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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
05.11.2005 to 24.11.2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Objective of study:
toxicokinetics
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
GLP compliance:
not specified
Radiolabelling:
yes
Remarks:
14C-HMDS
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: No data
- Age at study initiation: 8-10 weeks minimum
- Weight at study initiation: Males: 200-250 g; Females: 150-175 g minimum
- Fasting period before study: No
- Housing: Individually in suspended wire-mesh cages
- Individual metabolism cages: no
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.6 - 21.7
- Humidity (%): 24 - 65
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 05.11.2005 To: 24.11.2008
Route of administration:
inhalation: vapour
Vehicle:
unchanged (no vehicle)
Details on exposure:
TYPE OF INHALATION EXPOSURE: nose only


GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: Flow-past nose-only inhalation exposure chambers
- Method of holding animals in test chamber: Nose-only cones
- Source and rate of air: No data on source. Flow was 500 ml/min
- Method of conditioning air: Series of Balston brand filters
- Treatment of exhaust air: No data
Duration and frequency of treatment / exposure:
Six hours
Dose / conc.:
5 000 ppm
Remarks:
Average of actual concs: 4953±44 ppm
No. of animals per sex per dose:
Various (see Table 1)
Control animals:
yes
Positive control:
None
Details on study design:
- Dose selection rationale: Based on previously conducted studies
Details on dosing and sampling:
Each animal, with the exception of the control animals, was exposed to 14C-HMDS for six consecutive hours on the day of the single exposure. Cannulated animals were positioned such that the cannula was easily accessible for blood collection without interrupting exposure. Blood collection during the exposure occurred at the 3-hour time point following initiation of the exposure. Following six consecutive hours of exposure, the animals in the body burden group 12 were euthanised while on the chamber and the cones containing animals were removed from the chamber. The exposure completion time was defined as the time of euthanasia for the body burden animals and time of removal from the exposure chamber for all remaining animals. All animals were observed at least once per day for mortality, morbidity and moribundity. Body weights were recorded for each animal prior to exposure and on the scheduled sacrifice days. Radioactivity content in blood, fat, kidneys, ovaries, liver, lung, brain, feces, urine, charcoal tubes (volatiles) and potassium hydroxide (KOH, which represents trapped CO2), cage and cone rinses and waste generated when processing groups 7 and 8 animals was measured. The concentration of parent HMDS in blood, fat, kidney, ovaries, liver, lung, brain and charcoal tubes was measured. Urinary metabolite profiles were determined.
Statistics:
All analysis was done with SAS version 9.13. Areas under the curve (AUCs) were calculated for blood, tissues and charcoal for both the radiolabelled and the parent compound using Bailer's method which produces both a mean and standard error. These statistics were used to calculate upper and lower confidence limits on the AUCs. Comparisons between the parent and radiolabelled compound AUCs in the charcoal tubes, blood and the tissues of the lung, liver, kidney, brain ovaries and fat were done using the values from the Bailer ethod and the Satterthwaite approximation method. A half-life was computed for the parent and radiolabelled compounds in each of the media in which it was sampled.
Type:
absorption
Results:
Not calculated
Type:
distribution
Results:
Parent and metabolites were observed in the brain, kidney, liver and lung.
Type:
metabolism
Results:
Primary metabolites were 1,3-bis(hydroxymethyl)tetramethyldisiloxane combined with an unknown metabolite. Other metabolites that were detected at greater than 5% were hydroxymethyldimethylsilanol (14%), dimethylsilanediol (14%) and trimethylsilanol (6%).
Type:
excretion
Results:
The percentage of the recovered dose found in urine was approximately 37%, expired volatiles accounted for approximately 50% of the recovered radioactivity and fecal elimination was about 1% of the recovered dose following a single exposure.
Details on absorption:
In the body burden animals, approximately 3.1 ±0.17% and 3.4 ±0.12% of the total radioactivity was retained at the end of the exposure period in female and male rats, respectively.
Details on distribution in tissues:
