Reaction mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane

Endpoint summary

Additional information

There are no available toxicokinetics data for the registered substance “Reaction Mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane”. Therefore, data has been read-across from its four constituents:

1) HMDS: hexamethyldisiloxane (CAS 107-46-0)

2) L3: octamethyltrisiloxane (CAS 107-51-7)

3) L4: decamethyltetrasiloxane (CAS 141-62-8)

4) L5: dodecamethylpentasiloxane (CAS 141-63-9)

A detailed read-across explanation is also available in Section 7.5.

 

There are toxicokinetics data on HMDS (Dow Corning Corporation, 2001 and Dow Corning Corporation, 2008a); L3 (Dow Corning Corporation, 2017) and L5 (Dow Corning Corporation, 1985). There is dermal absorption data available for HMDS (Dow Corning Corporation, 2000) and L4 (Dow Corning Corporation, 2006). These data are used to confirm predictions for the kinetics of the registered substance “Reaction Products of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane” where appropriate.

 

The following summary has therefore been prepared based on in vitro data for the constituents of the registered substance and on validated predictions of the physicochemical properties of the constituents, using this data in algorithms that are the basis of many computer-based physiologically based pharmacokinetic or toxicokinetic (PBTK) prediction models. Although these algorithms provide a numerical value, for the purposes of this summary only qualitative statements or comparisons will be made. The main input variable for the majority of these algorithms is log K_owso by using this and, where appropriate, other known or predicted physicochemical properties of the constituents, reasonable predictions or statements can be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

All constituents of the registered substance are fully methyl substituted siloxanes with between two and five silicon atoms linked by oxygen atoms. The key physicochemical properties of the constituents are listed in the table below:

Table: Key physicochemical properties of constituents of the substance

Property	HMDS (107-46-0)	L3 (107 -51-7)	L4 (141-62-8)	L5 (141-63-9)
Molecular weight	162.38	236.54	310.69	348.9
Log Kow	5.06	6.60	8.21	9.3-9.5
Water solubility (mg/l)	0.93 (at 23°C)	3.4E-02 (at 23°C)	6.7E-03 mg/l at 23°C	7.0E-05 mg/l at 23°C
Vapour pressure at 25°C (Pa)	5500	530	73	7.8
Hydrolysis half- life at pH 7 (h) and 25°C	116	329	728	728
Ultimate hydrolysis product(s)	Trimethylsilanol	Trimethylsilanol and dimethylsilanediol	Trimethylsilanol and dimethylsilanediol	Trimethylsilanol and dimethylsilanediol

 

Human exposure can occur via the inhalation or dermal routes. Relevant inhalation and dermal exposure would be to the parent, due to the slow hydrolysis rate.

 

Absorption

Oral

Significant oral exposure is not expected for this substance.

When oral exposure takes place, it can be assumed (except for the most extreme of insoluble substances) that uptake through intestinal walls into the blood occurs. Uptake from intestines must be assumed to be possible for all substances that have appreciable solubility in water or lipid. Other mechanisms by which substances can be absorbed in the gastrointestinal tract include the passage of small water-soluble molecules (molecular weight up to around 200) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water (Renwick, 1993).

In a KMD study (Dow Corning Corporation, 2017), L3 was administered by single daily doses by oral gavage for 13 days followed by a radiolabeled dose on the 14th day of dosing and blood samples were then collected at 0.5, 1, 4 and 24 h. Measured blood concentrations data showed that L3 was absorbed and a difference in blood L3 and 14C-activity AUCs was observed. These data suggest that appreciable levels of metabolites/degradation products were present at the time that the animals were dosed with radiolabel. The molecular weight of the constituents HMDS and L3 (162 and 237 respectively) are close to the favourable range for absorption but due to their highly lipophilic nature and low water solubility the only means by which absorption from the gastrointestinal tract is likely to occur is via micellar solubilisation, consistent with the evidence from the KMD study with L3.In addition, there was evidence of oral absorption in the repeated dose toxicity study in rats with HMDS and L3.

A study conducted with L5 by Dow Corning Corporation (1985) showed that absorption following an oral gavage dose of 600 mg/kg bw to two Sprague-Dawley rats was approximately 25%. This is in agreement with predictions based on physicochemical properties. For the constituents L4 and L5, molecular weights unfavourable for absorption (310.69 and 348.9 respectively), combined with their highly lipophilic nature and extremely low water solubility, indicate that the likely means by which absorption from the gastrointestinal tract could occur is via micellar solubilisation., making systemic exposure limited.There was evidence of oral absorption in the repeated dose toxicity study in rats with both L4 and L5.

