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Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2016-06-15 to 2017-01-23
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Objective of study:
absorption
metabolism
toxicokinetics
Qualifier:
according to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Version / remarks:
adopted 22nd July 2010
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Sigma Aldrich, MKBR7817V
- Expiration date of the lot/batch: April 2019
- Purity test date: 98.4%

- Radiolabelled test item:
Position of radiolabel: * [4-14C]
Specific activity: 58.1 mCi/mmol
Source: Hartmann Analytic
Lot number: 362-104-0581-A-20160329-DRE
Radiochemical purity: > 97% (Appendix 1)
Storage: -10 to - 30 ºC


Radiolabelling:
yes
Species:
rat
Strain:
other: Sprague Dawley – Crl:CD(SD)
Details on species / strain selection:
Rats are recognised by international guidelines as the recommended test system
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd
- Age at study initiation: Approx. 8 - 10 weeks at dose administration
- Weight at study initiation: 304 - 341 g (Group 1); 318 – 352 g (Group 2)
- Housing: Groups of up to five in solid bottomed polycarbonate cages with stainless steel lids. The cages included ¾ grade wood flake and environmental enrichment.
- Diet (e.g. ad libitum): RF1 pellets, Special Diets Services Ltd, Witham, Essex, UK, ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 15
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
other: Group 1 - oral gavage; Group 2 - intravenous administration
Vehicle:
other: Group 1 (oral administration): Corn oil; Group 2 (iv administration): DMSO:water (6:4)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Group 1 (oral dose):
Non-radiolabelled (3E)-dec-3-en-2-one (9997.69 mg) and radiolabelled (3E)-dec-3-en-2-one (3.71 mg,51.1 MBq) were dissolved in 20 mL of acetonitrile. The solvent was removed under a gentle stream of nitrogen and the dried radiodiluted test item was suspended in 50 mL of corn oil.The dose solutions were administered orally using a graduated syringe with rubber gavage tube at a nominal volume of 5 mL formulation/kg body weight. To quantify the dose administered triplicate aliquots (0.01 mL) were taken for LSC before and after dose administration.

Group 2 (intravenous dose):
Non-radiolabelled 3-decen-2-one (9.56 mg) and radiolabelled 3-decen-2-one (5.56 mg, 76.6 MBq) were dissolved in 20 mL of acetonitrile. The solvent was removed under a gentle stream of nitrogen and the dried radiodiluted test item was dissolved in 11.25 mL of DMSO : water (6:4 v/v). The dose solution was administered intravenously into the left caudal vein at a nominal volume of 1 mL/kg bodyweight. To quantify the dose administered triplicate aliquots (0.05 mL) were taken and further diluted to 5 mL with acetonitrile prior to administration. Duplicate aliquots (0.025 mL) were taken from each dilution for LSC.
Duration and frequency of treatment / exposure:
Single treamtent
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
Oral administration
Dose / conc.:
1 mg/kg bw/day (nominal)
Remarks:
Intravenous administration
No. of animals per sex per dose / concentration:
4
Control animals:
no
Positive control reference chemical:
n.a
Details on study design:
[14C]-(3E)-dec-3-en-2-one was administered orally at a dose level of 1000 mg/kg bw and intravenously at a dose level of 1 mg/kg bw to male rats. Blood samples were taken at intervals up to and including 24 hours. Concentrations of radioactivity were measured in whole-blood and plasma. Concentrations of (3E)-dec-3-en-2-one were measured in plasma by GC-MS.