In tissues, the percentage of the recovered radioactivity was approximately 0.11% and both parent HMDS and metabolites were observed in brain, kidney, liver and lung. Following a single exposure, based on the calculated area-under-the-curves the percentage of the total radioactivity attributed to metabolites in blood and tissues ranged from 38.71 to 92.62%: liver (84.03%), blood (92.62%), brain (67.73%), lung (58.32%) and kidney (38.71%). The percentage of parent HMDS in blood and tissues was: liver (15.97%), blood (7.38%), brain (32.32%), lung (41.68%) and kidney (approx. 61.29%). In fat and ovaries the radioactivity concentrations were essentially the same as the parent HMDS concentrations throughout the time course indicating that all of the radioactivity was attributed to HMDS in these tissues.
Details on excretion:
Parent HMDS was eliminated from blood and tissues at a faster rate than total radioactivity. The percentage of the recovered dose found in urine was approximately 37%, expired volatiles accounted for approximately 50% of the recovered radioactivity and fecal elimination was about 1% of the recovered dose following a single exposure. Collected tissues accounted for less than 0.1% of the recovered dose and radioactivity remaining in the carcass was about 2% of the recovered dose. The overall mass balance of radioactivity, as a percent of the body burden was 115.6%. The majority of the radioactivity (approximately 75%) was eliminated by 24 hours post-exposure. Terminal elimination half-lives for radioactivity from the blood and tissues (excluding fat) were multiphasic with the majority of the radioactivity eliminated within 24 hours post-exposure. The terminal half-lives of elimination of radioactivity from blood, brain, fat, kidney, liver, lung and ovaries were 67, 31, 33, 44, 56, 53 and 22, respectively. In general, half-lives of elimination were 1 to 10 fold faster for parent HMDS than radioactivity. In lung, parent was not measurable at 168 hours post-exposure. In blood, parent HMDS levels were not measurable beyond 24 hours post-exposure. Approximately 29% of the total radioactivity in expired volatiles was attributed to metabolites following the single exposure. The maximum concentration of radioactivity found in expired volatiles was in the first 0-1 hour collection interval. Following a single exposure, the maximum concentration of radioactivity was found in the 12-24 hour post-exposure interval in feces and in the 6-12 hour post-exposure interval in urine. The highest concentration of 14CO2 was found in the first collection interval, 0-24 hour post-exposure. Half-lives of elimination of radioactivity were similar for expired volatiles, feces, urine and CO2: 21, 20, 18 and 32 hours, respectively.
Metabolites identified:
yes
Details on metabolites:
Urinalysis 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 914%) and trimethylsilanol (6%).
Conclusions:
Interpretation of results: no bioaccumulation potential based on study results
After a 6 hour inhalation exposure to 5000 ppm HMDS, approximately 3% of the achieved dose was retained. Parent HMDS was measured in blood and tissues: brain, fat, kidney, liver, lung and ovaries, and the highest concentrations were found in fat and ovaries. Elimination of radioactivity from blood and tissues (excluding fat) was multi-phasic, with the majority of the radioactivity eliminated within 24 hours post-exposure. The majority of the systemically absorbed HMDS 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. Considering the effective removal of HMDS through metabolism and exhalation, accumulation in the body after repeated exposures is unlikely despite its high lipophilicity (reliability score 2 study) .
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
20/05/2003 to 07/12/2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Objective of study:
toxicokinetics
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
GLP compliance:
yes (incl. certificate)
Radiolabelling:
yes
Remarks:
14C-HMDS
Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc.
- Age at study initiation: 67-74 days
- Weight at study initiation: 201-242.7 g
- Fasting period before study: Animals were only fasted during exposure periods
- Housing: Individually housed in suspended wire-mesh bottom stainless-steel cages (non-exposure period only)
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): Ad libitum except when loaded into restraint cones
- Water (e.g. ad libitum): Ad libitum except when loaded into restraint cones
- Acclimation period: Animals were acclimated to restraint cones on four consecutive days prior to initiation of the first exposure.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 02/06/2003 To: 31/10/2003
Route of administration:
other: Nose-only vapour inhalation
Vehicle:
unchanged (no vehicle)
Details on exposure:
TYPE OF INHALATION EXPOSURE: nose only

GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: Individual restraint cones (exposure cones) designed for attachment to the Cannon style nose-only system.
- Method of holding animals in test chamber: Animals were individually positioned in polycarbonate restraint tubes designed to directly attach to the nose-only exposure chamber. The cones were sealed using plastic bags designed with closable seals.
- Source and rate of air: Chamber air was supplied by a Nash compressor and filtered with a series of Balston filters. During exposures, airflow through the chamber was maintained at a rate providing a minimum of 500 ml/minute of air to each port on the chamber.
- Treatment of exhaust air: No data
Duration and frequency of treatment / exposure:
Four groups (Groups 3-6) exposed 6 hours per day for 14 consecutive days to HMDS followed by a single 6-hour exposure to 14C-HMDS on day 15. In the second part of the study four groups (Groups 9-12) of animals received a single 6-hour exposure to 14C-HMDS. Four control groups (Groups 1, 2, 7 and 8) were also included. Animals in these control groups remained in housing cages.
Dose / conc.:
5 000 ppm
No. of animals per sex per dose:
55 animals each for the repeat and single dose studies.
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: No rationale given
Details on dosing and sampling:
Excreta control (Groups 1 and 7): On day 15 of the repeated exposure and on the day of the single exposure, the control animals were transferred to individual glass metabolism cages until their scheduled sacrifice time (168-hour post-exposure). Urine and faeces were collected up to the time of euthanasia. These animals served as bakground controls for the distribution and excreta groups of the repeat or single exposures.

Body Burden control (Groups 2 and 8): These animals were sacrificed on the day of exposure to 14C-HMDS (day 1 or 15) and served as background controls for the body burden group animals.

Body Burden (Groups 3 and 9): This group was used to determine the total amount of radioactivity remaining in the animal immediately following the 14C-HMDS exposure period. These results were used for comparison to the excreta animals for determination of percents of administered dose. These animals were sacrificed while on the chamber and no earlier than 10 minutes before the end of the 14C-HMDS exposure (day 1 or 15).

Tissue Distribution (Groups 4 and 10): This group was used to evaluate tissue disposition and kinetics of both parent HMDS and total radioactivity following a single and repeated exposure. Four animals were sacrificed at each time point. On the day of the 14C-HMDS exposures, blood was drawn at the 3-hour time points during the exposure period. On removal from the exposure chamber, blood was collected at 0 (15 minutes), 10, 30 minutes, 1, 2, 12, 24, 72 and 120 hours.

Exceta (Groups 5 and 11): This group was used to determine the elimination pathway of HMDS. The amount of radioactivity in each of the possible elimination routes was directly compared as a fraction of the total amount of radioactivity found. The amount of radioactivity in each of the possible elimination routes was also compared as a percent of the radioactivity found in the body burden group post 14C-HMDS exposure (day 1 or 15). Blood was collected at 168 hours post 14C-HMDS exposure.

Body Burden Spares (Group 6 and 12): This group was used to replace any animals with non-patent cannulas in the body burden group before or during the 14C-HMDS exposures. Unused animals were sacrificed and discarded.

Statistics:
Alll statistical analyses were conducted using SAS version 9.13. Areas under the curve (AUC) were calculated for both radiolabelled and parent compound using Bailer's method, which produces both mean and standard error. These statistics were used to calculate upper and lower confidence limits on the AUCs. Comparisons between the parent and radiolabelled compound AUCs in the charcoal tubes, blood, lung, liver, kidney, brain, testes and fat were done using the values from the Bailer method and Satterthwaite approximation method.
Type:
distribution
Results:
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.
Type:
metabolism
Results:
Urinary elimination was as polar metabolites only.
Type:
excretion
Results:
The majority of systemically absorbed HMDS was eliminated in the urine or expired volatiles.
Details on absorption:
Overall absorption rates were not discussed.
Details on distribution in tissues:
Retention of HMDS at the end of exposure (body burden) was 3.6% and 3.8% for the single and repeated exposures, respectively.

