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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
14 May 2008 to 20 June 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Objective of study:
toxicokinetics
Qualifier:
according to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Version / remarks:
1984
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Specific details on test material used for the study:
RADIOLABELLING INFORMATION (if applicable)
- Radiochemical purity: 94.8%
- Specific activity: 0.07 MBq/mg
- Locations of the label: not specified
- Expiration date of radiochemical substance: not specified

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature, moisture and light protected under nitrogen.
- Stability under test conditions: Stability of the test item in the application solution was demonstrated by HPLC (Figure 1). The radio-purity of the test item in the formulation was found to be 99.78% after application.
- Solubility and stability of the test substance in the solvent/vehicle: not applicable
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: not applicable

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: On the day of administration, the administration solution was prepared. For administration at the target dose level of 2000 mg/kg, an aliquot of 300 mg of the radiolabelled test item, an aliquot of 2700 mg of the non-labelled test item and 12 mL corn oil were mixed to give a target concentration of 2000 mg/kg/10 mL.
- Preliminary purification step (if any): none
- Final dilution of a dissolved solid, stock liquid or gel: not applicable
- Final preparation of a solid: not applicable

Radiolabelling:
yes
Species:
mouse
Strain:
NMRI
Details on species / strain selection:
Recognized by international guidelines as an acceptable animal model for physiological, pharmacological, or toxicological studies.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Netherlands
- Age at study initiation: 8 weeks
- Weight at study initiation: 31 g ± 2.1 in males and 24 g ± 1.4 in females
- Housing: During acclimatisation in groups of 7/8 in macrolon type 3 cages. During the experiment. Group of 3 animals in metabolism cages with wire floor, 1 day prior to the treatment and during the experiment.
- Diet (e.g. ad libitum): Pelleted 3433 Kliba standard diet ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: 7 days to laboratory environment, including 1 day in metabolism cages

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30.0 - 70.0%
- Air changes (per hr): 10-15 times/hour
- Photoperiod (hrs dark / hrs light): 12 hours fluorescent light / 12 hours dark
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: On the day of administration, the administration solution was prepared. For administration at the target dose level of 2000 mg/kg, an aliquot of 300 mg of the radiolabeled test item, an aliquot of 2700 mg of the non-labeled test item and 12 mL corn oil were mixed to give a target concentration of 2000 mg/kg/10 mL. The exact amount of radioactivity in the application solution was determined by Liquid Scinitillation Counting (LSC) resulting in 21.5 MBq, equivalent to 308 mg of undiluted 14C-Silan 449029 VP. The total amount of diluted 14C-Silan 449029 VP was 3008 mg, resulting in a new specific activity of 0.0072 MBq/mg. The concentration of Silan 449029 VP (= Silan 449029 VP & 14C-Silan 449029 VP) in the formulation was 200.5 mg/mL.

Duration and frequency of treatment / exposure:
single oral administration
Dose / conc.:
2 000 mg/kg bw/day (nominal)
Remarks:
single oral administration of 14C-Silan 449029 VP
Dose / conc.:
0.007 other: MBq/mg
Remarks:
target specific radioactivity
Dose / conc.:
10 other: mL/kg
Remarks:
target administration volume
No. of animals per sex per dose / concentration:
12 male and 12 female
Control animals:
no
Positive control reference chemical:
Not used
Details on study design:
- Dose selection rationale: The current study supports a micronucleus study in bone marrow cells, where mice have been exposed through the oral route. A dose level of 2000 mg/kg was chosen, the same dose as the highest concentration in the micronucleus test.
- Rationale for animal assignment (if not random): random
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, plasma, serum, femur, stomach, large intestine, small intestine, GI tract contents, liver and kidney
- Time and frequency of sampling: Three male and three female animals each were sacrificed one and four hours after test item administration, and terminal blood, femur, stomach, combined GI tract contents, small intestine, large intestine, liver and kidney were isolated. At 24 h after test item administration the rest of the animals were sacrificed and terminal blood, femur, stomach, small intestine, large intestine, combined GI tract contents, liver, kidney as well as urine and faeces were isolated.

