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Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key 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:
OECD Guideline 417 (Toxicokinetics)
Version / remarks:
July 22 2010
Deviations:
no
GLP compliance:
yes (incl. certificate)
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 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:
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

The toxicokinetic behaviour assessment of the substance and its hydrolysis product was assessed by its physico-chemical properties. Diethoxy(dimehtyl)silane hydrolyses rapidly in contact with water, generating ethanol and dimethylsilanediol. Based on molecular structure, molecular weight, water solibility, and octanol-water partition coefficient it can be expected that the hydrolysis product is likely to be absorbed via the oral, inhalation and dermal routes. Based on the water solubility, the registered substance and its silanol-containig 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

The toxicokinetic behaviour assessment of diethoxy(dimethyl)silane (78-62-6) and its silicon-containing hydrolysis product dimethylsilanediol was assessed by its physico-chemical properties, the available toxicology studies on the substance itself and the read-across substances dimethoxydimethylsilane (CAS 1112-39-6), trimethoxy(methyl)silane (CAS 1185-55-3) and triethoxy(methyl)silane (CAS 2031-67-6).

 

Diethoxy(dimethyl)silane hydrolyses rapidly in contact with water (half-life 5.5 hours at pH 7 and 25°C), generating ethanol and dimethylsilanediol. This, therefore, suggests that systemic exposure of the parent substance, dimethoxydimethylsilane as well as the hydrolysis product, dimethylsilanediol, is also likely. Therefore, this toxicokinetic behaviour assessment will try to predict the behaviour of both these substances. The toxicokinetics of ethanol is discussed elsewhere and is not included in this summary. 

 

The molecular weight and the predicted water solubility of diethoxy(dimethyl)silane are148.3 g/mol and 957 mg/L, respectively. In contrast, the molecular weight and predicted water solubility of the hydrolysis product, dimethylsilanediol, are 92.169 g/mol and 1E+6 mg/L, respectively. This shows that the hydrolysis product is smaller in size and is more water soluble and, thereby, suggests that it will have the higher potential to be absorbed through biological membranes than the parent substance. Also, the predicted log Kowof 3.0 for the parent substance and -0.4 for the hydrolysis product indicates that both substances are lipophilic enough to pass through biological membranes efficiently.

 

Absorption

 

Oral: The predicted water solubility of the parent (957 mg/L) and the hydrolysis product (1E+6 mg/L) suggests that both substances will readily dissolve in the gastrointestinal fluids. Also, the low molecular weight (≤ 148.3 g/mol) of the substances suggests they will have the potential to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. Furthermore, the moderate log Kowof 3.0 for the parent and -0.4 for the hydrolysis product suggest that they are likely to be absorbed by passive diffusion.

In the acute oral study conducted with the registered substance mortality and systemic effects in rats at 13840 mg/kg bw were seen (Chemical hygiene fellowship, 1979). Furthermore, in the oral repeated dose toxicity study with the registered substance mortality and evidence of systemic toxicity were observed at the highest tested concentration of 1000 mg/kg bw (Eurofins, 2018), therefore showing that absorption via the oral route is possible. Moreover, the assumption that the registered substance can be absorbed by the oral route was further confirmed by the findings in the available toxicokinetic study after repeated oral gavage of diethoxy(dimethyl)silane in Wistar rats (Charles river laboratories, 2018).After oral administration of [methyl-14C] diethoxy(dimethyl)silane, the blood concentration of total radioactivity increased rapidly. The peak blood concentration, Cmax, was reached at 0.5 to 2 hours after dosing. For all groups tlastwas 24 hours, as this was the time point on which the last sample was taken. A dose proportional increase in exposure, in terms of Cmaxand 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)). There was no general difference noted in exposure to males and females (pre-mated and pregnant (GD18).

 

 

If ingestion occurs, the hydrolysis of the parent substance in the low pH of the stomach will be rapid, so any absorption of the parent substance is expected to be minimal and it is more likely to be the hydrolysis product dimethylsilanediol that is absorbed.

 

 

Inhalation:The medium fugacity of the registered substance (890 Pa) indicates that inhalation as a vapour could be possible. The water solubility, log Kow value and low molecular weight of the parent and hydrolysis product, suggests that absorption from the respiratory tract epithelium by passive diffusion is likely for both substances.

 

In the non-reliable acute inhalation (vapour) study with the registered substance, there were mortalities and systemic toxicity observed (Chemical hygiene fellowship, 1979).

Furthermore, a sub-chronic inhalation toxicity study with the source substance trimethoxy(methyl)silane (CAS 1185-55-3) showed evidence of systemic toxicity at doses ≥560 mg/m³, therefore indicating that absorption via the inhalation route is possible for the registered substance.

Dermal:The moderate water solubility (857 mg/L), log Kow (3.0) and low molecular weight (148.3 g/mol) of the parent substance indicates that absorption by the dermal route is possible. For the hydrolysis product, dimethylsilanediol, the moderate water solubility (1E+6 mg/L), log Kow (-0.4) and low molecular weight (92.169 g/mol) suggest that absorption by the dermal route will be potentially higher than the parent molecule due to the lower molecular weight. QSAR based dermal permeability prediction (DERMWIN V2.00.2009) using molecular weight, log Kowand water solubility, calculated a dermal penetration rate of 0.0192 mg/cm²/h for diethoxy(dimethyl)silane and 0.263 mg/cm²/h for dimethylsilanediol, respectively. This suggests that dermal penetration of the parent substance and silicon-containing hydrolysis product will be high and confirms that the hydrolysis product will have a higher dermal penetration potential than the parent substance.

Distribution

The low molecular weight, moderate and high water solubility of the parent and hydrolysis product, respectively, suggest they will both have the potential to diffuse through aqueous channels, pores and will be widely distributed; however, the log Kowof -0.4 for dimethylsilanediol indicates it is unlikely to be distributed into cells. Therefore, the extracellular concentration will be higher than the intracellular concentration. Conversely, the log Kow (3.0) of the parent product suggests it is lipophilic enough to distribute into cells and therefore the intracellular concentration will be higher than the extracellular concentration. The high water solubility and the moderate log Kowof both the parent and hydrolysis product suggest that accumulation in the body is not likely for both substances.

Metabolism

Since diethoxy(dimethyl)silane hydrolyses rapidly, the absorbed test substance is more likely to be in the form of the hydrolysis product dimethylsilanediol than the parent substance. There are no data regarding the metabolism of dimethylsilanediol.

Excretion

The low molecular weight and good water solubility of the parent and hydrolysis product suggest that they are likely to be excreted by the kidneys into urine.