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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non GLP study with limited but sufficient documentation

Data source

Reference
Reference Type:
publication
Title:
The Fate of [14C]Thiodipropionates in Rats
Author:
Reynolds, R.C., Astill, B. D., and Fassett, D.W.
Year:
1974
Bibliographic source:
TOXICOLOGY AND APPLIED PHARMACOLOGY 28, 133-141 (1974)

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
limited reporting details
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Didodecyl 3,3'-thiodipropionate
EC Number:
204-614-1
EC Name:
Didodecyl 3,3'-thiodipropionate
Cas Number:
123-28-4
Molecular formula:
C30H58O4S
IUPAC Name:
didodecyl 3,3'-sulfanediyldipropanoate
Constituent 2
Reference substance name:
Reference substance 001
Details on test material:
Carboxy 14C-labeled didodecyl thiodipropionate ([14C]DDTDP), specific activity 60 microCi/mmol, was purified (99.2% by chromatography) by recrystallization from aqueous acetone.

[14]Thiodipropionate, specific activity 1.71 mCi/mmol
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 215 - 325g
- Fasting period before study:
- Housing: in glass metabolism cages, for collection of urine, feces and exhaled carbon dioxide
- Individual metabolism cages: yes
- Diet: animals were starved prior to dosing
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: From: To: no data

Administration / exposure

Route of administration:
other: oral in feed, and oral by gavage
Vehicle:
other: see below
Details on exposure:
In some experiments the dose was incorporated into powdered Purina Lab Chow (20 mesh), homogenized hen’s egg (1 egg/50 g) and water to a stiff paste which was heated and formed into sticks (10-12 g).
In other experiments, didodecylthiodipropionate was dissolved in corn oil and applied by gavage.
[14]Thiodipropionate was dissolved in ethanol: water 1:1 if given by gavage.
Duration and frequency of treatment / exposure:
single treatment
Doses / concentrations
Remarks:
Doses / Concentrations:
Thiodipropionic acid: 3.1 mg/kg bw (gavage), 650 mg/kg bw (gavage), 572 mg/kg bw (gavage), 551 mg/kg bw (gavage) and 241 mg/kg bw (feed)
Didodecylthiodipropionic acid: 107 and 208 mg/kg bw (gavage), 166 mg/kg bw (feed)
No. of animals per sex per dose / concentration:
1
Control animals:
no
Positive control reference chemical:
not required
Details on study design:
Thin-layer and paper chromatography of urine for metabolite detection was unsuccessful because of the tendency of dithiopropionic acid to migrate as more than one spot with most solvent systems. In consequence, reverse isotope dilution studies were carried out with untreated and hydrolyzed urines to assay elimination of free and combined [14C]-ditihiopropionic acid.
Details on dosing and sampling:
For feed application, rats were kept in the metabolism cages for 34 days.
For gavage application, rats were kept in the metabolism cage for 4 days or 8 days.
Urines and CO2 absorbers were processed daily. Liver, kidneys, brain, heart, lungs, whole gastrointestinal tracts and fat samples were removed at sacrifice and frozen with carcasses until assayed.

Metabolites were isolated by consecutive continuous ether extractions of urine at pH >9 and <2. Glucuronidase treatment was performed to identify glucuronic acid conjugates.
Statistics:
not applicable

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Complete absorption of both thiodipropionic acid and Didodecyl thiopropionic acid
Type:
excretion
Results:
as acid labile conjugate of thiodipropionic acid or free thiodipropionic acid, >90% in urine, less than 5% as carbon dioxide
Type:
distribution
Results:
Low amounts of [14C]-Didodecylthiodipropionate is found in fat tissues at the last sacrifice on day 34.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The didodeylester is completely absorbed when fed at a single dose of 210 mg/kg bw. Thiodipropionic acid is completely absorbed when fed at a single doses of 3 - 6 or 650 mg/kg bw.
Details on distribution in tissues:
Distribution in tissues was close to normal values except that for the didoceylester, the value of radioactivity in the fat were elevated at 4 days after dosing and remained so at 8 and 34 days. Data is given for liver, kidney, brain, heart, lung, gastrointestinal tract, fat and carcass.
Details on excretion:
Urinary elimination accounts for more than 90% of the dose. Elimination in carbon dioxide accounts for ca 5% of the dose. More than 90% of the dose is eliminated within the first 24h. This data is given as a graph. Didodecyl thiodipropionate appears to be almost completely eliminated within 3 days.
Acid hydrolysis of urine samples afforded high rates of recovery approaching 100% of the urinary radioactivity after feeding.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Dithiopropionic acid is recovered as a acid-labile conjugate if given at doses of 3 - 6 mg/kg bw. At 650 mg/kg bw, the major fraction is recovered in the non-conjugated form. The acid-labile conjugate is not or only to a small fraction a glucuronidate. Further identification was not performed.

Any other information on results incl. tables

Table 1: Cumulative elimination in the rat after gavage and feed application

Compound Rat no. dose [mg/kg bw] dose [μCi] gavage/feed time [days] Elimination
urine carbon dioxide feces total
Thiodipropionic acid 1 3.1 9.3 gavage  4 90.10% 3.10% 0.50% 93.60%
2 650 9 gavage  4 78.10% 8.20% 0.50% 86.80%
3 572 9.3 gavage  4 84.50% 2.80% 0.90% 88.40%
4 551 8.9 gavage  8 88.50% 7.20% 0.20% 95.90%
5 241 8.2 feed 34 87.40% 3.30% 0.10% 90.70%
                   
Didodecyl thiodipropionate 1 107 3.3 gavage  4 84.60% 2.90% 3.50% 90.90%
2 208 6.6 gavage  8 88.50% 3.90% 1.80% 94.40%
3 166 4 feed 34 86.10% 3.20% 0.10% 89.40%

Applicant's summary and conclusion

Conclusions:
low bioaccumulation potential based on study results