Type:
excretion
Results:
At the end of the 24 hours time period, 24.9% and 17.4% of the applied dose was detected in urine, 3.4% and 9.8% of the applied dose in cage wash of male and female mice, respectively.
Type:
absorption
Results:
At the end of the 24 hours time period, the systemic absorption (bioavailability) for Silan 449029 VP was at least 28.3% in male mice and 27.2% in female mice.
Type:
excretion
Results:
At the end of the 24 hours time period, a total of 63.8% and 64.2% of the applied dose was excreted via faeces in male and female mice, respectively.
Details on absorption:
At the end of the 24 hours time period, the systemic absorption (bioavailability) for Silan 449029 VP was at least 28.3% in male mice and 27.2% in female mice. Overall significant mean levels of the test item were found in blood and plasma as early as 1 hour after application. This indicates that after oral administration the test item was rapidly absorbed in significant amounts.
Details on distribution in tissues:
One hour after application the mean total radioactive residue concentrations in male and female mice were found to be between 70.0 – 74.6 µgeq/g in blood, 72.7 – 78.2 µgeq/g in plasma, 42.4 – 48.9 µgeq/g in femur, 5512.9 – 9183.3. µgeq/g in stomach, 2867.6 – 3180.5 µgeq/g in small intestine, 1221.5 – 1328.9 µgeq/g in large intestine, 8480.0 – 23815.0 µgeq/g in GI tract contents, 177.0 – 179.2 µgeq/g in liver and 332.8 – 481.3 µgeq/g in kidney.
4 hours after application in stomach (6090.4 - 12986 µgeq/g), in small intestine (2211.9 – 4543.4 µgeq/g), in large intestine (1524.0 – 3170.4 µgeq/g) and in combined GI tract contents (28315.7 – 30171.4 µgeq/g). In blood (42.4 – 48.3 µgeq/g), in plasma (45.4 – 50.6 µgeq/g), in kidney (193.4 – 262.3 µgeq/g) and in liver (127.8 – 145.9 µgeq/g) a decrease in mean radioactive residue concentration was observed. In femur (32.5 – 49.2 µgeq/g) similar or slightly lower mean radioactive residue concentrations were observed.
24 hours after application only minor mean radioactive residue concentrations were left in stomach (30.9 – 47.1 µgeq/g), small intestine (16.3 – 22.4 µgeq/g), large intestine (17.1 – 21.0 µgeq/g) and combined GI tract contents (11.1 – 29.1 µgeq/g) compared to the 1 and 4 hours sampling time points. The same was true for blood (3.7 µgeq/g), plasma (4.7 – 4.9 µgeq/g) and femur (7.3 – 8.4 µgeq/g).
Key result
Test no.:
#1
Toxicokinetic parameters:
Cmax:
Remarks:
Males: 70.0 ± 11.2 µgeq/g (blood), 72.7 ± 12.9 µgeq/g (plasma), 49.2 ± 12.7 µgeq/g (femur), 179.2 ± 40.1 µgeq/g (liver), and 481.3 ± 340.4 µgeq/g (kidney). Females: 74.6 ± 12.3 µgeq/g, 78.2 ± 11.9 µgeq/g, 177 ± 36.3 µgeq/g and 332.8 ± 98.7 µgeq/g,
Key result
Test no.:
#1
Toxicokinetic parameters:
Cmax:
Remarks:
Males: 12986.0 ± 7940.9 (stomach), 4543.4 ± 1710.2 (small intestine), 1524.0 ± 1311.7 (large intestine) and 30171.4 ± 4649.0 µgeq/g (GI tract) Females: 9183.3 ± 3435.5, 2867.6 ± 503.0, 3170.4 ± 1792.8 and 28315.7 ± 1552.2 µgeq/g.
Metabolites identified:
no
Conclusions:
Overall significant mean levels of the test item were found in blood and plasma as early as 1 hour after application. This indicates that after oral administration the test item was rapidly absorbed in significant amounts.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
13 July 2017 to 20 Oct 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Objective of study:
toxicokinetics
Qualifier:
according to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Version / remarks:
July 22 2010
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Specific details on test material used for the study:
RADIOLABELLING INFORMATION
- Radiochemical purity: 95.3%
- Specific activity: 325.6 MBq/mmol (8.8 mCi/mmol)
Radiolabelling:
yes
Species:
rat
Strain:
other: Crl:WI (Han)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: males: 10 weeks, females: 10 weeks
- Weight at study initiation: males: 273 - 291 g, females: 170 - 227 g
- Housing: on arrival, pre-mating period: up to 3 animals of the same sex and same dosing group in plolycarbonated cages (Macrolon, MIV type, height 18 cm); during the mating phase, males and females were cohabitated on a 1:1 basis in Macrolon plastic cages (MIII type, height 18 cm); during the post-mating phase, males were housed in their home cage (Macrolon plastic cages, MIV type, height 18 cm) with a maximum of 3 males/cage; females were individually housed in Macrolon plastic cages (MIII type, height 18 cm); following radioactive dose administration animals were housed individually in Macrolon cages (type MII)
- Diet: pelleted rodent diet ad libitum
- Water: municipal tap water ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 22
- Humidity (%): 45 - 72
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Duration and frequency of treatment / exposure:
males: 29 days
females: 15 days prior mating up to day 18 post-coitum
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
600 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose / concentration:
control: 2 males, 4 females
all dosing groups: 3 males, 6 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The oral route of exposure and dose levels were selected based on the earlier conducted OECD 422 range finder study. In order to investigate non-linearity and derive a kinetically derived maximum dose (KMD) for Diethoxy(dimethyl)silane in male and female Wistar rats 4 dose levels were selected with the highest dose at 1000 mg/kg/day.
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption)
- Tissues and body fluids sampled: blood, plasma, serum
- Time and frequency of sampling: 0.5, 1, 2, 4 and 24 hours on Day 29 for males, on premating for females and on GD18 for females