 

Oral exposure to the hydrolysis products dimethylsilanediol and trimethylsilanol is potentially possible via the environment. As they are both highly water soluble and have molecular weights below 200 they therefore possess favourable characteristics for absorption so should oral exposure occur then systemic exposure is likely.

 

Dermal

The fat solubility and the potential dermal penetration of a substance can be estimated by using the water solubility and log K_owvalues. Substances with log K_owvalues between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high. Therefore, asnone of the constituents of this substancefulfil either of these criteria, dermal absorption is unlikely to occur asthe constituents arenot sufficiently soluble in water to partition from the stratum corneum into the epidermis.Furthermore, after or during deposition of a liquid on the skin, evaporation of the substance and dermal absorption occur simultaneously so the vapour pressure of a substance is also relevant. The constituents have moderate to high vapour pressures, so volatilisation from the skin would further reduce the potential for dermal absorption.

In an in vitro dermal absorption study with HMDS (Dow Corning Corporation, 2000), a statistical analysis of the data indicated that only 0.023% of the applied dose of HMDS was absorbed through human cadaver skin. The majority of the dose volatilised from the application site (97.5%).An in vitro dermal penetration study has also been conducted on L4. In this study, conducted using a study protocol comparable to OECD 428 and to GLP (Dow Corning Corporation, 2006), almost all (99.9%) of the recovered 14C-L4 volatilised from the skin surface and was captured in the charcoal baskets placed above the exposure site. Only a small amount of the applied dose (0.06%) was found on the skin surface after 24 hours exposure or remained in the skin after washing and tape stripping (0.03%). Little, if any (0.001%) of the applied dose penetrated through the skin into the receptor fluid. The total percent dose absorbed was estimated to be 0.03% of applied dose with virtually all of the absorbed test substance retained in the skin. The results of these studies confirm the predicted dermal absorption of the other constituents.

 

Inhalation

There is a QSPR to estimate the blood:air partition coefficient for human subjects as published by Meulenberg and Vijverberg (2000). The  resulting  algorithm  uses  the  dimensionless  Henry’s  Law coefficient and the octanol:air partition coefficient (Koct:air) as independent variables. Using these values for the constituents of the registered substance results in an extremely low blood:air partition coefficient (between ~2.9E-05:1 (L5) to ~2.8E-03:1 (HMDS) ) so absorption across the respiratory tract epithelium is likely to be restricted to micellar solubilisation.

There is an inhalation toxicokinetics study available on HMDS (Dow Corning Corporation, 2008) which supports the predictions for the other constituents. After a 6 hour inhalation exposure of female rats to 5000 ppm HMDS, approximately 3% of the achieved dose was retained and confirms absorption following inhalation is low. Once inhaled, the registered substance could be absorbed by micellar solubilisation. There are no inhalation toxicokinetics studies available on L3, L4 or L5.

 

Distribution

For blood:tissue partitioning a QSPR algorithm has been developed by DeJongh et al. (1997) in which the distribution of compounds between blood and human body tissues as a function of water and lipid content of tissues and the n-octanol:water partition coefficient (Kow) is described. Using this for the constituents suggest that they will distribute into the main body compartments as follows: fat >> brain > liver ≈ kidney > muscle:

Table: Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
HMDS	5.06	1.1E+05	8.8	5.4	113.8	13.7	7.2
L3	6.6	3.98E+06	8.9	5.5	113.9	18.9	8.2
L4	8.21	1.62E+08	8.9	5.5	113.9	20.3	8.4
L5	9.4	2.51E+09	8.9	5.5	113.9	20.6	8.4

 

In the toxicokinetics studies with HMDS (Dow Corning Corporation 2006, Dow Corning Corporation 2008), radioactivity was distributed to the tissues; brain, fat, kidney, liver, lung and testes, with the highest concentrations found in fat, kidney and liver. The highest concentrations of parent HMDS was found in fat and kidney. Elimination of radioactivity from blood and tissues (excluding fat) was multiphasic, with the majority of the radioactivity eliminated within 24 hours post-exposure.

Further experimental evidence is available from a study with L5. Due to the rapid excretion of L5 very little of this test substance was detected in the tissues and organs of rats exposed to a single 600 mg/kg bw oral gavage dose (measurements taken 96 hours after administration). The organs with the highest concentration of test substance were the liver and lungs, which are the organs primarily involved in the excretion of it (Dow Corning Corporation, 1985).

