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Toxicological information

Basic toxicokinetics

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Administrative data

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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Version / remarks:
July 22 2010
Deviations:
no
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
Diethoxy(dimethyl)silane
EC Number:
201-127-6
EC Name:
Diethoxy(dimethyl)silane
Cas Number:
78-62-6
Molecular formula:
C6H16O2Si
IUPAC Name:
Diethoxy(dimethyl)silane
Test material form:
liquid
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

Test animals

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

Administration / exposure

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
Doses / concentrationsopen allclose all
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.

Results and discussion

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.
Main ADME results
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

Toxicokinetic / pharmacokinetic studies

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

Metabolite characterisation studies

Metabolites identified:
not measured

Applicant's summary and conclusion