Furthermore, throughout the study, animals were observed for general health/mortality and moribundity twice daily, in the morning and at the end of the working day. Clinical observations were performed once daily, beginning during the first administration of the test item and lasting throughout the dosing periods up to the day prior to necropsy. Animals were weighed individually on the first day of treatment (prior to dosing), and weekly thereafter. Mated females were weighed on Days 0, 4, 7, 11, 14, 17, and 18 post-coitum. After 15 days of treatment, animals were cohabitated on a 1:1 basis within the same treatment group, avoiding sibling mating. Detection of mating was confirmed by evidence of sperm in the vaginal lavage or by the appearance of an intravaginal copulatory plug. This day was designated Day 0 post-coitum. Once mating had occurred, the males and females were separated.
For one couple (Male No. 13, Female No. 43), detection of mating was not confirmed in first instance. As sperm cells were detected in the vaginal lavage during the oestrous cycle examination, which was performed 1 day later, this couple was separated 1 day after the actual mating date. The actual mating date was designated Day 0 post-coitum. From the mating period onwards, the following parameters were recorded for each female: male number paired with, mating date and confirmation of pregnancy.
Cage debris of pregnant females was examined for evidence of premature delivery and pregnant females were examined to detect signs of difficult or prolonged parturition.



Statistics:
Descriptive statistics (means and standard error) were generated using Phoenix WinNonlin. PK table and graphs were also generated by Phoenix WinNonlin.
Details on absorption:
Blood concentration and Pharmacokinetics of total radioactivity:
The t1/2 value could not be calculated in all groups at all occasions, because no log linear regression was possible (Cmax was always one of the three last points). The variability per group in the TK parameters, evaluated by %CV was low.
The blood concentrations of total radioactivity increased slowly. The peak blood concentration, Cmax, was reached at 2 to 4 hours after dosing. For all groups t(last) was 24 hours, as this was the time point on which the last sample was taken.
Dose effect was evaluated by comparing the exposure parameters, Cmax and AUC, at doses of 100 to 1000 mg/kg/day. Values were compared to the preceding dose. A dose proportional increase in exposure, in terms of Cmax and AUClast, was noted over the used dose range of 100 to 1000 mg/kg bw/day in both males and females (pre-mated and pregnant (GD18)).
After repeated administration the exposure, in terms of Cmax and AUC, was comparable in males, pre-mated and pregnant (GD18) females.

