Trimethoxypropylsilane

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

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 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.
- 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.

Reference 2

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

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Non-radiolabelled test item dosing formulations (v/v) were homogenized to visually acceptable levels at appropriate concentrations to meet dose level requirements. The dosing formulations were prepared daily and dosed within 6 hours after adding the vehicle to the test item, in this period the formulation was considered stable as communicated by the sponsor responsible for the test item. Test item dosing formulations were kept at room temperature until dosing. If practically possible, the dosing formulations and vehicle were continuously stirred until and during dosing. Adjustment was made for specific gravity of the vehicle and test item where applicable. No correction was made for the purity/composition of the test item.
The radiolabeled formulation (v/v) was prepared by first preparing a radiolabeled stock solution (containing approximately 60 to 70 MBq/mL in corn oil) and a stock solution of 500 mg/mL of the unlabeled compound in 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.

Preliminary studies:

Investigation of the pharmacokinetics of Diethoxy(dimethyl)silane after a single oral gavage administration to male and female Wistar Han rats. 2 males and 2 female rats received a single dose (1000 mg/kg bw) of Diethoxy(dimethyl)silane. The following parameters and endpoints were evaluated in this study: clinical signs, body weights and pharmacokinetic parameters.
No treatment-related clinical signs were noted. After oral administration of 1000 mg/kg bw Diethoxy(dimethyl)silane, the blood concentration increased rapidly. Most measured concentrations were above the ULOQ (=1000 ng/mL). The extrapolated peak plasma concentration, Cmax, on average 7420 ng/mL in males and 23500 ng/mL in females, was reached at 0.5 hour after dosing, which was the first blood collection time point. Tlast ranged between 4 to 6 hours after dosing. Approximately a 4-fold higher exposure to Diethoxy(dimethyl)silane was noted in females compared with males. After absorption, Diethoxy(dimethyl)silane was rapidly eliminated with an individual half-life ranging between 1.06 to 1.27 hours for males and females.
In conclusion, administration of Diethoxy(dimethyl)silane at a single oral gavage dose of 1000 mg/kg bw in a corn oil vehicle was well tolerated in Wistar male and femae rats. Diethoxy(dimethyl)silane was quickly absorbed and rapidly eliminated. In addition, a revalidation of the bioanalytical method is necessary before the conduct of the main study to broaden the concentration range.

Type:

clearance

Results:

terminal half-lives ranged from 0.6 to 1.3 hours in males and 0.6 to 1.5 hours in premated females, and between 0.7 to 1.3 hours in pregnant females on GD18

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 bw/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 bw/day. Values were compared to the preceding dose. 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 bw/day, from 600 to 1000 mg/kg bw/day the increase in exposure was slightly less than dose proportional. Over the widest dose range of 100 to 1000 mg/kg bw/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 bw/day. In pregnant females a more than dose-proportional increase in terms of Cmax and AUC, was noted from 100 to 300 mg/kg bw/day and from 300 to 1000 mg/kg bw/day a more or less dose-proportional increase was noted. Over the widest dose range of 100 to 1000 mg/kg bw/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 bw/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

No studies are available. Based on molecular structure, molecular weight, water solubility, and octanol-water partition coefficient it can be expected that the submission substance is likely to be absorbed via the oral, dermal, and inhalation routes. Hydrolysis occurs rapidly, and systemic exposure is expected to both the parent substance and the hydrolysis product. Based on the water solubility, the registered substance and its silanol-containing hydrolysis product are likely to be distributed in the body, and excretion via the renal pathway can be expected. Bioaccumulation is not expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no measured data on the toxicokinetics of trimethoxy(propyl)silane (CAS 1067-25-0).

