4 (or its metabolites) is widely distributed to tissues following inhalation exposure. Fischer 344 and Sprague-Dawley IGS female rats were exposed to a 14C-D4 vapour concentration of 700 ppm for 6 h in a single nose-only inhalation study. The concentration of radioactivity over time in blood and lung was similar over the 168 h post-exposure period, while differences were seen in fat, liver, faeces, and urine. D4-associated radioactivity supports the conclusion that D4 (or its metabolites) is widely distributed in tissues following inhalation exposure (Dow Corning Corporation, 1996b). Another study focused on evaluating the effects of repeated inhalation exposure on hepatic microsomal induction, female Fischer 344 rats, D4 content in fat, liver, and plasma increased proportionally with increasing exposure concentrations. The liver-to-plasma D4 ratio remained constant over the dose range (Dow Corning Corporation, 2005b).

In these studies, fat appeared to be a depot for radioactivity as maximum concentrations were sustained up to 48 h post exposure. At 700 ppm the concentration of D4 was 100 µ eq/g in fat, lung, liver and kidney with a slight decrease over time in fat and a significant decrease over time in lung, liver and kidney. At 7 ppm 1 µ eq/g was detected in fat, lung, liver, and kidney, where a slight decrease over time was noted in fat and lung, and significant decrease in kidney and liver. In the 700 ppm female group the concentration in fat was higher, around 500 µ eq/g. The combined (male and female) mean radioactivity t½ ranged from 68 h in plasma to 154 h in skin. Tissues having the longest half-life were testes, skin, lung, nasal mucosa, fat, eye, uterus and vagina. High levels of radioactivity were found in the respiratory tract (nasal mucosa and lung), tissues functionally involved in the uptake and elimination of D4.

Overall, higher D4 levels were found in lung tissue and fat than in other tissues although this could be expected, as D4 is lipid soluble and would preferentially deposit in fat and highly lipophilic tissues.

 

Metabolism

In a key oral ADME study (Domoradzkiet al.,2017a), the percentage of the total radioactivity attributed to metabolites in tissues and blood from females ranged from 9.51% to 83.29% with blood (83.29%) and liver (61.53%) with the greatest percentage of metabolites and the fat (9.51%) with the least percentage of metabolites. Similar percentages of radioactivity attributed to metabolites were observed for males. Metabolites found in urine and feces were Dimethylsilanediol (51 - 65%), methylsilanetriol (16- 27%) and Dimethyldisiloxane-1, 3, 3, 3-tetrol (9 - 13.1%). Hexamethyltrisiloxane-1, 5-diol was only noted in females.

In a human volunteer study, males (24 - 52 years old) inhaled 10 ppm 14C-labelled D4 via a mouth-piece for one hour. Metabolites were far more persistent in blood and plasma than parent D4 and were still present at 24 hours, post-exposure. Approximately 25-30 % of the D4 uptake was found in urine when the C14 activity of the metabolites was expressed in D4 equivalents. There was one urinary metabolite tentatively identified as trimethyldisiloxane-1,3,3-triol, which has not been identified in rats (Dow Corning Corporation, 2001a; for historical reasons the study summary for this study is in IUCLID Section 7.10.5).

In studies in which 14C-D4 was incubated with liver microsomes obtained from human, saline-treated rats and phenobarbital-treated rats to assess species differences, 14C-D4 was converted by liver microsomes from the phenobarbital-treated rats to at least eight metabolites, designated M1 through M8, based on their retention times. M8 was the major metabolite formed in incubations with human liver microsomes and also in liver microsomes from saline-treated rats, suggesting a similarity in the metabolism of D4 for rats and humans (XenoTech LLC, 2001).

A human liver microsome study showed D4 to be a non-competitive inhibitor of human CYP2B6, CYP2D6 and CYP3A4/5, a competitive inhibitor of human CYP1A2, and either a competitive or non-competitive inhibitor of CYP2C19. D4 appears to have no capacity to inhibit rat CYP1A2 or human CYP2A6, CYP2C9 and CYP4A9/11 activity. Because D4 is an activator, not an inhibitor of human CYP2E1, D4 has little or no capacity to function as a metabolism-dependent inhibitor of any of the P450 enzymes examined with the possible exception of rat CYP1A1/2 and human CYP3A4/5 (XenoTech LLC, 1998).

The metabolic profile in rats was obtained using a high-pressure liquid chromatography (HPLC) system equipped with a radioisotope detector (Dow Corning Corporation, 1997a). The HPLC radiochromatogram revealed two major and at least five minor metabolites in urine following intravenous administration of 70 mg/kg 14C-D4. The two major metabolites, constituting 75-85% of the total components, were identified as dimethylsilanediol [Me2Si(OH)2] and methylsilanetriol [MeSi(OH)3]. Formation of MeSi(OH)3 clearly established demethylation at the silicon-methyl bonds of D4, which is presumptive evidence that the liver is an apparent first step in the metabolism of D4. No parent D4 was present in the urine.

The minor metabolites identified were:

[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].