Blood concentration and Pharmacokinetics of parent compound:
After oral administration of Diethoxy(dimethyl)silane, the plasma concentration increased rapidly. The peak plasma concentration, Cmax, was generally reached at 0.5 hour after dosing, the first blood collection time point, and ranged between 0.5 to 2 hours after dosing. t(last) was 4 hours after dosing, the time when the last blood sample was taken, except for 2 animals (numbers 30 and 41) where t(last) was 2 hours after dosing because no sample could be collected at 4 hours. After absorption Diethoxy(dimethyl)silane was rapidly eliminated with individual apparent terminal half-lives ranging between 0.6 to 1.0 hours in males, 0.6 to 1.5 hours in pre-mated females and between 0.7 to 1.3 hours in pregnant females on GD18.
Dose effect was evaluated by comparing the exposure parameters, Cmax and AUC, at doses of 100 to 1000 mg/kg/day. Values were compared to the preceding dose, see Figure 18. In males a dose proportional increase in exposure, in terms of Cmax and AUClast, was noted over the dose range of 100 to 600 mg/kg/day, from 600 to 1000 mg/kg/day the increase in exposure was slightly less than dose proportional. Over the widest dose range of 100 to 1000 mg/kg/day Diethoxy(dimethyl)silane a less than dose-proportional increase was noted. In pre-mated females a more than dose-proportional increase, in terms of Cmax and AUC, was noted from 100 to 1000 mg/kg/day. In pregnant females a more than dose-proportional increase in terms of Cmax and AUC, was noted from 100 to 300 mg/kg/day and from 300 to 1000 mg/kg/day a more or less dose-proportional increase was noted. Over the widest dose range of 100 to 1000 mg/kg/day Diethoxy(dimethyl)silane a more than dose-proportional increase was noted.
After repeated administration a lower exposure, in terms of Cmax and AUC, was noted in males compared with pre-mated and pregnant (GD18) females, except at the lowest dose level (100 mg/kg/day) where the exposure was similar between males and females.
Details on distribution in tissues:
no determined
Details on excretion:
not determined
Metabolites identified:
not measured

Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

There are no measured data on the toxicokinetics of trimethoxy(vinyl)silane.

 

The following summary has therefore been prepared based on the predicted and measured physicochemical properties of the registered substance and its hydrolysis product (see Table 5.1.2 below). The data have been used in algorithms which are the basis of many physiologically based pharmacokinetic and toxicokinetic (PBTK) prediction models. Although these algorithms provide quantitative outputs, for the purposes of this summary only qualitative statements or predictions will be made because of the remaining uncertainties that are characteristic of prediction models.

The main input variable for the majority of the algorithms is the log Kow. By using this and, where appropriate, other known or predicted physicochemical properties of trimethoxy(vinyl)silane or its hydrolysis product, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

Trimethoxy(vinyl)silane hydrolyses very rapidly in contact with water (half-life approximately 0.1 hours at pH 7 and at 20-25°C), generating vinylsilanetriol and methanol. Direct exposure of workers and the general population to the parent substance or its hydrolysis products might occur via the inhalation and dermal routes. Exposure of the general population via the environment might occur via the oral route but would be limited to the hydrolysis product due to the very rapid hydrolysis.

The toxicokinetics of methanol have been reviewed in other major reviews and are not considered further here.

Table 5.1.2: Physicochemical properties

Physicochemical properties

Trimethoxy(vinyl)silane

 

Vinylsilanetriol

 

Water solubility

not relevant due to very rapid hydrolysis in contact with water

1.0E+06 mg/L (QSAR)

Vapour pressure

640 Pa at 10°C, 1190 Pa at 20°C and 6000 Pa at 50°C (EU Method A.4)

0.017 Pa at 25°C (QSAR)

Log Kow

not relevant due to very rapid hydrolysis in contact with water

-2.0 at 20°C (QSAR)

Molecular weight (g/mol)

148.24

106.15

Half-life

0.1 hour at pH 7 and at 20-25°C

N/A

 

Absorption

Oral

Direct oral exposure is not expected for this substance. However, oral exposure to the hydrolysis product is potentially possible via the environment.

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 can 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 g/mol) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water (Renwick, 1993).

Therefore, if oral exposure to parent did occur, molecular weight of trimethoxy(vinyl)silane (148.24 g/mol) is in the favourable range and would favour absorption, so systemic exposure by this route is likely. At pH 2 in the stomach, the parent compound is predicted to hydrolyse into the hydrolysis product vinylsilanetriol within 5 seconds at the temperature of 37.5°C. Vinylsilanetriol has a favourable molecular weight and water solubility values for absorption so systemic exposure to this would also be likely.

Signs of systemic toxicity were evident in the acute toxicity (Bushy Run Research Center, 1984) and repeat dose toxicity (Hashima Laboratories, 2005) oral studies, which indicates systemic exposure to either the parent or hydrolysis product.

There are supporting toxicokinetic data on two related alkoxysilane substances that show rapid absorption of alkoxysilanes following oral administration.

In the first toxicokinetic test (Charles River, 2017), diethoxy(dimethyl)silane (CAS 78-62-8) was administered as a single oral gavage dose (1000 mg/kg bw) to male and female rats (2/sex). Blood samples were collected at 0.5, 1, 2, 4, 6 and 24 hours after dosing. The peak plasma concentration was reached rapidly, at the first blood collection point, just half an hour after dosing.