Radioactivity was distributed to the tissues; brain, fat, kidney, liver, lung and testes, with the highest concentrations found in fat, kidney and liver.
14CO2 represented approximately 2% of the recovered body burden for both exposure scenarios. Based on calculated AUCs, the µg eq HMDS/g*h, in fat, kidney and liver following a single exposure were 58090, 5690 and 4225, respectively. Following repeated exposure the AUC calculated for radioactivity in fat, kidney and liver were 42671, 4979 and 3939, respectively. Parent HMDS was measured in blood and tissues; brain, fat, kidney, liver, lung and testes, and the highest concentrations were found in fat and kidney. Based on calculated AUCs, the µg HMDS/g*h, in fat and kidney following a single exposure were 47939 and 2198, respectively. Following repeated exposure the AUCs for HMDS in fat and kidney were 94058 and 3081, respectively.

Elimination of radioactivity from blood and tissues (excluding fat) was multiphasic, with the majority of the radioactivity eliminated within 24h post-exposure. Elimination half-lives for radioactivity and parent HMDS were similar between the single exposure and the repeated exposure groups. The terminal half-life for elimination of radioactivity from blood was approximately 36 hours and 39 hours for the single and repeated exposures, respectively. Terminal half-lives of elimination for radioactivity of over 40 hours were measured in liver, lung and testes after the single exposure and in liver, lung, testes and brain after repeated exposures. In general, half-lives of elimination were 1 to 3 fold faster for parent HMDS than radioactivity; notable was the faster elimination half-life of HMDS from lung tissue. Elimination of parent HMDS from blood and tissues was multi-phasic, with the majority of parent HMDS eliminated within 24 hours post-exposure. Following a single exposure, the terminal half-life in blood was 59 hours and the shortest half-life was found in lung (16 hours). Following the repeated exposures, the terminal half-life in blood was 37 hours and that in lung was 18 hours.
Details on excretion:
The greatest percentage of radioactivity was recovered in the urine; 46% and 64% following the single and repeated exposures, respectively. HMDS in expired volatiles was 46% and 28%, respectively, and in faeces approximately 2% in both exposures.

The primary route of elimination following a single exposure was in urine and expired volatiles, both at 46%. However, following repeated exposures the percentage excreted in the urine increased to 64% while the expired volatiles decreased to 28%. The majority of the radioactivity eliminated in urine, expired volatiles, CO2 and faeces was eliminated by 24 hours post-exposure. Following a single exposure, terminal half-lives of elimination were 19, 16, 18 and 22 hours for expired volatiles, faeces, urine and CO2, respectively. Terminal half-lives of elimination were 19, 19, 15 and 17 hours for expired volatiles, faeces, urine and CO2, respectively following repeated exposures.

Parent HMDS was measured in expired volatiles and based on AUC calculations, 47% of the total radioactivity in expired volatiles was attributed to parent HMDS in the single exposure. The percentage of parent HMDS in total 14C-radioactivity in expired air remained constant throughout the collection intervals (approximately 47%). The percentage of parent HMDS in expired volatiles following repeated exposure could not be determined due to the elimination of residual parent HMDS from the 14 days of non-radiolabelled HMDS exposures.