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 below). The data have been used in algorithms that 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(propyl)silane or its hydrolysis product, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

Trimethoxy(propyl)silane hydrolyses in contact with water (half-life of 2.6 h at pH 7 and at 20-25°C (QSAR)), generating propylsilanetriol and methanol. Direct exposure of workers and the general population to the parent substance or its hydrolysis products might occur via 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: Physicochemical properties

Physicochemical properties	Trimethoxy(propyl)silane	Propylsilanetriol
Water solubility	9200 mg/L at 25°C (QSAR)	1E+06 mg/L at 25°C (QSAR)
Vapour pressure	1.9 kPa at 25°C (OECD 104)	0.285 Pa at 25°C (QSAR)
Log Kow	1.7 at 20°C (QSAR)	-1.4 at 20°C (QSAR)
Molecular weight (g/mol)	164.27	122.1
Half-life	2.6 h at pH 7, 0.2 h at pH 4, 0.3 h at pH 5 and 0.1 h at pH 9. at 20-25°C (QSAR)

 

Absorption

Oral

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. Generally, the smaller the molecule the more easily it may be taken up. Molecular weights below 500 are favourable for absorption. 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 (ECHA, 2017).

If oral exposure to parent did occur, the physicochemical properties of trimethoxy(propyl)silane (M.W. 164.27 g/mol, log Kow 1.7 and water solubility of 9200 mg/L) are 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 very rapidly into the hydrolysis product propylsilanetriol within 5 seconds at the temperature of 37.5°C. This suggests that absorption mainly of the hydrolysis product will occur. The hydrolysis product propylsilanetriol has a favourable molecular weight and water solubility value for absorption so systemic exposure would be very likely. The predicted water solubility of the hydrolysis product (1E+06 mg/L) suggests that propylsilanetriol will readily dissolve in the gastrointestinal fluids. Also, the low molecular weight (≤ 200 g/mol) of the hydrolysis product suggests it will have the potential to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water.

No repeated dose toxicity data is available for trimethoxy(propyl)silane, however, in the available acute oral toxicity studies (ASTA Pharma, 1988 and INBIFO, 1979a) narcosis was observed, as well as mortality, indicating that systemic exposure to either the parent or hydrolysis product occurred.

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

In a toxicokinetic test (Charles River, 2017), diethoxy(dimethyl)silane (CAS 78-62-6) was administered repeatedly by oral gavage between 100 and 1000 mg/kg bw to male and female as well as pregnant rats (3/sex). Blood samples were collected at 0.5, 1, 2, 4, 6 and 24 hours after dosing on Day 29 for males, premating for females and on gestation day 18 for females. The peak plasma concentration was reached rapidly, at the first blood collection point, just half an hour after dosing. A dose proportional increase in exposure, in terms of Cmax and AUClast, was generally noted over the used dose range of 100 to 1000 mg/kg/day in both males and females (pre-mated and pregnant (GD18)). 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.

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, 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 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.

The high water solubility of 9200 mg/L, log Kow of 1.7 and molecular weight of 164.27 g/mol of the parent substance suggest that absorption is moderate to high. For the hydrolysis product propylsilanetriol the high water solubility of 1E+06 mg/L and log Kow value of -1.4 indicate that the substance may be to hydrophilic to cross the lipid rich environment of the stratum corneum. QSAR based dermal permeability prediction (DERMWIN V2.02.2012) using molecular weight, log Kow and water solubility, calculated a dermal penetration rate of 23.2 µg/cm²/h for trimethoxy(propyl)silane and 37.9 µg/cm²/h for propylsilanetriol, respectively. This shows that dermal penetration of both the parent substance and the hydrolysis product will be high.

 

Inhalation

The vapour pressure of the parent substance (1.9 kPa) indicates that this substance has a moderate volatility, and therefore inhalation as a vapour may occur. The very hydrophilic nature of the hydrolysis product suggest that it may be retained more efficiently within the mucus compared to the parent substance. The moderate log Kow (between -1 and 4) of the parent substance indicates that absorption directly across the respiratory tract epithelium by passive diffusion is possible.

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 20-25 °C and pH 7 (relevant for lungs and blood) is 2.6 h. This prediction is based on a validated QSAR estimation 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 uncatalysed 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(propyl)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(propyl)silane predicts a blood: air partition coefficient of approximately 30:1 meaning that, high levels of systemic exposure are expected, therefore, if lung exposure occurs the majority of parent substance available would be absorbed. However, hydrolysis is expected. For the hydrolysis product, (propylsilanetriol), the predicted blood: air partition coefficient is approximately 1.5E+07:1 meaning that systemic exposure is even much 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(propyl)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 expected to be present in the mucous lining following inhalation of trimethoxy(propyl)silane, from which there is potential for passive absorption.