Overall, HPLC profiles in urine collected from rats exposed to D4 by several routes reveal at least eight metabolites with no parent D4 excreted in urine. It appears that the liver is the first step in the metabolism of D4. From in vitro studies, it would appear that rats and humans metabolise D4 in a similar manner.

Studies that investigated the differences between Sprague Dawley and Fischer 344 rat metabolism of D4 show that Fischer 344 rats generally had a lower percentage of the total radioactivity (measured in various tissues) present as parent D4 (Dow Corning Corporation, 2000a and 2002a). This suggests that the Fischer 344 rats may more readily metabolise D4 as compared to Sprague Dawley rats. No parent D4 was found in the urine samples from either strain indicating all radioactivity present in the urine was as metabolites. The radioactivity present in the urine consisted entirely of polar metabolites of D4. Differences between Fischer 344 and Sprague-Dawley rats occurred in the amounts of metabolites found in the urine. The major metabolite present in both strains is dimethylsilanediol, however, this accounts for statistically significantly more of the total urinary radioactivity in the Sprague Dawley rat urine. The Fischer 344 rat urine contains a greater number of different metabolites and more of the metabolites that are demethylated when compared to the Sprague Dawley rats, suggesting again that Fischer 344 rats are better able to metabolise D4.

 

Excretion

In a key oral ADME study (Domoradzkiet al.,2017a), a total of 29.9 and 18.4% of the recovered dose was accounted for in expired volatiles in females and males, respectively. A total of 32.1 and 40.0% of the recovered dose was accounted for in the urine in females and males, respectively. A total of 22.6 and 27.2% of the recovered dose were accounted for in feces in females and males, respectively. Terminal half-lives of elimination for radioactivity were similar for female and male animals for expired volatiles, urine and feces. Half-lives ranged from 50.1 to 63.9 h in females and 35.7 to 55.2 h in males. The half-lives of elimination (terminal phase) of radioactivity in blood were; 104.5 and 80.6 h for females and males, respectively. The slowest t1/2s of eliminations were in perirenal fat; 225.2 and 217.9 h for females and males, respectively and in lungs, 311.9 and 212 h for females and males, respectively.

D4 excretion pathways have been studied in Fischer 344 rats, Sprague-Dawley rats, and in human volunteers. Two groups of Fischer 344 rats (five/sex/group/subset combination) were exposed to two doses (7 or 700 ppm) of unlabelled D4 vapour by nose for 6 hours/day for 14 consecutive days, followed by a single 6 h exposure to14C-D4 vapour on day 15. At cessation of exposure, the retained total radioactivity ranged from 4.38% to 6.14% and was readily taken up by the tissues, especially by fat (the fat and liver had the highest percentage of body burden). The recovery of radioactivity in excreta ranged from 89.2% to 92.8% of total recovered: urine (37.4–40.0%), faeces (12.6–19.1%), expired volatiles (25.9–35.4%), and expired14CO2(2.06–4.54). At the high exposure level, significantly higher proportions of radioactivity were eliminated through the lung (as both volatiles and14CO2) and a significantly lower proportion was eliminated through the gastrointestinal tract in the faeces. Based on normalised values, the portion of radioactivity remaining in the carcasses at 168 h post-exposure ranged from 6.53% to 8.50%. The mean radioactivity t1/2ranged from 56 h to 253 h (Dow Corning Corporation, 1997b). A similar experiment with Sprague-Dawley rats yielded the same results. Fischer 344 rats generally showed a lower percentage of total radioactivity present as parent D4. No parent D4 was found in the urine samples from either strain, indicating all radioactivity present in the urine was as metabolites. The major metabolite present in both strains was dimethylsilanediol. Fischer 344 rat urine contains a greater number of different metabolites and more of the metabolites that are demethylated when compared to the Sprague-Dawley rats, suggesting that Fischer 344 rats are better able to metabolise and excrete D4 (Plotzkeet al., 2000). In an in vivo toxicokinetics study in humans, six male human volunteers (24–52 years old) inhaled 10 ppm14C D4 for 1 h. At several time points before, during, and after exposure,14C activity was measured in blood and urine samples. In addition, respiratory uptake and elimination were measured. Metabolites were far more persistent in blood and plasma than parent D4 and were still present at 24-h post exposure. A rapid respiratory elimination of 28% of the D4 uptake was observed, with 25–30% found in urine (Dow Corning Corporation, 2001).

 

Pharmacokinetic modelling

Based on the studies that have been conducted to assess the dermal absorption of D4 through human skin in vivo and in vitro, a physiologically based pharmacokinetic model was developed. The compartment model for D4 dermal absorption included (1) volatilisation of applied chemical from the skin surface, (2) a storage compartment in the skin tissue, (3) diffusion of absorbed chemical within the skin back to the skin surface, (4) evaporation of this chemical from the skin surface even though the applied dose was no longer present, and (5) uptake from the skin compartment into blood. Time course of blood and exhaled breath data from human volunteers were used to estimate model parameters.