In a toxicokinetic test on morpholinotriethoxysilane (CAS 21743-27-1), the radiolabelled test substance was administered by oral gavage to mice (12/sex) as a single dose of 2000 mg/kg bw (Harlan Laboratories, 2009). Three male and three female animals were sacrificed one and four hours after test substance administration, and terminal blood, femur, stomach, combined gastrointestinal (GI) tract contents, small intestine, large intestine, liver and kidney were collected. Terminal blood, femur, stomach, small intestine, large intestine, combined GI tract contents, liver, kidney as well as urine and faeces were collected from the remaining animals 24 hours after administration. Overall significant mean levels of the test item were found in blood and plasma as early as 1 hour after application. This indicates that after oral administration the test item was rapidly absorbed in significant amounts.

 

Dermal

If dermal exposure were to occur, in practice this would be to the parent compound as well as the hydrolysis product.

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

Due to the likely very rapid hydrolysis of the parent substance, trimethoxy(vinyl)silane, on contact with skin, systemic exposure via this route is predicted to be minimal. The hydrolysis product vinylsilanetriol is highly soluble, and the log Kow value (-2.0) indicates it will not be lipophilic enough to cross the stratum corneum and therefore dermal absorption into the blood is unlikely to occur.

The acute dermal toxicity study (Bushy Run Research Center, 1984) showed evidence of systemic toxicity at high doses of parent test substance, implying that dermal absorption of substance-related material had occurred.

Inhalation

The pH of the airway surface liquid has been determined to be in the range 6.7-7 (Jayaraman et al.,2000), without significant inter- or intraspecies variation.

The predicted hydrolysis half-life at 37.5ºC and pH 7 (relevant for lungs and blood) is approximately 2 minutes. This prediction is based on a weight of evidence of data from validated QSAR estimation method and measured data (reliability 4 due to lack of methodology details), and the following principle. As the hydrolysis reaction may be acid or base catalysed, the rate of reaction is expected to be slowest at around pH 7 and increase as the pH is raised or lowered. For an acid-base catalysed reaction in buffered solution, the measured rate constant is a linear combination of terms describing contributions from the uncatalyzed reaction as well as catalysis by hydronium, hydroxide, and general acids or bases.

kobs= k0+ kH3O+[H3O+] + kOH-[OH-] + ka[acid] + kb[base]

This chemical reaction is independent of enzymatic involvement. It is reasonable to assume that the parent and hydrolysis products of trimethoxy(vinyl)silane will be present in the airway surface liquid, without significant variation between individuals.

Proving the hydrolysis rate in the lungs of experimental animals in vivo would present many complicated (possibly insurmountable) technical difficulties, and therefore the presence of parent and hydrolysis product is assumed as a worst-case scenario.

There is a Quantitative Structure-Property Relationship (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 trimethoxy(vinyl)silane predicts a blood: air partition coefficient of approximately 62:1 meaning that, in steady state, approximately 98% of this substance will be in blood and approximately 2% in air, and therefore if lung exposure occurs the majority of parent substance available would be absorbed. However, hydrolysis is expected. For the hydrolysis product, vinylsilanetriol, the predicted blood: air partition coefficient is approximately 5.3 E+08:1 meaning that systemic exposure is even more likely. Again, this prediction is based on physicochemical properties and is not expected to vary between individuals.

It is also important to consider the water solubility of trimethoxy(vinyl)silane and its hydrolysis product with respect to dissolving in the mucous of the respiratory tract. The parent is expected to hydrolyse in the aqueous mucous. The hydrolysis product is highly soluble in water and therefore also expected to be present in the mucous lining following inhalation of trimethoxy(vinyl)silane, from which there is potential for passive absorption.

The key inhalation study on trimethoxy(vinyl)silane (Bushy Run Research Center, 1990) showed adverse systemic effects, specifically involving the kidneys and bladder. These findings are reliable evidence that the test substance was absorbed following inhalation exposure.

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 value for trimethoxy(vinyl)silane (log Kow = 1.1) predicts that, should systemic exposure occur, potential distribution into the main body compartments would be minimal.

Similarly, for the hydrolysis products, distribution into the main body compartments is predicted to be minimal.

