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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report date:
2019

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
toxicokinetics
Test guidelineopen allclose all
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Qualifier:
according to guideline
Guideline:
other: National Toxicology Program
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Tetrahydrothiophene 1,1-dioxide
EC Number:
204-783-1
EC Name:
Tetrahydrothiophene 1,1-dioxide
Cas Number:
126-33-0
Molecular formula:
C4H8O2S
IUPAC Name:
1λ⁶-thiolane-1,1-dione
Test material form:
liquid
Radiolabelling:
yes

Test animals

Species:
mouse
Strain:
B6C3F1
Remarks:
/N
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Taconic Farms
- Age at study initiation: 8-10 weeks
- Weight at study initiation: 25.2-30.5 g for male mice and 18.6-21.7 g for female mice.
- Fasting period before study: not specified
- Housing: Individual metabolism cages with ability to separately collect urine, faeces and expired air.
- Individual metabolism cages: yes
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: At least one week's quarantine before initiating of the study.

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2 °C
- Humidity: 35-65 %
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12 h /12 h

IN-LIFE DATES: not specified

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
All dose formulations contained [14C]sulfolane and an appropriate amount of unlabeled sulfolane to achieve the final desired sulfolane concentration and specific activity. The target radioactivity per animal was ~ 10 μCi/rat. Oral dose formulations were prepared in water; a single dose was administered in a volume of 10 mL/kg by intragastric gavage.
Duration and frequency of treatment / exposure:
single exposure
Doses / concentrations
Dose / conc.:
100 other: mg/kg bw
No. of animals per sex per dose / concentration:
1
Control animals:
no
Positive control reference chemical:
No
Details on study design:
- Dose selection rationale: Randomised
- Rationale for animal assignment: Randomised
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, plasma, cage washes,
- Time and frequency of sampling: 24 h and 48 h
- Other:
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces, tissues, cage washes
- Time and frequency of sampling: 24 h and 48 h
- From how many animals: 2
- Method type(s) for identification: HPLC; LC-MS; NMR
- Limits of detection and quantification: not specified
Statistics:
Standard deviation, nothing else specified

Results and discussion

Main ADME results
Type:
absorption
Results:
Sulfolane was well-absorbed

Toxicokinetic / pharmacokinetic studies

Details on absorption:
In total was ≥ 89.5 % of the dose absorbed.
Details on distribution in tissues:
The total radioactivity remaining in mouse tissue was ~ 7% 24 h post administration of 100 mg/kg bw. After 48 and 72 h, the radioactivity decreased to ~ 2% regardless of administered dose. The highest detected concentrations of [14C] sulfolane were in blood, liver, lung and kidney. Higher levels observed in the bladder are likely to have occurred due to contamination from urine.
Details on excretion:
In total was 28.7 – 98.5 % of the administered dose excreted in the urine whereas 0 – 61.6% of the administered dose was excreted by the faeces.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Treatment of urine with β-glucuronidase, sulfatase, or acylase resulted in no change to the profile, indicating that conjugates are not present. Furthermore, the presence of 3-hydroxysulfolane was confirmed in several different metabolomic tests.

Any other information on results incl. tables

Table 1. Disposition of radioactivity following a single oral of [14C]sulfolane in male and female B6C3F1/N mice

Sample

Collection Interval (h)

Male, 100 mg/kg (% of dose recovered)

Female, 100 mg/kg (% of dose recovered)

Urine

0-8

 ND

 1.3 ± 2.3

Urine

8-24

 66.9 ± 8.4

 16.4 ± 24.4

Urine

24-48

 1.3 ±1.2

 3.4 ± 3.7

Urine

Sub Total

 68.2 ± 8.2

 21.0 ± 22.4

Cage Rinse

0-8

 2.6 ± 3.7

 38.3 ± 34.0

Cage Rinse

8-24

 13.8 ± 3.2

 12.9 ± 9.6

Cage Rinse

24-48

 1.8 ± 1.0

 1.1 ± 1.2

Cage Rinse

Sub Total

 17.6 ± 3.6

 42.7 ± 27.3

Total Urine + Cage Rinse

0-72

 85.8 ± 4.8

 63.6 ± 34.9

Faeces

0-24

 6.6 ± 4.4

 30.0 ± 30.7

Faeces

24-48

 1.2 ± 0.8

 0.6 ± 0.5

Faeces

Sub Total

 7.8 ± 4.9

 30.5 ± 31.1

GI Tract Contents

-

 0.01 ± 0.01

 0.02 ± 0.01

Tissues

-

 0.7 ± 0.0

 0.6 ± 0.1

Total Dose Recovered

-

 94.3 ± 0.3

 94.8 ± 5.2

ND – not detected

Applicant's summary and conclusion

Conclusions:
Following oral administation of 100 mg/kg bw sulfolane to mouse, ≥ 89.5 % of the dose was absorbed. Moreover, the main excretion route in male and female mouse was by the urine (86 % and 64 %) followed by the faeces (8 % and 31 %) respectively. Nevertheless, the variability was significant at different time-points. Radioactivity was observed in all examined blood and tissues where the highest concentrations were detected in blood, liver, lung, kidney, thyroid and skin.
Executive summary:

In an in vivo oral toxicokinetic study which was performed according to a similar approach as in OECD guideline 417, however, not in accordance to GLP, reported that following a single oral dose of 100 mg/kg bw sulfolane to one female and one male mouse respectively, ≥ 89.5 % of the dose was absorbed. Furthermore, the main excretion route in male mouse was by the urine (86 %) followed by the faeces (8 %). The main excretion route in female mouse was also by urine (64 %), however, more excretion had occurred in female mouse by the faeces (31 %) compared to the male mouse. Nevertheless, the variability was significant at different time-points.

Following oral ingestion of 100 mg/kg bw of the test substance in male mouse, radioactivity was observed in all examined blood and tissues where the highest concentrations were detected in blood, liver, lung, kidney, thyroid and skin. No sex differences could be identified between the two tested mice.