The repeated dose toxicity studies with L3 and L4 showed effects in the liver, kidney (oral and inhalation exposure) and spleen (oral exposure) therefore the test substance must have distributed to these organs. 

 

 

Metabolism

Urinalysis conducted in the inhalation toxicokinetics study (Dow Corning Corporation, 2008a) on HMDS demonstrated that several peaks were present, but none corresponded to the retention time of the parent. Primary metabolites detected were 1,3-bis(hydroxymethyl)tetramethyldisiloxane combined with an unknown metabolite with retention time of 26.6 minutes (61%; 6-12 h sample). Other metabolites that were detected at greater than 5% were hydroxymethyldimethylsilanol (14%), dimethylsilanediol (14%) and trimethylsilanol (6%).

Following  oral  exposure  to  HMDS,  these  are  among  the  major  metabolites  identified  in  urine   (Dow Corning Corporation, 2001a): Me2Si(OH)2 (dimethylsilanediol); HOMe2SiCH2OH (hydroxymethyldimethylsilanol); HOCH2Me2SiOSiMe2CH2OH (1,3-bis(hydroxymethyl)tetramethyl-disiloxane; predominant); HOCH2Me2SiOSiMe3 hydroxymethylpentamethyldisiloxane); HOMe2SiOSiMe3 (hydroxypentamethyldisiloxane); Me3SiOH (trimethylsilanol). Besides these there were also three other metabolites: HOMe2SiOSiMe2CH2OH (1-hydroxy-3-hydroxymethyltetramethyldisiloxane; 2,2,5,5-tetramethyl-2,5-disila-1,3-dioxalene and 2,2,5,5-tetramethyl-1,4-dioxa-2,5-disilacyclohexane inferred from GC-MS analyses. Their presence in the HPLC metabolite profile was not established. No parent HMDS was present in urine.

These studies on HMDS suggest that it is extensively metabolised to a number of metabolites following demethylation at the silicon-methyl bond. Based on the structural similarity between HMDS, L3, L4 and L5, corresponding metabolites are likely to be formed following the registered substance metabolism. The metabolism of silanes and siloxanes is influenced by the chemistry of silicon, and it is fundamentally different from that of carbon compounds. These differences are due to the fact that silicon is more electropositive than carbon; Si-Si bonds are less stable than C-C bonds and Si-O bonds form very readily, the latter due to their high bond energy. Functional groups such as -OH, -CO2H, and -CH2OH are commonly seen in organic drug metabolites. If such functionalities are formed from siloxane metabolism, they will undergo rearrangement with migration of the Si atom from carbon to oxygen. Consequently, alpha hydroxysilanes may isomerise to silanols and this provides a mechanism by which very polar metabolites may be formed from highly hydrophobic alkylsiloxanes in relatively few metabolic steps.

 

Excretion

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSRs as developed by DeJongh et al. (1997) using log Kow as an input parameter, calculate the solubility in blood based on lipid fractions in the blood assuming that human blood contains 0.7% lipids. Using the algorithm, the soluble fraction in blood is <1% for all constituents.

According to data for the constituent, HMDS (Dow Corning Corporation, 2008a) the majority of systemically absorbed HMDS (3% of applied dose) was eliminated in the urine or expired volatiles and urinary excretion consisted of entirely polar metabolites. The primary route of elimination was in expired volatiles and 71% of this radioactivity was attributed to parent HMDS with the remainder as metabolites.

Based on an oral toxicokinetics study with L5 (Dow Corning Corporation, 1985) in two male rats, approximately 74% of the dose was recovered from the faeces, while 23% was eliminated through the expired air. Only 2.2% was recovered in urine. The elimination was found to be rapid (65 and 97% by 24 and 48 hours, respectively), so by 96 hours after dosing there were only trace amounts of the test substance in tissues and organs (0.09% of administered dose across all tissues and organs).

 

References

Renwick A. G. (1993) Data-derived safety factors for the evaluation of food additives and environmental contaminants.Fd. Addit. Contam.10: 275-305.

Meulenberg, C.J. and H.P. Vijverberg, Empirical relations predicting human and rat tissue:air partition coefficients of volatile organic compounds. Toxicol Appl Pharmacol, 2000. 165(3): p. 206-16.

De Jongh, J., H.J. Verhaar, and J.L. Hermens, A quantitative property-property relationship (QPPR) approach to estimate in vitro tissue-blood partition coefficients of organic chemicals in rats and humans. Arch Toxicol, 1997.72(1): p. 17-25.