2,11-Dioxa-3,10-disiladodecane, 3,3,10,10-tetramethoxy-

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2009-10-8 to 2009-11-17

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Test conducted in accordance with generally accepted scientific standards, described in sufficient detail and with GLP, but limited compared to a standard guideline study.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Objective of study:

other: determination of systemic availability

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

This study design was not based on a specific guideline. Its aim was to determine the systemic availability of 1,6- bis(trimethoxysilyl)hexane (test article and/or its derivatives) in rats following a single gavage dose.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Reference substance 001

Cas Number:

87135-01-1

Molecular formula:

C12H30O6Si2

Constituent 2

Reference substance name:

3,3,10,10-tetramethoxy-2,11-dioxa-3,10-disiladodecane

EC Number:

617-969-6

Cas Number:

87135-01-1

Molecular formula:

(CH3O)3Si(CH2)6Si(OCH3)3 C12 H30 O6 Si2

IUPAC Name:

3,3,10,10-tetramethoxy-2,11-dioxa-3,10-disiladodecane

Test material form:

other: liquid

Radiolabelling:

no

Test animals

Species:

rat

Strain:

other: Crl CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: not stated
- Age at study initiation: 8 wk
- Weight at study initiation: 244-272 (m); 169-207 (f)
- Fasting period before study: none reported
- Housing: 2/suspended wire mesh cage
- Individual metabolism cages: yes/no
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.2-21.7
- Humidity (%): 41-63
- Air changes (per hr): 14.5 or 15.6 depending on room
- Photoperiod (hrs dark / hrs light):12 h/12/ h

IN-LIFE DATES: for main study From: 2009-10-19 To: 2009-10-20

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Each dosing solution was prepared individually: 125 mg/ml, 250 mg/ml, 500 mg/ml. Dose volume was 4 ml/kg body weight. Dosing solutions were not analysed.

Storage conditions
The dosing solutions for the definitive study were prepared three days prior to experimental start and stored at room temperature.

HOMOGENEITY AND STABILITY OF TEST MATERIAL: No details.

Duration and frequency of treatment / exposure:

Single gavage dose

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 500, 1000, 2000 mg/kg bw

No. of animals per sex per dose / concentration:

8 (4 each for blood sampling at 2 h and 5 h post-dosing)

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

No

Details on study design:

- Dose selection rationale: none given (possibly based on phase 1 and 2 preliminary studies but no data are given)
- Rationale for animal assignment: after release from quarantine/acclimation, animals were weight stratified by sex then randomized into groups using Provantis™ v8.2. Animals were within ± 20% of the mean body weight for each sex.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled : blood
- Time and frequency of sampling: 2 h and 5 h post-dosing


METABOLITE CHARACTERISATION STUDIES
None

Statistics:

Standard error of means only.

Results and discussion

Preliminary studies:

Phases 1 and 2 were conducted without GLP to refine the analytical approach for the main study (phase 3). Data from these preliminary studies are not included in the report.

Main ADME results

Type:

other: systemic availability

Results:

1,6- bis(trimethoxysilyl)hexane and/or its derivatives were systemically available based on the total silicon content detected in the plasma at 2 h and 5 h post dosing.

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

See table 1.

The report notes: 1,6-Bis(TMS)H is a hydrolytically active alkoxysilane and as such absorption from the gastrointestinal (GI) tract of various derivative molecular species (i.e., hydrolysis products. metabolites, and conjugation products) was possible. In order to more broadly assess systemic availability of the test article following absorption from the GI tract, the total silicon (Si) content in plasma was determined using inductively coupled plasma-optical emission spectroscopy (ICP­ OES) rather than selecting for a specific derivative molecular species. The units were expressed as µg equivalents of 1 ,6-Bis(TMS)H. The limit of quantitation was 4.8 µg equivalents of 1,6- Bis(TMS)H/g plasma.

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

Table 1: Observed silicon concentration ( μg equivalents of 1,6-bis(trimethoxysilyl)hexane per g plasma)

Approximate time after dose administration	Dose level (mg/kg bw)	Males	Females
2h	0	<LOQ	<LOQ
	500	65.3 +/-5.3	35.3 +/-4.4
	1000	113.4 +/-11.3	73.2 +/-13.4
	2000	235.3+/-43.7	130.2 +/-21.4
5h	0	<LOQ	<LOQ
	500	10.8 +/-1.0	15.2 +/-1.6
	1000	24.1 +/-2.8	32.7 -/-2.3
	2000	35.9 +/-3.2	25.6 +/-0.9

LOQ: limit of quantitation – 4.8 μg equivalents of 1,6-bis(trimethoxysilyl)hexane

Reviewer's note: the use of μg equivalents of parent substance may be misleading as the extent of hydrolysis prior to absorption may lead to absorption of hydrolysis product; the μg equivalents of the hydrolysis product 1,6-bis(trihydroxysilyl)hexane would be lower. For example, 100 μg equivalents of 1,6-bis(trimethoxysilyl)hexane would be 74 μg equivalents of 1,6-bis(trihydroxysilyl)hexane.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: not possible to comment based on the data presented
A well reported non-guideline study conducted according to GLP found that single oral doses of the test substance given to male and female rats resulted in the presence of silicon in the blood sampled at 2 and 5 hours after dosing. Blood silicon concentrations were generally higher at 2 h than at 5 h, and higher in males than females. No other toxicokinetic evaluations were made.