- Dose selection rationale:
Oral administration was chosen as this is expected to be an important route for human exposure to (3E)-dec-3-en-2-one and intravenous administration as a reference to evaluate bioavailability.
The following dose levels were selected:
Oral administration 1000 mg/kg bw
Intravenous administration 1 mg/kg bw



Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled : whole blood
- Time and frequency of sampling: Animals in each group were divided into three subgroups of four animals. Routine blood samples (ca. 0.8 mL) were taken from the right caudal vein and terminal blood samples were obtained under anaesthetic by cardiac puncture. Blood samples were collected in heparinised tubes at the following times from each group:
Group 1:
Subgroup 1: 0.25, 2 and 8 hours
Subgroup 2: 0.5, 3 and 24 hours
Subgroup 3: 1 and 4 hours
Group 2:
Subgroup 1: 0.083, 1 and 4 hours
Subgroup 2: 0.25, 2 and 8 hours
Subgroup 3: 0.5, 3 and 24 hours
Each subgroup of animals was sacrificed by cervical dislocation on completion of the specified sampling schedule. The following tissues/organs were removed from the carcass: Liver, Duodenum, Femur, Bone marrow. The tissues and the remaining carcass were retained for possible future analysis.

- Sample preparation and processing:
Duplicate aliquots of whole blood (0.05 mL) were taken for combustion/LSC immediately after sampling. The whole blood was then centrifuged (4 ºC, 3200 rpm for 10 minutes) to remove the blood cells and the plasma was separated. A portion of the plasma (0.1 mL) was taken for analysis of (3E)-dec-3-en-2-one. Duplicate aliquots of the remaining plasma (0.05 mL) were taken for LSC. For the determination of total radioactivity and concentrations of radioactivity in samples, replicate weights and liquid scintillation counting data were recorded and processed using the DEBRA automated laboratory data capture and processing system (V5.5.4.49, LabLogic Systems Ltd, Sheffield, UK).

- Extraction of plasma for radio-HPLC analysis:
Proportionate pools of plasma were prepared for the following time points:
- Group 1 – 2 hours, 4 hours and 24 hours
- Group 2 – 0.083 hours, 1 hour and 4 hours
Portions of the pooled plasma (0.1 – 0.5 mL) were mixed with 0.4 - 1 mL of a 5 mg/mL trypsin (from porcine pancreas) suspension in 1mM hydrochloric acid. The samples were incubated at 37 ºC for approximately 18 hours. The incubated samples were extracted with methanol (× 2) and methanol : acetonitrile (1:1 v/v) by sonication for 5 minutes followed by centrifugation at 2000 g for 10 minutes. The supernatants were removed, weighed and duplicate weighed aliquots taken for LSC. The first methanol extract supernatant appeared to still contain a high proportion of protein and therefore required further clean-up prior to HPLC analysis. An additional portion of acetonitrile was added to the extract and the sample was centrifuged to separate the supernatant. The supernatant were removed, weighed and duplicate weighed aliquots taken for LSC. The residue was then further extracted with acetonitrile : glacial acetic acid (1:1 v/v) by sonication for 5 minutes followed by centrifugation at 2000 g for 10 minutes. The supernatant were removed, weighed and duplicate weighed aliquots taken for LSC. All extracts containing radioactivity above the limit of detection were pooled and analysed directly by HPLC. The stability of (3E)-dec-3-en-2-one during the extraction method was investigated in plasma and buffer fortified with [14C]3-decen-2-one.

- Measurement of radioactivity:
Radioactivity was measured by liquid scintillation counting (LSC) using either LKB-Wallac model 1219 Rackbeta Spectral or Wallac models 1409 or 1410 liquid scintillation counters with automatic quench correction. Aliquots of plasma samples were mixed with Ultima Gold scintillator (PerkinElmer). Whole blood samples were combusted using an automatic sample oxidiser and combustion products were absorbed into Carbosorb E and mixed with Permafluor E+ scintillator (PerkinElmer). The efficiency of the oxidiser was determined using aliquots of Spec-Chec-14C check source for sample oxidisers (PerkinElmer) and was greater than 95%. Measurements of radioactivity were corrected for oxidiser efficiency. Radioactivity in gross amounts of less than twice the background level was considered to be below the limit of accurate determination (limit of detection).

- Analysis of (3E)-dec-3-en-2-one:
Plasma samples were subsequently analysed for concentrations of (3E)-dec-3-en-2-one using a validated GC-MS method.

