Tetrahydrothiophene 1,1-dioxide

Dermal absorption

Administrative data

Endpoint:

dermal absorption 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

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD Guideline 417

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 427 (Skin Absorption: In Vivo Method)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: National Toxicology Program

GLP compliance:

no

Test material

Test material information

Constituent 1

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

Remarks:

[2,5-14C]sulfolane (14[C]sulfolane, 58.2 mCi/mmol)

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 (°C): 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

Type of coverage:

other: A metal mesh tissue capsule (placed immediately after dose administration) was used to protect the dose site from grooming.

Vehicle:

ethanol

Duration of exposure:

48 hours

Doses:

- Actual doses: 100 mg/kg bw

No. of animals per group:

2

Control animals:

no

Details on study design:

DOSE PREPARATION
- Method for preparation of dose suspensions: Approximately 24 h prior to dermal dosing, each mouse was anesthetized with isoflurane.
- Method of storage: not specified

APPLICATION OF DOSE:

VEHICLE
- Justification for use and choice of vehicle (if other than water): not specified
- Amount(s) applied (volume or weight with unit): not specified
- Concentration (if solution): 95 %
- Lot/batch no.: not specified
- Purity: not specified

TEST SITE
- Preparation of test site: Fur was clipped from each animal’s back and wiped with water. Following the cleaning, examination for nicks were performed and an outline of the dose area, 1 cm2 (1 x 1 cm), was inscribed on backs of each animal with a permanent-type felt tip marker. A single dose was applied to the dose area in a volume of 1 mL/kg using a syringe with a ball tipped feeding needle and spread evenly over the dose site.
- Area of exposure: on the back of the animal
- % coverage: not specified but an area of 1 cm2 (1 x 1 cm)
- Type of cover / wrap if used: immediately after the application of the test material, a metal mesh tissue capsule was placed to protect the dose site.
- Time intervals for shavings or clipplings: not specified

SITE PROTECTION / USE OF RESTRAINERS FOR PREVENTING INGESTION: n/a

REMOVAL OF TEST SUBSTANCE
- Removal of protecting device: following termination and blood collection, the metal appliance was removed with acetone to enable that cyanoacrylate adhesive (which were used to secure the metal appliances) was dissloved properly.
- Washing procedures and type of cleansing agent: acetone
- Time after start of exposure: 48 hours

SAMPLE COLLECTION
- Collection of blood: yes
- Collection of urine and faeces: yes
- Collection of expired air: yes
- Terminal procedure: the animals were euthanized by asphyxiation with CO2 and blood was collected via cardiac puncture and added to tubes containing K2EDTA.
- Analysis of organs: liver, kidney, heart, lung, spleen, brain, bladder, thyroid, pancreas, testes or uterus and ovaries, small intestine, large intestine, cecum and stomach (all gastrointestinal (GI) tract tissues were collected without contents) and samples of muscle (hind leg), abdominal skin and adipose (perirenal).

SAMPLE PREPARATION
- Storage procedure: All samples were stored at -20 °C until analysis.
- Preparation details: The GI tract tissues were rinsed with deionized water and the rinsate was collected separately. Tissues were divided into 2-4 aliquots (depending on tissue weight) and weighed. Liver was minced and 4 aliquots were weighed for analysis. GI tract tissues, GI contents, skin, and carcass were digested in 2N ethanolic NaOH. Triplicate faeces and tissue aliquots were digested in Soluene®-350; after digestion, samples (requiring bleaching) were decolorized with 70% perchloric acid and hydrogen peroxide. Triplicate aliquots of GI tract tissue, GI contents, skin and tissues digests and duplicate aliquots of urine, VOC and CO2 trapping solutions, plasma, cage rinse, and GI tract rinsates were added to vials containing Ultima Gold™ scintillation cocktail. All samples were analysed for radioactivity content.

ANALYSIS
- Method type(s) for identification: HPLC; LC-MS; NMR
- Liquid scintillation counting results (cpm) converted to dpm as follows: not specified
- Validation of analytical procedure: not specified
- Limits of detection and quantification: not specified

Results and discussion

Signs and symptoms of toxicity:

not specified

Dermal irritation:

not specified

Absorption in different matrices:

In total was ≥ 63.5 % of the dose absorbed.

Total recovery:

The total dose recovered was between 63.5 – 87.3 % in mouse following dermal application of the test substance.

Any other information on results incl. tables

Table 1 - Disposition of radioactivity following a single dermal application of 100 mg/kg

[¹⁴C]sulfolane in male and female B6C3F1/N mice

Sample	Collective Interval (h)	Male - Percent of dose recovered	Female – Percent of Dose Recovered
Urine	0-8	No sample	No Sample
Urine	8-24	25.9 ±17.3	17.0 ± 8.0
Urine	24-48	3.18 ± 2.0	2.7 ± 1.6
Urine	Sub Total	43.7 ± 20.2	19.7 ± 9.6
Cage rinse	0-8	11.1 ± 2.6	32.1 ± 15.4
Cage rinse	8-24	5.8 ± 4.1	12.7 ± 8.0
Cage rinse	24-48	1.4 ± 0.8	4.9 ± 2.9
Cage rinse	Sub Total	18.3 ± 6.9	49.7 ± 9.6
Total Urine + Cage Rinse	0-48	62.0 ± 16.8	69.4 ± 2.0
Faeces	0-24	6.2 ± 5.5	7.8 ± 4.6
Faeces	24-48	1.2 ± 1.0	1.5 ± 0.9
Faeces	Sub Total	7.4 ± 6.5	9.4 ± 5.1
GI Tract Contents	-	0.02 ± 0.01	0.04 ± 0.02
Tissues	-	0.8 ± 0.3	1.7 ± 1.5
Total Absorbed Dose	-	70.2 ± 12.0	80.4 ± 3.5
Dose Site Skin	-	1.4 ± 1.4	0.9 ± 0.6
Gauze	-	1.2 ± 0.9	1.1 ± 0.7
Dermal Appliance	-	2.6 ± 3.1	1.4 ± 1.1
Dose Site Skin Rinse	-	0.1 ± 0.1	0.2 ± 0.1
Total Unabsorbed Dose	-	3.9 ± 2.9	2.7 ± 1.9
Total Dose Recovered	-	75.5 ± 11.8	84.0 ± 2.3

Applicant's summary and conclusion

Conclusions:

Following dermal application of 100 mg/kg bw of sulfolane to mice, 70 % and 80 % of the applied dose was absorbed to male and female respectively. The total recovered dose recovered in males and females were 76 % and 84 % respectively.

Executive summary:

In an in vivo dermal absorption study which was performed according to a similar approach as described in the OECD guideline 427, however, not in accordance to GLP, reported that following dermal application of 100 mg/kg bw of sulfolane to the back, ≥ 63.5 % was absorbed in male and female mice respectively. The majority of the recovered dose were in the urine (62 % / 70 %); faeces (7 % / 9 % and tissue (<1 % / 2 %) to male and female respectively. The total recovered dose recovered in males and females were between 63.5 – 87.3 %.