Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
05.11.2005 to 24.11.2008
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
It was not compliant with GLP.

Data source

Reference Type:
study report
Report Date:

Materials and methods

Objective of study:
Test guideline
equivalent or similar to
OECD Guideline 417 (Toxicokinetics)
GLP compliance:
not specified

Test material


Test animals

Fischer 344
Details on test animals and environmental conditions:
- 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

- 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

Administration / exposure

Route of administration:
inhalation: vapour
unchanged (no vehicle)
Details on exposure:

- 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
Doses / concentrations
Dose / conc.:
5 000 ppm
Doses / Concentrations:
Average of actual concs: 4953±44 ppm
No. of animals per sex per dose:
Various (see Table 1)
Control animals:
Positive control:
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.
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.

Results and discussion

Main ADME resultsopen allclose all
Not calculated
Parent and metabolites were observed in the brain, kidney, liver and lung.
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%).
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.

Toxicokinetic / pharmacokinetic studies

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.

Metabolite characterisation studies

Metabolites identified:
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%).

Applicant's summary and conclusion

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) .