- Pharmacokinetic analysis:
Maximum mean plasma concentrations (Cmax) and their times of occurrence (Tmax) were the observed values. Areas under the mean plasma concentration-time curves up to the time of the last quantifiable sample (AUCt) were estimated by the linear trapezoidal rule. In the calculation of AUCt values following intravenous administration the mean concentrations at zero hours (C0) were estimated by back extrapolation using log-linear regression analysis, based on the first two sampling times. Areas under the mean plasma radioactivity concentration-time curves to infinite time (AUC) were calculated using the expression: AUC = AUCt + Clast/k
Where Clast is the predicted concentration at the time of the last quantifiable sample and k is the terminal rate constant, determined by regression analysis of log mean concentration against time.
For the estimate of k to be accepted as reliable, the following criteria were imposed:
1. The terminal data points used were randomly distributed about a single straight line
2. A minimum of three data points was available for the regression
3. The correlation coefficient was ≥0.95 and the fraction of the variance accounted for
by the regression was ≥0.90
4. The interval including the data points chosen for the regression was at least two-fold
greater than the half-life itself
Terminal half-lives (t½) were calculated as ln2/k. Systemic bioavailability (F) was calculated
as follows: F = (AUCoral / AUCiv) × (Doseiv / Doseoral)and expressed as a percentage (by multiplying the result by 100), based on AUCt values.
Statistics:
n.a.
Preliminary studies:
N.a.
Details on absorption:
n.a.
Details on distribution in tissues:
n.a.
Details on excretion:
n.a.
Test no.:
#1
Toxicokinetic parameters:
AUC: Oral: 11.6 ng.h/mL
Test no.:
#2
Toxicokinetic parameters:
AUC: IV: 0.0802 ng.h/mL
Test no.:
#1
Toxicokinetic parameters:
Cmax: Oral: 0.920 ng/mL
Test no.:
#2
Toxicokinetic parameters:
Cmax: IV:0.312 ng/mL
Test no.:
#1
Toxicokinetic parameters:
Tmax: Oral: 4 h
Test no.:
#2
Toxicokinetic parameters:
Tmax: IV:0.083 h
Metabolites identified:
yes
Details on metabolites:
Oral administration (Group 1):
(3E)-dec-3-en-2-one was detected by GC-MS in all samples and accounted for 0.1 – 1.0% of plasma radioactivity in the samples selected for radioanalysis. However, due to the low radioactivity concentrations in plasma it was not possible to detect [14C]-(3E)-dec-3-en-2-one in any of the analysed samples. [14C]-(3E)-dec-3-en-2-one was extensively metabolised to at least 10 radioactive metabolites following oral administration. Unidentified metabolites P2 to P9 were poorly resolved therefore one or more of these components may consist of multiple coeluting metabolites.
The major metabolite detected in all analysed samples was unidentified polar fraction P1 which increased from 23.4% plasma radioactivity (16.0 μg equiv./mL) at 2 hours after administration to 52.4% plasma radioactivity (114 μg equiv./mL) at 24 hours after administrationPolar fraction P1 may be composed of more than one unretained component.
Two other metabolites accounting for > 10% were detected. Unidentified metabolite P3 accounted for 10.8% plasma radioactivity (7.42 μg equiv./mL) at 2 hours after administration decreasing to 5.3% plasma radioactivity (11.5 μg equiv./mL) at 24 hours after administration. Unidentified metabolite P4 increased to 14.3% plasma radioactivity (31.1 μg equiv./mL) at 24 hours after administration.
Component P10, which was tentatively identified as 2-decanone, accounted for 2.7% plasma radioactivity (1.87 μg equiv./mL) at 2 hours after administration before decreasing to below the limit of detection. Metabolite 2-decanol was not detected in any of the analysed samples. All other metabolites accounted for < 9.2% plasma radioactivity.