Metabolites identified:
yes
Details on metabolites:
Only metabolites of HMDS were detected in urine and these were determined to be polar metabolites. Primary metabolites detected in urine in the 0-12 hour and 12-24 hour collection intervals following a repeated exposure to HMDS were 1,3-bis(hydroxymethyl)tetramethyldisiloxane and hydroxymethyldimethylsilanol. Followingt the single exposure (6-12 hour collection interval), the primary metabolites were 1,3-bis(hydroxymethyl)tetramethyldisiloxane and an unknown metabolite, with retention times of 25 minutes and 26.5 minutes, respectively. The primary metabolite following the single exposure, 0-6 and 12-24 hour collection intervals was an unknown metabolite with a retention time of 26.5 minutes. Other metabolites that were detected at greater than 4% of the total urinary radioactivity following both the single and repeated exposures were dimethylsilanediol and trimethylsilanol.
Conclusions:
Interpretation of results: no bioaccumulation potential based on study results
In a good quality toxicokinetic study conducted to GLP (reliability score 1), rats were exposed (6-hour nose-only) to HMDS for either 14 consecutive days followed by a single exposure (6-hour) to 14C-HMDS, or to a single exposure (6-hour) of 14C-HMDS. All concentrations of HMDS were 5000ppm. In both experiments approximately 4% of the dose was retained. Parent HMDS was measured in blood and tissues; brain, fat, kidney, liver. lung and testes and the highest concentrations were 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. The majority of systemically absorbed HMDS was eliminated in the urine or expired volatiles. Urinary elimination was as polar metabolites only. Considering the effective removal of HMDS through metabolism and exhalation, the authors of the study considered accumulation in the body after repeated exposures to be unlikely.

Description of key information

There are no measured data on the toxicokinetics of 1,1,3,3-tetramethyl-1,3-divinyldisiloxane (Vi2-L2). Read-across data are available from the structurally-related substance hexamethyldisiloxane (HMDS; CAS 107-46 -0).

In a well conducted in vitro dermal absorption study (Dow Corning Corporation, 2000) conducted to GLP, 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%).

Two inhalation toxicokinetics studies are available for HMDS (Dow Corning Corporation, 2006 and 2008), both of which were well conducted. These studies showed that the highest concentrations of HMDS are found in the kidney and fat, the majority of HMDS is eliminated from tissues and blood within 24 hours of exposure and subsequently excreted in urine as polar metabolites, or expired volatiles.  In a non-GLP study (Dow Corning Corporation, 2001) that investigated the metabolism of HMDS in rats, metabolites (abundant in hydroxymethyl groups) of this linear siloxane were found to be structurally different from that obtained for cyclic siloxanes (D4 and D5, which are mainly silanols).

Key value for chemical safety assessment

Absorption rate - dermal (%):
0.023

Additional information

There are no data on the toxicokinetics of 1,1,3,3-tetramethyl-1,3-divinyldisiloxane (Vi2-L2).

Read-across data are available from the structurally-related substance hexamethyldisiloxane (HMDS; CAS 107 -46 -0).

The substances are both disiloxanes, with the general structural formula Me2Si(R)-O-Si(R)Me2, where R may be methyl or vinyl. Vi2-L2 has two methyl and one vinyl group at each silicon. HMDS has three methyl groups at each silicon.

Therefore, the similarities between the two substances are that they are both disiloxanes, both have at least two methyl groups bound to each silicon and the third group bound to each silicon is a short-chain hydrocarbon group.

The difference between the two substances is that one of the three methyl groups at each silicon in HMDS is replaced by a vinyl group in Vi2-L2.

The difference in structure does not generally lead to a significant difference in physicochemical properties. The largest difference is for vapour pressure, with the source substance being more volatile than the target substance. The substances have similar partition coefficient and water solubility values.

Both substances are predicted to hydrolyse forming the hydrolysis products dimethyl(vinyl)silanol and trimethylsilanol, respectively.