Table: 5.1.3 Tissue: blood partition coefficients

 

Log Kow

Kow

Liver

Muscle

Fat

Brain

Kidney

Trimethoxy(vinyl)silane

1.1

12.59

1.0

1.0

9.8

1.1

1.0

 

Vinylsilanetriol

-2.0

0.01

0.6

0.7

0.0

0.7

0.8

 

Additionally, there is a supporting study on a structurally-related substance (morpholinotriethoxysilane, CAS 21743-27-1) which show that there is no bioaccumulation in any organ (Harlan Laboratories, 2009). In this test (described above) mean plasma concentrations declined during the 24 h observation period to approximately 6.8% of the peak value in male mice and to 6.0% of the peak value in female mice. A comparable effect was seen in all tissues analysed. Together with excretion data (described later) these findings provide supporting evidence for the conclusion that trimethoxy(vinyl)silane is not expected to accumulate in any organ or tissue.

 

Metabolism

There are no data on the metabolism of trimethoxy(vinyl)silane. However, it will hydrolyse to form methanol and vinylsilanetriol once absorbed into the body. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation.

Trimethoxy(vinyl)silane is within an analogue group of substances for which, in general, there is no evidence of any significant biodegradation once hydrolysis and subsequent biodegradation of alkoxy/acetoxy groups has been taken into account (PFA, 2013f). In a ready biodegradation study with trimethoxy(vinyl)silane, the biodegradation observed is attributable to the non-silanol hydrolysis product (methanol). Mass-balance calculation has been undertaken to determine the percentage by weight of the parent substance that is associated with the biodegradable by-product. Once the biodegradation of the hydrolysed methoxy- groups is taken into account, there is no evidence of any biodegradation of the silanol hydrolysis product, vinylsilanetriol. This observation is supported by studies with silanols that are structurally similar to vinylsilanetriol. Studies with hydroxytrimethylsilane (CAS 1066-40-6) and dimethylsilanediol (CAS 1066-42-8) show no evidence of biodegradation (Clarke, 2008; Dow Corning Corporation, 1984). It is therefore concluded that the substance and its silanol hydrolysis product are not recognised by biological systems containing all the mammalian enzymes and metabolic systems.

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 of trimethoxy(vinyl)silane in blood is approximately 92%. Similarly, for the hydrolysis product vinylsilanetriol, the figure is >99% meaning that, once absorbed, both the parent substance and hydrolysis product are likely to be eliminated via the kidneys in urine, and accumulation is unlikely.

This prediction is supported by in vivo toxicokinetic data on two related substances (morpholinotriethoxysilane and diethoxy(dimethyl)silane). The details of these tests are described above. With regard to excretion it has been demonstrated that both of these substances are rapidly absorbed, but also rapidly excreted.

In the test conducted by Harlan Laboratories (2009), morpholinotriethoxysilane peak concentration to radioactivity in the blood, plasma, femur, liver and kidney were found after just one hour. However, by 24 hours after administration concentrations had declined to 6-7% of the peak concentrations in plasma and tissues. After 24 hours 24.9% and 17.4% of the applied dose was detected in urine, 3.4% and 9.8% of the applied dose in cage wash of male and female mice, respectively. Also, 63.8% and 64.2% of the applied dose was excreted via faeces in male and female mice, respectively.

In the test conducted by Charles River (2017), the maximum plasma concentration of diethoxy(dimethyl)silane was measured at 1 hour after dosing (the first sampling point). The test substance was also rapidly eliminated with an individual half-life ranging between 1.06 to 1.27 hours for males and females, respectively.

In conclusion, rapid absorption into the blood and fast elimination from the blood via urine was observed with related alkoxysilane substances.

These findings support the hypothesis that after hydrolysis, a water-soluble silanol is formed (supported by log Kow calculation) which is rapidly excreted from the body. Since, this hydrolysis occurs without enzymatic involvement it is appropriate to reduce the intraspecies assessment factor from 5 to 2.2 for workers and from 10 to 3.2 for the general population, by exclusion of the toxicokinetic element of this assessment factor.

 

References: 

                                                          

Charles River (2017) Single Dose Pharmacokinetics of Diethoxy(dimethyl)silane after Oral Administration in Male and Female Wistar Rats (non-GLP) (ReachCentrum/Charles River, 2017) (Single Dose Pre-Study; final study report not yet available).

Clarke, N (2008). Trimethylsilanol (CAS No. 1066-40-6) Assessment of Ready Biodegradability; CO2 in Sealed Vessels (CO2 Headspace Test). Safepharm Laboratories Limited, Shardlow Business Park, Shardlow, Derbyshire, DE72 2GD. Report number: 2581/0002. Report date: 2008-10-14.

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