Intravenous administration (Group 2):
[14C]-(3E)-dec-3-en-2-one was extensively metabolised to at least 14 radioactive metabolites following intravenous administration. Unidentified metabolites P2 to P9 were poorly resolved therefore one or more of these components may consist of multiple co-eluting metabolites.
The major metabolite in all samples was unidentified polar fraction P1 which increased from 7.7% plasma radioactivity (0.104 μg equiv./mL) at 0.083 hours after administration to 47.4% plasma radioactivity (0.120 μg equiv./mL) at 4 hours after administration. Polar fraction P1 may be composed of more than one unretained component.
Components P5, P7, P8 and P11 accounted for 10.8 – 15.5% plasma radioactivity (0.145 – 0.208 μg equiv./mL) at 2 hours after administration decreasing to < 10% plasma radioactivity (0.032 μg equiv./mL) by 4 hours. Component P10, tentatively identified as 2-decanone, accounted for 2.9% plasma radioactivity (0.039 μg equiv./mL) at 0.083 hours decreasing to below the limit of detection
by 1 hour post dose. Metabolite 2-decanol was not detected in any of the analysed samples. All other metabolites accounted for < 7.3% plasma radioactivity.
Bioaccessibility (or Bioavailability) testing results:
n.a.

Detail on results:

The objectives of the study were to investigate the blood and plasma kinetics of (3E)-dec-3-en-2-one and total radioactivity after single oral and intravenous administration to male rats and to investigate metabolites and degradation products in plasma. Single oral (Group 1, nominally 1000 mg/kg bw) and single intravenous (Group 2, nominally 1 mg/kg bw) doses of [14C]- (3E)-dec-3-en-2-one were administered to male rats and blood and plasma samples were collected at selected times post dose for measurement of the test item and radioactivity concentrations.  Following administration of [14C]- (3E)-dec-3-en-2-one, serial blood samples were taken up to 24 hours post-dose. Plasma samples were analysed for concentrations of (3E)-dec-3-en-2-one using a validated GC-MS method.

Pharmacokinetic parameters for (3E)-dec-3-en-2-one in plasma and total radioactivity in whole blood and plasma are summarised below in Table 1.

Following oral administration, the terminal half-life of (3E)-dec-3-en-2-one was 7.97 hours, however the terminal half life of total radioactivity could not be estimated from the available data. Following intravenous administration, the terminal half-life of (3E)-dec-3-en-2-one was estimated to be 0.0631 hours and the terminal half-life for total radioactivity was estimated to be 13.9 hours and 18.3 hours in plasma and whole blood respectively. The oral bioavailability (calculated based on AUCt) of (3E)-dec-3-en-2-one was relatively low at approximately 18%. The oral bioavailability (calculated based on AUCt) of total plasma

radioactivity was much higher at approximately 91%. (3E)-dec-3-en-2-one accounted for approximately 0.3 – 1.5% of the total exposure to radioactivity (in terms of AUCt) following both oral and intravenous administration indicating that a substantial proportion of the radioactivity in plasma was present as metabolites.

Following oral administration, [14C]-(3E)-dec-3-en-2-one was extensively metabolised to at least 10 radioactive metabolites (see Table 2 below). The major metabolite detected was polar fraction P1 which increased with time in the samples analysed to a maximum of 52.4% plasma radioactivity (114 µg equiv./mL) at 24 hours. Low levels of [14-C]-2-decanone (2.7% plasma radioactivity, 1.87 µg equiv./mL) were tentatively identified. [14-C]-2-decanol was not detected in any of the analysed samples. Following intravenous administration (see Table 3 below), low levels of [14C]-(3E)-dec-3-en-2-one (2.1% plasma radioactivity, 0.029 µg equiv./mL) were detected at 0.083 hours. [14C]-(3E)-dec-3-en-2-one was extensively metabolised to at least 14 radioactive metabolites. The major metabolite detected was polar fraction P1 which increased in the samples analysed to 47.4% plasma radioactivity (0.120 µg equiv./mL) at 24 hours. Low levels of 2-decanone (2.9% plasma radioactivity, 0.039 µg equiv./mL) were tentatively identified. [14-C]-2-decanol was not detected in any of the analysed samples.