The hydrolysis products of V2-L2 and HMDS are structurally similar. They are both monosilanols of the general structural formula Me2Si(R)OH. Dimethyl(vinyl)silanol (hydrolysis product of V2-L2) has two methyl groups and one vinyl group at each silicon in addition to the -OH group. Trimethylsilanol (hydrolysis product of HMDS) has three methyl groups at each silicon. Therefore, the similarities between the two hydrolysis products are that they are both monosilanols, they have one Si-OH group, both have at least two methyl groups bound to each silicon and the third group bound to each silicon is a short-chain hydrocarbon group. As for the parent substances, the difference between the two hydrolysis products is that one of the three methyl groups bound to silicon in HMDS hydrolysis product is replaced with a vinyl group in V2-L2 hydrolysis product.

In an in vitro dermal absorption study (Dow Corning Corporation, 2000) using a Bronaugh Flow Through method, human cadaver skin was exposed to the HMDS for 24 hours. A statistical analysis of the data indicated that only 0.023% of the applied dose of HMDS was absorbed through the human cadaver skin. The majority of the dose volatilised from the application site (97.5%). The vapour pressure of HMDS is 5500 Pa at 25°C while for Vi2-L2 it is 1700 Pa at 25°C so the registered substance will not volatise to quite the same extent, however, based on the HMDS data, dermal absorption of Vi2-L2 is expected to be minimal.

The fat solubility and therefore potential dermal penetration of a substance can be estimated by using the water solubility and log Kowvalues. Substances with log Kowvalues between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high.

Vi2-L2 has a log Kowvalue (5.4) above the favourable range and low water solubility therefore absorption across the skin is not likely to occur and significant systemic exposure following dermal exposure is unlikely, consistent with the measured data for read-across substance HMDS.

In a toxicokinetic study (Dow Corning Corporation, 2006) rats were exposed (6-hour nose-only) to HMDS for either

14 consecutive days followed by a single exposure (6-hour) to14C- HMDS, or to a single exposure (6-hour) of 14C- HMDS. All concentrations of HMDS were 5000 ppm. In both experiments approximately 4% of the dose was retained. Parent HMDS was measured in blood and tissues; brain, fat, kidney, liver, lung and testes and the highest concentrations were 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. The majority of systemically absorbed HMDS was eliminated in the urine or expired volatiles. Urinary elimination was as polar metabolites only. Considering the effective removal of HMDS through metabolism and exhalation, the authors of the study considered accumulation in the body after repeated exposures to be unlikely. However, as the metabolic pathway for Vi2-L2 may not be exactly the same, the HMDS data should be considered as indicative only.


After a 6-hour inhalation exposure of female rats to 5000 ppm HMDS, approximately 3% of the achieved dose was retained. Parent HMDS was measured in blood and tissues: brain, fat, kidney, liver, lung and ovaries, and the highest concentrations were found in fat and ovaries. Elimination of radioactivity from blood and tissues (excluding fat) was multi-phasic, with the majority of the radioactivity eliminated within 24 hours post-exposure. The majority of the systemically absorbed HMDS 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 HMSD with the remainder as metabolites. Considering the effective removal of HMDS through metabolism and exhalation, accumulation in the body after repeated exposures is unlikely despite its high lipophilicity (Dow Corning Corporation, 2008).

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 coefficient and the octanol:air partition coefficient (Koct:air) as independent variables.

Using these values for Vi2-L2 results in a very low blood:air partition coefficient (approximately 0.001:1) meaning that if lung exposure occurred there would be minimal uptake into the systemic circulation, consistent with the measured data for read-across substance HMDS (which has a slightly higher predicted blood:air partition coefficient value of 0.003:1).

In a non-GLP study (Dow Corning Corporation, 2001) of the metabolism of HMDS in rats, metabolites (abundant in hydroxymethyl groups) of this linear siloxane were found to be structurally different from that obtained for cyclic siloxanes (D4 and D5, which are mainly silanols).

In a non-GLP study (Dow Corning Corporation, 2001) of the metabolism of HMDS in rats, metabolites (abundant in hydroxymethyl groups) of this linear siloxane were found to be structurally different from that obtained for cyclic siloxanes (D4 and D5, which are mainly silanols).