In an acute inhalation toxicity study in rats, animals were exposed to vapours of the test item via whole body exposure at a concentration of 22.2 g/m³ for one single period of 4 hours. Shortly after the beginning of exposure, restlessness started and irregular breathing was observed, followed by signs of narcosis, and deep and irregular breathing. Three rats died during or after exposure (two males and one female). No abnormalities were observed at necropsy in the animals that survived to scheduled sacrifice at the end of the observation period. In the animals which died during or after exposure, dark-red discoloured, occasionally spotted and swollen, lungs were found. The clinical signs and mortality observed in the study support the conclusion that the test substance was absorbed following inhalation exposure.

 

Distribution

The low molecular weight (122.1 g/mol) and very high water solubility (1E+06 mg/L) of propylsilanetriol suggest that it will have the potential to diffuse through aqueous channels, pores and will be widely distributed; however, the log Kow of -1.4 indicates it is unlikely to be distributed into cells. Therefore, the extracellular concentration will be higher than the intracellular concentration.

The low molecular weight (164.27) and moderate-high water solubility (9200 mg/L) of trimethoxy(propyl)silane suggests that it will have the potential to diffuse through aqueous channels, pores and will be widely distributed. The log Kow (1.7) suggests that the parent is likely to distribute into cells and so the intracellular concentration may be higher than extracellular concentration. 

For both the parent and hydrolysis product, the water solubility (moderate-high and high, respectively) and log Kow (moderate and low, respectively) suggest that accumulation in the body is not favourable.

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(propyl)silane (log Kow = 1.7) predicts that, should systemic exposure occur, distribution would primarily be into fat, with potential distribution into liver, muscle, brain and kidney but to a lesser extent. For the hydrolysis products, distribution into the main body compartments is predicted to be minimal.

Table: Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
Trimethoxy(propyl)silane	1.7	50.12	1.8	1.4	32.3	1.5	1.2
Propylsilanetriol	-1.4	0.04	0.6	0.7	-0.1	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(propyl)silane is not expected to accumulate in any organ or tissue. 

 

Metabolism

Trimethoxy(propyl)silane is a moisture-sensitive liquid that hydrolyses in contact with water (estimated half-life of 2.6 h at pH 7 and 25°C), generating methanol and propylsilanetriol. There is no data on the metabolism of trimethoxy(propyl)silane. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation.

Trimethoxy(propyl)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, 2013).

No significant biodegradation of the hydrolysis product propylsilanetriol is expected. 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

The low molecular weight (below 300 g/mol) and moderate-high and high water solubility of the parent and hydrolysis product, respectively suggest that they are likely to be excreted by the kidneys into urine.

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(propyl)silane in blood is approximately 75% and of propylsilanetriol is approximately 100%. Therefore, these figures suggest that the hydrolysis product is likely to be effectively eliminated via the kidneys in urine but the parent substance would be predicted to be eliminated from the body to a slightly lesser extent via the kidneys.

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 (2018), the maximum plasma concentration of diethoxy(dimethyl)silane was reached rapidly. 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.

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

ECHA (2017). Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.7c: Endpoint specific guidance. Version 3.0. June 2017                                                  

DeJongh, J., H.J. Verhaar, and J.L. Hermens, A quantitative property-property relationship (QPPR) approach to estimate in vitro tissue-blood partition coefficients of organic chemicals in rats and humans. Arch Toxicol, 1997.72(1): p. 17-25.

Jayaraman, S.; Song, Y.; Vetrivel, L.; Shankar, L. & Verkman, A. Noninvasive in vivo fluorescence measurement of airway-surface liquid depth, salt concentration, and pH Journal of Clinical Investigation, American Society for Clinical Investigation, 2000, 107, 317-324.

Meulenberg, C.J. and H.P. Vijverberg, Empirical relations predicting human and rat tissue:air partition coefficients of volatile organic compounds. Toxicol Appl Pharmacol, 2000. 165(3): p. 206-16.

PFA, 2013, Peter Fisk Associates, Biodegradation Main Analogue Group report, PFA.300.005.007