Table 1: Toxicokinetic parameters for (3E)-dec-3-en-2-one in plasma and total radioactivity in whole blood and plasma:

Toxicokinetic

Parameter

3-decen-2-one

Plasma radioactivity

Whole blood radioactivity

 

Oral

IV

Oral

IV

Oral

IV

C0 (ng/mL)

-

0.779

-

1.61

180

1.16

Cmax (ng/mL)

0.920

0.312

218

1.34

24

0.953

T max (h)

4

0.083

24

0.083

3170

0.083

AUCt (ng.h/mL)

11.6

0.0756

4020

5.11

-

4.31

AUC (ng.h/mL)

13.4

0.0802*

-

7.00*

-

6.90*

k (h-1)

0.0869

10.9837*

-

0.0498*

-

0.0379*

t½ (h)

7.97

0.0631*

-

13.9*

-

18.3*

* Did not meet the data processing acceptance criteria

- Could not be calculated from the available data

k Terminal rate constant

C0 Concentration at time zero (following intravenous administration)

Cmax Maximum mean plasma concentrations

Tmax Time of Cmax occurrence

AUCt Area under the mean plasma concentration-time curve up to the time of the last quantifiable sample was estimated by the linear trapezoidal rule

AUC area under the mean plasma radioactivity concentration-time curve to infinite time

t½ Terminal half-life

Table 2: Proportions of radioactive metabolites in plasma after single oral doses of [14C]-(3E)-dec-3-en-2-one at a nominal dose level of 1000 mg/kg (Group 1)

Component

Typical HPLC retention time (minutes

2 hours

4 hours

24 hours

 

 

%

µg equiv./mL

%

µg equiv./mL

%

µg equiv./mL

Analysed fraction

 

73.8

50.5

83.7

120

92.6

202

P1

2.7

23.4

16.0

48.5

69.6

52.4

114

P2

10.5

6.0

4.09

1.9

2.76

1.6

3.43

P3

11.3

10.8

7.42

9.2

13.2

5.3

11.5

P4

12.3

4.7

3.23

7.6

10.9

14.3

31.1

P5

12.9

5.8

3.94

2.5

3.60

9.2

20.0

P6

13.4

2.5

1.72

2.8

4.08

3.0

6.46

P7

14.0

2.4

1.62

-

-

2.0

4.44

P8

14.9

4.9

3.38

1.6

2.28

-

-

P9

15.3

-

-

2.1

3.00

-.

-

P10 (2-decanone)

16.1

2.7

1.87

-

-

-

-

P11

16.5

-

-

-

-

-

-

P13

17.1

-

-

-

-

-

-

(3E)-dec-3-en-2-one

17.6

-

-

-

-

-

-

P15

21.6

-

-

-

-

-

-

Others (a)

 

10.6

7.22

7.4

10.2

4.9

10.7

Unextractable residue

 

26.2

17.9

16.3

23.3

7.4

16.1

Total

 

100

68.4

143

143

100

218

Results are expressed as % plasma radioactivity and μg equivalent (3E)-dec-3-en-2-one/mL

(a) Non-common minor metabolites or radioactivity distributed throughout regions of the chromatogram other than those specified, and which did not contain any discrete radioactive metabolites

- Not apparent or below the limit of detection

Table 3: Proportions of radioactive metabolites in plasma after single intravenous doses of [14C]-(3E)-dec-3-en-2-one at a nominal dose level of 1 mg/kg (Group 2)

Component

Typial HPLC retention time (minutes

0.083 hour

1 hour

4 hours

 

 

%

µg equiv./mL

%

µg equiv./mL

%

µg equiv./mL

Analysed fraction

2.7

93.1

1.25

81.5

0.377

91.8

0.233

P1

10.5

7.7

0.104

53.1

0.246

47.4

0.120

P2

11.3

1.4

0.019

-

-

2.6

0.007

P3

12.3

0.7

0.010

6.7

0.031

7.3

0.018

P4

12.9

2.6

0.035

5.7

0.026

6.4

0.016.

