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There is an in vivo toxicokinetics study on dodecamethylpentasiloxane (L5) (Dow Corning Corporation, 1985), and a dermal absorption study available on the structurally-related substance, decamethyltetrasiloxane (L4, 141-62-8) (Dow Corning Corporation, 2006). There are also data on the structurally-related substance, hexamethyldisiloxane (HMDS; 107-46-0), which are used to confirm predictions for the kinetics of dodecamethylpentasiloxane and support read-across justifications where appropriate. The available data on another structurally-related substance, octamethyltrisiloxane (L3; CAS 107-51-7) have also been incliuded to the dataset to support read-across justifications.

L5 is a low volatility (predicted vapour pressure of 7.8 Pa) liquid that is insoluble in water (0.00007 mg/l at 23°C). The octanol-water partition coefficient value is approximately 9.4, making this substance very lipophilic.

Human exposure can occur via the oral, inhalation or dermal routes.

Absorption

Oral

A toxicokinetics study conducted by Dow Corning Corporation (1985) showed that absorption of L5 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, which would suggest that due to its highly lipophilic nature and extremely low water solubility the likely means by which absorption from the gastrointestinal tract could occur is via micellar solubilisation. There was also evidence of oral absorption in the repeated dose toxicity study in rats for this substance.

Dermal

Dermal absorption is unlikely to occur as L5 is not sufficiently soluble in water to partition from the stratum corneum into the epidermis. There was no evidence of absorption in the acute dermal toxicity study or in the skin irritation study. An in vitro dermal penetration study has been conducted on the related substance, 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-decamethyltetrasiloxane (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 this study therefore confirm the predicted dermal absorption of L5. Since L4 is the closer structural analogue to L5, dermal absorption data for L4 was used as key.

In a well conducted supporting in vitro dermal absorption study for L2, conducted in compliance with GLP (reliability score 1), a statistical analysis of the data indicated that only 0.023% of the applied dose of L2 was absorbed through human cadaver skin. The majority of the dose volatilised from the application site (97.5%).

Inhalation

Owing to its low vapour pressure, inhalation of vapours of L5 is likely to be minimal. Inhalation of aerosols could occur. Once inhaled, L5 could be absorbed by micellar solubilisation. There are no inhalation studies on L5 to check for signs of absorption.

There is an inhalation toxicokinetics study on HMDS (Dow Corning Corporation, 2008a) which supports the predictions on L5. After a 6 hour inhalation exposure of female rats to 5000 ppm HMDS, approximately 3% of the achieved dose was retained. Due to the difference in log Kow between HMDS (log Kow 5.3) and L5 (log Kow 9.4) the results for HMDS can only be used to confirm qualitatively that absorption following inhalation is low.

Distribution

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).

Metabolism

There are no data regarding the metabolism of L5. 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. Studies on the structurally-related substance, HMDS, suggest that the linear siloxanes are extensively metabolised to a number of metabolites following demethylation at the silicon-methyl bond.

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%).

Also, following oral exposure to HMDS

the following are among the major metabolites identified in urine (Dow Corning Corporation, 2001a): Me2Si(OH)2; HOMe2SiCH2OH; HOCH2Me2SiOSiMe2CH2OH (predominant); HOCH2Me2SiOSiMe3; HOMe2SiOSiMe3; Me3SiOH. Besides these there were also three other metabolites: HOMe2SiOSiMe2CH2OH; 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.

Excretion

Based on an oral toxicokinetics study (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. About 65 and 97% of the applied dose was eliminated within 24 and 48 hours, respectively. Therefore, elimination was rapid.

Kinetics following inhalation might differ to kinetics following oral exposure according to data for the related substance, HMDS. The majority of systemically absorbed HMDS (3% of applied dose) was eliminated in the urine or expired volatiles. 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. It might be expected that, due to the lower vapour pressure of L5 (7.8 Pa) compared with HMDS (4451 Pa), L5 elimination as expired volatiles is less than that of HMDS, with excretion of metabolites in urine being the major route of excretion for L5.