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Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10 Jun - 29 Aug 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to the appropriate OECD test guideline and in compliance with GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report date:
2013

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Version / remarks:
(2010)
Deviations:
yes
Remarks:
The relative humidity went up to 77.1% therefore exceeding the higher limit of 70%. Epididymis were collected at necropsy and separately analyzed.
GLP compliance:
yes (incl. QA statement)
Remarks:
Swiss Federal Office of Public Health Consumer protection directorate Notification authority for chemicals

Test material

Constituent 1
Reference substance name:
Didocosyl sebacate
EC Number:
255-730-4
EC Name:
Didocosyl sebacate
Cas Number:
42233-75-0
Molecular formula:
Not applicable (UVCB substance)
IUPAC Name:
Decanedioic acid, diesters with Fatty alcohols C20-22 (even numbered)
Test material form:
other: solid
Details on test material:
- Name of test material (as cited in study report): only trade name given
- Physical state: white solid
- Storage condition of test material: room temperature
- Expiration date of the lot/batch: 10 Mar 2014
- Radiochemical purity (if radiolabelling): 99.5%
- Specific activity (if radiolabelling): 68.1 mCi/mmol
- Locations of the label (if radiolabelling): docsoyl-1-14C
- Expiration date of radiochemical substance (if radiolabelling): The radiochemical purity was checked at the time of administration. Therefore an expiration date is not relevant.
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
other: RccHan:WIST(SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories, B.V., NM Horst, The Netherlands
- Age at study initiation: 7 weeks
- Weight at study initiation: 189 ± 4 g (males), 179 ± 5 g (females)
- Housing: During acclimatization the animals were kept in groups of 2 animals under conventional hygienic conditions in Makrolon cages with standard soft wood bedding. One day prior to the administration the animals were individually kept in metabolism cages
- Diet: 2914C Teklad Global Rodent diet, ad libitum
- Water: (tap/filtered) water, ad libitum
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
72 mg of unlabelled test item was weighed. A volume of the stock solution containing 16.9 mg of the [14C]registered substance (spec act. 3067 kBq/mg) was added and used to dissolve the unlabelled test item. This procedure led to a final specific activity of 582 kBq/mg. The solvent was evaporated. Once dried, the test item was dissolved in arachis oil. The mixture was heated for a few minutes to help dissolution. Once prepared, the dose formulation was kept under magnetic stirring until end of dosing. An actual specific activity of 4309 kBq/mL and concentration of 7.404 mg/mL for the dose solution were determined by Liquid Scintillation Counting (LSC).

VEHICLE:
- Justification for use and choice of vehicle (if other than water): Arachis oil was used because the test item did not dissolve in distilled water.
- Concentration in vehicle: 7.404 mg/mL
- Amount of vehicle (if gavage): 4 mL/kg bw

HOMOGENEITY AND STABILITY OF TEST MATERIAL:
The radiochemical purity of the test item in the application vehicle was checked by HPLC before and after dosing. [14C]ST1797KS represented at least 96.3% of the radioactivity. Therefore, it could be concluded that the test item remained stable in the administration solution.
Duration and frequency of treatment / exposure:
single treatment
Doses / concentrations
Remarks:
Doses / Concentrations:
30 mg/kg bw (nominal dose)
29.46 mg/kg bw (administered dose)
No. of animals per sex per dose / concentration:
4
Control animals:
no
Positive control reference chemical:
Not applicable
Details on study design:
Absorption, distribution, excretion and metabolism of the registered substance were investigated by measuring the concentration of radioactivity in urine, feces, expired air, blood, tissues, organs and in the remaining carcass, after a single oral administration of [14C]ST1797KS at 30 mg/kg, by LSC Metabolite patterns in feces corresponding to sample type and sampling interval 0-24 and 24-48 hours were determined by HPLC analysis.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, feces, blood, expired-air, cage washes, terminal blood and plasma, tissues, organs, gastrointestinal tract (including contents), remaining carcass
- Time and frequency of sampling: urine: 0-6, 6-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168 hours after administration; feces: 0-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168 hours after administration; blood: 0.5, 1, 2, 4, 8, 24, 48, 72 and 96 hours after administration by tail vein cut off or sublingual puncture; expired-air: 0-24, 24-48, 48-72, 72-96, 96-144, 144-168 hours after administration. Radioactivity in expired-air traps at 96 hours was getting close to the 0.1% of dose. To avoid contamination of the room, the collection was continued up to the end of the experiment. However, the expired-air was collected over 2 days between 96-144 hours in two traps and over one day 144-168 hours in one trap; cage wash: at the end of the collection period, cages were washed with ethanol:water (1:1 v/v) and the radioactivity was determined by LSC.

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, feces
- Time and frequency of sampling: feces: 0-24 h and 24-48 h; urine: with less than 0.3% of the administered dose recovered in urine over 168 hours, the metabolite pattern in urine was not investigated.
- From how many animals: pooled according to dose group, sampling time, and sex
- Method type(s) for identification: HPLC-UV, Liquid scintillation counting, TLC
Statistics:
Mean values and standard deviation were calculated. The calculated blood and plasma concentrations are based on duplicate measurements, except for serial blood of rats from 0-24 hours which were performed as single measurement. All radioactivity counting of specimens were corrected for background by subtraction to give net "dpm" per specimen. Quantification of the radio-HPLC-chromatograms was done by electronic integration with the FLO-ONE for Windows Analysis software. For the metabolite distribution only roi’s (regions of interest) were used. The limits of quantification (LOQ) for tissue residues were calculated according to Currie. The depletion half lifes (t½) were calculated assuming a first order kinetics: log y = a + bx