P5

13.4

13.0

0.175

7.0

0.032

9.9

0.025

P6

14.0

2.9

0.039

-

-

3.5

0.009

P7

14.9

13.5

0.181

-

-

4.4

0.011

P8

15.3

15.5

0.208

-

-

1.9

0.005

P9

16.1

2.0

0.028

-

-

-

-

P10 (2-decanone)

16.5

2.9

0.039

-

-

-

-

P11

17.1

10.8

0.145

-

-

-

-

P12

21.6

4.1

0.055

 

 

 

 

P13

23.6

5.0

0.068

1.5

0.007

-

-

(3E)-dec-3-en-2-one

 

2.1

0.029

-

-

-

-

P15

 

2.8

0.038

-

-

-

-

Others (a)

 

6.0

0.080

7.4

0.034

8.4

0.021

Unextractable residue

 

6.9

0.924

18.5

0.085

8.2

0.021

Total

 

100

1.34

100

0.462

100

0.254

Results are expressed as % plasma radioactivity and μg equivalent (3E)-dec-3-en-2-one/mL

(a) Non-common minor metabolites or radioactivity distributed throughout regions of the chromatogram other than those specified and which did not contain any discrete radioactive metabolites

- Not apparent or below the limit of detection

Dose levels:

The achieved doses of [14C] -(3E)-dec-3-en-2-one administered to rats are shown in Appendix 3. The mean achieved dose level was 900.6 mg/kg for the oral administration (Group 1) and

1.04 mg/kg for the intravenous administration (Group 2).

Clinical signs:

No clinical signs attributable to the administration of [14C]-(3E)-dec-3-en-2-one were observed.

Conclusions:
The objectives of the study were to investigate the blood and plasma kinetics of (3E)-dec-3-en-2-one and total radioactivity after single oral and intravenous administration to male rats and to investigate metabolites and degradation products in plasma. Following oral administration, the terminal half-life of (3E)-dec-3-en-2-one was 7.97 hours. However, the terminal half-life of total [14C]-radioactivity could not be estimated from the available data. The systemic bioavailability of(3E)-dec-3-en-2-one following oral administration was approximately 18% (based on plasma AUCt). The systemic bioavailability based on total [14C]-radioactivity was higher, at approximately 91% (based on plasma AUCt). (3E)-dec-3-en-2-one accounted for approximately 0.3 – 1.5% of the total exposure to radioactivity (in terms of AUCt) following both oral and intravenous administration, indicating that a substantial proportion of the radioactivity in plasma was present as metabolites. Following oral administration, [14C]-(3E)-dec-3-en-2-one was not detected in any of the analysed samples. [14C]-(3E)-dec-3-en-2-one was extensively metabolised at least 10 radioactive metabolites being detected. The major metabolite detected was polar fraction P1, which increased with time in the samples analysed to a maximum of 52.4% plasma radioactivity (114 μg equiv./mL) at 24 hours. Low levels of 2-decanone (2.7% plasma radioactivity, 1.87 μg equiv./mL) were tentatively identified. Following intravenous administration, low levels of [14C]-(3E)-dec-3-en-2-one (2.1% plasma radioactivity, 0.029 μg equiv./mL) were detected at 0.083 hours. [14C]-3-decen-2-one was extensively metabolised with up to at least 14 radioactive metabolites being detected. The major metabolite detected was polar fraction P1 which increased to 47.4% plasma radioactivity (0.120 μg equiv./mL) at 24 hours. Low levels of 2-decanone (2.9% plasma radioactivity, 0.039 μg equiv./mL) were tentatively identified.
In conclusion, 3-decen-2-one is almost completely absorbed following oral administration to rats and extensively metabolised, with a terminal half-life of less than 8 hours.
Executive summary:

The objectives of the study were to investigate the blood and plasma kinetics of (3E)-dec-3-en-2-one and total radioactivity after single oral and intravenous administration to male rats and to investigate metabolites and degradation products in plasma. Following oral administration, the terminal half-life of (3E)-dec-3-en-2-one was 7.97 hours. However, the terminal half-life of total [14C]-radioactivity could not be estimated from the available data. The systemic bioavailability of (3E)-dec-3-en-2-one following oral administration was approximately 18% (based on plasma AUCt). The systemic bioavailability based on total [14C]-radioactivity was higher, at approximately 91% (based on plasma AUCt). (3E)-dec-3-en-2-one accounted for approximately 0.3 – 1.5% of the total exposure to radioactivity (in terms of AUCt) following both oral and intravenous administration, indicating that a substantial proportion of the radioactivity in plasma was present as metabolites. Following oral administration, [14C]- (3E)-dec-3-en-2-one was not detected in any of the analysed samples. [14C]- (3E)-dec-3-en-2-one was extensively metabolised at least 10 radioactive metabolites being detected. The major metabolite detected was polar fraction P1, which increased with time in the samples analysed to a maximum of 52.4% plasma radioactivity (114 μg equiv./mL) at 24 hours. Low levels of 2-decanone (2.7% plasma radioactivity, 1.87 μg equiv./mL) were tentatively identified. Following intravenous administration, low levels of [14C]- (3E)-dec-3-en-2-one (2.1% plasma radioactivity, 0.029 μg equiv./mL) were detected at 0.083 hours. [14C]- (3E)-dec-3-en-2-one was extensively metabolised with up to at least 14 radioactive metabolites being detected. The major metabolite detected was polar fraction P1 which increased to 47.4% plasma radioactivity (0.120 μg equiv./mL) at 24 hours. Low levels of 2-decanone (2.9% plasma radioactivity, 0.039 μg equiv./mL) were tentatively identified.

In conclusion, (3E)-dec-3-en-2-one is almost completely absorbed following oral administration to rats and extensively metabolised, with a terminal half-life of less than 8 hours.

Description of key information

The objectives of the study were to investigate the blood and plasma kinetics of (3E)-dec-3-en-2-one and total radioactivity after single oral and intravenous administration to male rats and to investigate metabolites and degradation products in plasma. Following oral administration, the terminal half-life of (3E)-dec-3-en-2-one was 7.97 hours. However, the terminal half-life of total [14C]-radioactivity could not be estimated from the available data. The systemic bioavailability of (3E)-dec-3-en-2-one following oral administration was approximately 18% (based on plasma AUCt). The systemic bioavailability based on total [14C]-radioactivity was higher, at approximately 91% (based on plasma AUCt). (3E)-dec-3-en-2-one accounted for approximately 0.3 – 1.5% of the total exposure to radioactivity (in terms of AUCt) following both oral and intravenous administration, indicating that a substantial proportion of the radioactivity in plasma was present as metabolites. Following oral administration, [14C]-(3E)-decen-2-one was not detected in any of the analysed samples. [14C]- (3E)-dec-3-en-2-one was extensively metabolised at least 10 radioactive metabolites being detected. The major metabolite detected was polar fraction P1, which increased with time in the samples analysed to a maximum of 52.4% plasma radioactivity (114 μg equiv./mL) at 24 hours. Low levels of 2-decanone (2.7% plasma radioactivity, 1.87 μg equiv./mL) were tentatively identified. Following intravenous administration, low levels of [14C]- (3E)-dec-3-en-2-one (2.1% plasma radioactivity, 0.029 μg equiv./mL) were detected at 0.083 hours. [14C]- (3E)-dec-3-en-2-one was extensively metabolised with up to at least 14 radioactive metabolites being detected. The major metabolite detected was polar fraction P1 which increased to 47.4% plasma radioactivity (0.120 μg equiv./mL) at 24 hours. Low levels of 2-decanone (2.9% plasma radioactivity, 0.039 μg equiv./mL) were tentatively identified.

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