In volunteers exposed to D4, the maximum concentration of chemical in exhaled air was reached at or prior to 1 h following administration of the test chemical. Based on model calculations, the percent of applied dose of D4 that was absorbed into systemic circulation for men and women was 0.12 and 0.30%, respectively. Model calculations indicate that more than 83% of the chemical that reached systemic circulation was eliminated by exhalation within 24 h (Reddy, M. B.et al., 2007).

An assumption inherent in the calculation of margins of safety (MOS) is that once D4 crosses the initial biological barrier, i. e. the lung for inhalation exposure, or the skin for dermal exposure, then delivery to the target tissue and hence the biologically relevant dose at the target tissue is independent of initial route of exposure. Recent pharmacokinetic studies and pharmacokinetic modelling (Andersen, M. E.et al., 2001; Reddy, M. B.et al., 2003) have demonstrated that such an assumption greatly overestimates the delivered dose of D4 by the dermal route compared with the inhalation route of exposure. When absorbed through the lungs, D4 enters the arterial systemic circulation where it is distributed throughout the body to potentially all organ systems. When absorbed by the dermal route, D4 enters the venous circulation, which moves directly to the heart and lungs where the majority of the D4 is then eliminated via exhaled air prior to being available systemically. A series of studies were conducted and a physiologically based pharmacokinetic model constructed to evaluate the magnitude of the difference.

A model was used to compare the estimated D4 body burden from a dermal absorption study to that achieved following a 6-hour inhalation exposure at 700 ppm (Jovanovic, M. L.et al., 2004). This pharmacodynamic model predicted that the area under the curve (AUC) of free D4 in blood for the 6-hour occluded dermal exposure would be 60-fold lower than the AUC for free D4 following a 6-hour inhalation exposure at 700 ppm. Since absorption across human skin is considerably less than for the rat and human skin would not be occluded, the 60-fold factor is likely to be an underestimation.

Conclusion:

D4 is a highly lipophilic and volatile compound with a particular kinetic behaviour after oral administration (predicted uptake and distribution in the form of microemulsions) (Dekant et al., 2017). After oral administration, the extent of absorption of D4 depends on carrier and dose.

In contrast, absorption of D4 after inhalation and dermal contact studied significantly and considered most relevant to humans, occurs by their molecules diffusing through cell membranes. Therefore, these studies provide useful information on their hazard properties potentially relevant to humans. Studies have identified that D4 is highly absorbed by the oral route (Domoradzki et al.,2017a).

Due to the very low permeability of D4 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, D4 is absorbed though the lungs and inhalation therefore is the only reasonable route of exposure resulting with a potentially important contribution to systemic availability. Recently an integrated D4 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 D4 is preferentially distributed to lipid-rich tissues. However, due to its high volatility, exhalation of unchanged D4 is the major route of elimination of absorbed D4. Due to this rapid elimination by inhalation and despite the high octanol/water partitioning, bioaccumulation of D4 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.

 

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

 

References:

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Domoradzki, J. Y., Christopher M. Sushynski, Jacob M. Sushynski, Debra A. McNett, Cynthia Van Landingham, Kathleen P. Plotzke (2017a); PUBLICATION: Metabolism and disposition of [14C]-methylcyclosiloxanes in rats; Toxicology Letters 279 (2017a) 98–114, journal homepage: www.elsevier.com/locate/toxlet;

Dekant W., Scialli A.R., Plotzke K., and Klaunig, J.E. (2017) Biological relevance of effects following chronic administration of octamethylcyclotetrasiloxane (D4) in Fischer 344 rats. Toxicol Lett 279, Supplement 1: 42-53, https://doi.org/10.1016/j.toxlet.2017.01.010.

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Dow Corning Corporation (DCC) (1997b) Primary Eye Irritancy Study of Dow Corning 556 Cosmetic Grade Fluid in Rabbits. DCC Report no. 1996-10000 -42469. Midland, MI: Dow Corning Corporation.

 

Dow Corning Corporation (DCC) (1999) Effects of Repeated Whole Body Inhalation Exposure to D4 Vapors on Hepatic Microsomal CYP2B1/2 Induction in Female Fischer 344 Rats. DCC Report No. 1998-I0000 -44687. Midland, MI: Dow Corning Corporation.

 

Dow Corning Corporation (DCC) (2001) Effects of Repeated Whole Body Inhalation Exposure to Octamethylcyclotetrasiloxane (D4) Vapors on Hepatic Microsomal CYP2B1/2 Induction in Female Fischer 344 Rats: A Dose Response Study—Amendment to Report 1998-I0000-44687. DCC Report no. 2000-I0000 -48438. Midland, MI: DCC, Health and Environmental Sciences.

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Dow Corning Corporation. (2005b). Non-Regulated Study: Effect of Cyclic Siloxanes on Dopamine Receptor Regulation of Prolactin Release from Rat Pituitary Tumor-Derived Transformed Cell Lines. Testing laboratory: Dow Corning Corporation. Report no.: Study Number 9872-102 (2005-STEC-2824). Report date: 2005-06-20.

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.