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Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Jan - Feb 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2014
Report date:
2014

Materials and methods

Objective of study:
bioaccessibility (or bioavailability)
Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
3-(trimethoxysilyl)propyl (2E,4E)-hexa-2,4-dienoate
EC Number:
642-902-2
Cas Number:
163802-53-7
Molecular formula:
C12H22O5Si
IUPAC Name:
3-(trimethoxysilyl)propyl (2E,4E)-hexa-2,4-dienoate
Constituent 2
Reference substance name:
2,4-Hexadienoic acid, 3-(trimethoxysilyl)propyl ester, (2E,4E)-
IUPAC Name:
2,4-Hexadienoic acid, 3-(trimethoxysilyl)propyl ester, (2E,4E)-
Constituent 3
Reference substance name:
3-(trimethoxysilyl)propyl-(2E,4E)-hexa-2,4-dienoate
IUPAC Name:
3-(trimethoxysilyl)propyl-(2E,4E)-hexa-2,4-dienoate
Test material form:
liquid

Test animals

Species:
rat
Strain:
other: Crl: CD(R) (SD) lGS BR VAF/Plus(R))
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Remarks:
dried and deacidified
Duration and frequency of treatment / exposure:
single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
Test article solutions with nominal concentrations of 100 mg/mL, 200 mg/mL, and 400 mg/mL were prepared. Dose volume was 5 mL/kg body
weight. Dose Levels: 500, 1000 and 2000 mg/kg
No. of animals per sex per dose / concentration:
Phase 1:
2000 mg/kg: 4 animals/sex/dose

Phase 2:
500/1000/2000 mg/kg: 4 animals/sex/dose
Control animals:
yes

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
Cmax: 0mg/kg, Female: N/A, Male: N/A
Test no.:
#1
Toxicokinetic parameters:
Tmax: 0 mg/kg, Female: N/A, Male: N/A
Test no.:
#1
Toxicokinetic parameters:
AUC: 0mg/kg, Female: 175, Male: 237 µg eq. TA* h/g plasma
Test no.:
#2
Toxicokinetic parameters:
Cmax: 500mg/kg, Female: 98.39, Male: 107.66 µg eq. TA/g plasma
Test no.:
#2
Toxicokinetic parameters:
Tmax: 500 mg/kg, Female: 0.5 (h), Male: 0.5 (h)
Test no.:
#2
Toxicokinetic parameters:
AUC: 500 mg/kg, Female: 510, Male: 483 µg eq. TA* h/g plasma
Test no.:
#3
Toxicokinetic parameters:
Cmax: 1000 mg/kg, Female: 187.92, Male: 193.51 µg eq. TA/g plasma
Test no.:
#3
Toxicokinetic parameters:
Tmax: 1000 mg/kg, Female: 0.5 (h), Male: 0.5 (h)
Test no.:
#3
Toxicokinetic parameters:
AUC: 1000 mg/kg, Female: 727, Male: 723 µg eq. TA* h/g plasma
Test no.:
#4
Toxicokinetic parameters:
Cmax: 2000 mg/kg, Female: 303.98, Male: 285.80 µg eq. TA/g plasma
Test no.:
#4
Toxicokinetic parameters:
Tmax: 2000 mg/kg, Female: 1.0 (h), Male: 1.0 (h)
Test no.:
#4
Toxicokinetic parameters:
AUC: 2000 mg/kg, Female: 1411, Male: 1185 µg eq. TA* h/g plasma

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:
The test article and/or its derivatives were determined to be systemically available at least one hour post dose administration at dose levels ranging from 500 to 2000 mg/kg.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Under the conditions of this study, none of the dose levels administered caused any test article related mortality during the period between dose administration and blood collection. Based on the total silicon content post dose administration, the test article and/or its derivatives were determined to be systemically available at least one hour post dose administration at dose levels ranging from 500 to 2000 mg/kg. The total silicon content measured at five different time points from 0.5 to 24 hours post dose administration showed that the response increased with dose level and were approximately proportional to the dose administered. These analyses also indicated that saturation of kinetic processes was not occurring, it is not likely that accumulation of the degradation products/metabolites would occur upon repeated daily oral administration based on an LOQ of 44.4 Jlg equivalents of test article/g plasma ..
Executive summary:

The purpose of the study was to determine the systemic availability of test article in rats over selected time points following a single bolus dose. This study was based on the Bioavailability section of OECD TG 417. The study was divided into two phases. Phase 1 was conducted to refine the analytical method for plasma analysis. This phase had two groups, control (1 animal/sex/group) and 2000 mg/kg (4 animals/sex/group). Phase 2 was the definitive study. For this phase, the control group had 2 animals/sex/group) and the three treatment groups (500, 1000, and 2000 mg/kg) had 4 animals/sex/group. Prior to study initiation, it was determined that the dose concentrations administered would be stable for up to 11 days. In addition, prior to experimental start for both phases, the dosing solutions were analysed to verify test article concentration and homogeneity. The study director determined that dosing solutions prepared for both phases were acceptable for use on study. Body weights were collected prior to randomization and on study day 0 of both phases to determine the volume of dosing solution to administer. Each animal received a single bolus dose by oral gavage of the dried and deacidified corn oil alone or test article in dried and deacidified corn oil. The dose volume for both phases was 5 mL/kg. Blood was collected at scheduled time points from all animals assigned to Phase 1 and Phase 2 with the exception of one Group 1 female from Phase 2. This animal was found dead following the eight hour post dose administration time point. The plasma obtained following centrifugation of the blood collected was aliquoted into pre-labelled, pre-weighed vials, and refrigerated until analysis. For both Phase 1 and Phase 2 following the final blood collection interval, all animals were subjected to a macroscopic examination of the cranial, thoracic, and abdominal cavities. There were no remarkable findings noted during those examinations. Since it was not known how hydrolytically active the test article was, the decision was made to analyse the plasma samples for test article content (ng/g) and total silicon (µg test article equivalents/g plasma). For the test article content in plasma analysis, a sensitive and selective tetrahydrofuran(THF) extraction method was developed for determining concentration of test article in the rat plasma using Gas Chromatography/Mass Spectrometry (GC/MS). Total silicon content was determined using a method to analyse plasma samples using inductively coupled plasma-optical emission spectroscopy (ICP-OES). During Phase 1, blood samples were collected one hour, 4 hours, and 24 hours post dose administration. All plasma samples received during Phase 1 were analysed for test article content expressed as ng/g and total silicon content expressed as µg equivalents of the test article per gram of plasma. No test article was detected in the plasma samples. The limit of quantitation (LOQ) for the test article content was 300 ng test article/gram of plasma. Total silicon content above the LOQ was detected in animals that received 2000 mg/kg. The LOQ for the total silicon content was determined to be 44.4 µg equivalents of the test article per gram of plasma. For Phase 2, because test article was not detected in the plasma from any of the blood collection time points in Phase 1, the plasma samples from Phase 2 were only analysed for total silicon content. All samples received were analysed. During Phase 2, blood samples were collected 30 minutes, 1 hour, 4 hours, 8 hours, and 24 hours post dose administration. The mean total silicon content for the low-, mid-, and high-dose groups was above LOQ for all groups at least one hour post dose administration. At the four hour post dose administration interval, the mean Total Silicon content was near the LOQ for the mid-dose group and above the LOQ for the high dose group. The standard error, degrees of freedom, mean Area Under the Curve (AUC) and confidence limits (lower and upper) for the Total Silicon content results were calculated for each group by sex to assess the pharmacokinetics/ toxicokinetics parameters of the test article. A two-way ANOVA test was conducted to examine significant differences among the treatment groups, the collection time and the interaction of the two independent variables. The comparison of the AUCs between two different groups showed statistically significant differences between groups however the AUCs for the males and females within each group were determined to be similar. The conclusion of the two-way ANOVA test was there were statistically significant differences among the treatment groups for both female and male. The differences were caused not only by treatment or time, but also combination of the two. Under the conditions of this study, none of the dose levels administered caused any test article related mortality during the period between dose administration and blood collection. Based on the total silicon content post dose administration, the test article and/or its derivatives were determined to be systemically available at least one hour post dose administration at dose levels ranging from 500 to 2000 mg/kg. The total silicon content measured at five different time points from 0.5 to 24 hours post dose administration showed that the total silicon content in plasma increased with dose level and were approximately proportional to the dose administered. These analyses also indicated that saturation of kinetic processes was not occurring, therefore it is not likely that accumulation of the degradation products/metabolites would occur upon repeated daily oral administration based on an LOQ of 44.4 µg equivalents of test article/g plasma.