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
After oral administration of [14C]registered substance at a nominal dose level of 30 mg/kg bw, absorption was low and excretion was rapid mainly via feces. Male and female blood kinetics were similar with a maximum concentration of radioactivity in blood found at sampling time point 4 hours and 8 hours for males and females, respectively. A Cmax of 0.701 and 0.733 μg ST1797KS eq/g was reached for males and females, respectively. Terminal half-life was calculated to be approximately 71.4 hours for males and 63.0 hours for females. AUC0-t in blood was calculated to be 32.9 and 43.0 μg.h/g for males and females, respectively.
Details on distribution in tissues:
Residual radioactivity was found in all tissues and organs at higher concentrations than in blood (0.074 μg/g and 0.092 μg/g for males and females, respectively), except for the brain. Highest residual radioactivity was found in the adrenals, epididymus (males only), white fat, liver, ovaries (females only), pancreas, spleen and thyroids.
Details on excretion:
The absorbed radioactivity was predominately excreted with the expired air, accounting for 5.2% and 6.9% for male and female rats, respectively. Very low amounts of the absorbed radioactivity were excreted with the urine, accounting for less than 0.3% for male and female rats. The major part of the radioactivity (approximately 94% of administered dose) was excreted with the feces for male and female rats. The amount absorbed was calculated based on the radioactivity determined in urine, cage wash, expired-air and residues in carcass and tissues. At least 6.85% and 7.96% of the dose for male and female rats, respectively, were absorbed from the gastrointestinal tract into systemic circulation. Within 48 hours after administration, over 90% of the dose was totally excreted. After 7 days almost the complete dose was excreted, accounting totally for 99.7% and 101.3% of the dose in male and female rats, respectively. Between 1.1% and 0.7% of the dose was found in the remaining carcass and tissues of male and female rats, respectively, seven days after dosing. Total recoveries were between 100.8% and 102.1%.
Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
other: Terminal half-life: 71.4 and 63.0 h for males and females
Test no.:
#2
Toxicokinetic parameters:
AUC: 32.9 and 43.0 µg*h/g for males and females
Test no.:
#3
Toxicokinetic parameters:
Cmax: 0.701 and 0.733 µg eq/g for males and females

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
With less than 0.3% of the administered dose recovered in urine over 168 hours, the metabolite pattern in urine was not investigated. For the investigation of the fecal metabolite pattern, feces from time intervals 0-24 h and 24-48 h were pooled according to dose group, sampling time, and sex. The metabolite pattern was dominated by one major fraction, i.e. F4 which was assigned as unchanged parent test substance based on the retention time of the radiopeak observed when the purity check of the test item was performed. The other three fractions were below 2.1% of the dose. Fraction F1 and F3 had similar retention times to radiopeaks observed during the purity check.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:
Not applicable

Any other information on results incl. tables

Table 1: Absorption, distribution, excretion and metabolism of the test substance in male and female rats (% of dose)

 

Group

Sex

Males

Females

Dose (mg/kg)

29.46

29.46

Urine

0 – 6h

6 – 24 h

24 – 48 h

48 – 72 h

72 – 96 h

96 – 120 h

120 – 144 h

144 – 168 h

 

0.01

0.14

0.03

<0.01

<0.01

<0.01

<0.01

<0.01

 

0.04

0.17

0.04

0.02

<0.01

<0.01

<0.01

<0.01

Subtotal

0.22

0.29

Feces

0 – 24 h

24 – 48 h

48 – 72 h

72 – 96 h

96 – 120 h

120 – 144 h

144 – 168 h

 

79.40

13.50

0.91

0.05

0.02

0.03

0.01

 

62.53

29.72

1.67

0.08

0.03

0.04

0.03

Subtotal

93.93

94.11

Expired air

0 – 24 h

24 – 48 h

48 – 72 h

72 – 96 h

96 – 144 h

144 – 168 h

 

4.06

0.60

0.27

0.15

0.12

0.02

 

5.36

0.87

0.24

0.28

0.14

0.03

Subtotal

5.22

6.92

Cage Wash

0.31

0.02

Total Excretion

0 – 168 h

 

99.68

 

101.33

Tissue Residue

Tissues a)

Carcass

 

0.26

0.85

 

0.25

0.48

Subtotal

1.10

0.73

Amount Absorbed b)

6.85

7.96

Total Recovery

100.78

102.06

a) total recovery in excised part of the tissue

b) sum of dose recovered in urine, cage wash, expired-air and residues in carcass and tissues

Table 2: Metabolic Pattern Feces (% of Dose)

Metabolite Pattern Feces (% of Dose)

Group

1

 

Assignment

Sex

Male

Female

Sampling Time

0-48 h

0-48 h

Metabolic Fraction

F1

F2

F3

F4*

 

0.6

0.2

1.6

90.1

 

1.4

-

2.1

88.0

 

Unknown

Unknown

Unknown Test substance

Extract 1

Non-extractable

92.4

0.5

88.0

0.7

 

Total

92.9

92.2

*F4 assigned as unchanged parent based on retention time of the radiopeak

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
The fate of the test substance was investigated according to OECD TG 417 in male and female Wistar rats after single oral administration at one dose level. [14C]registered substance, formulated in arachis oil, was orally administered to male and female rats by gavage at an average dose level of 29.5 mg/kg body weight. No sex differences in the toxicokinetic behaviour and metabolic fate were observed after oral administration of the test substance. Briefly, absorption of the registered substance was very low and excretion of absorbed material was via exhaled air, whereas unabsorbed material was rapidly excreted unchanged via feces. Urinary excretion of absorbed material was negligible. No metabolites where detected in feces.