3-methyltetrahydrothiophene 1,1-dioxide

Endpoint summary

Description of key information

Toxicokinetic evaluation of 3-methylsulfolane (CAS: 872-93-5 / EC: 212-833-9) based on existing data

REACH indicates that an “assessment of the toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information” should be performed at Annex VIII level.

General information

3-methylsulfolane (EC: 212-833-9, CAS: 872-93-5) is a mono-constituent substance, consisting of a 5-ring which has 4 carbon atoms and 1 sulphur atom with two double bonded oxygens. A methyl group is attached to its ring. An overview of the relevant physicochemical parameters for 3-methylsulfolane is provided below.

Physical state	Liquid at room temperature
Molecular weights	134.193 g/mol
Log Kow	-0.4 (at 20°C)
Water solubility (mg/l)	>1000 g/L (pH = 7.9)
Boiling point (°C)	285.9°C (at 1008 hPa)
Vapour pressure	0.885 Pa (at 25°C) (QSAR)
Viscosity	Not available

               

ADME data

Absorption, distribution, metabolism and excretion data on 3-methylsulfolane itself are not available and therefore the toxicokinetic assessment is based on the available physico-chemical and toxicology data for 3-methylsulfolane.

Absorption

Oral: As the molecular weight of the substance is below 500, the molecules are likely to be absorbed via the oral/GI tract. Uptake through aqueous pores or carriage of such molecules across membranes with the bulk passage of water in the GI tract can be expected. Furthermore, uptake by passive diffusion is likely based on the low log Kow value of 3-methylsulfolane (ECHA guidance, 7.12, Table R.7.12-1).

Based on the previous, the substance could be absorbed in the human body via the oral route. This is supported by the findings in an oral acute toxicity study, which reported clinical signs such as convulsions, hunched posture, piloerection, decreased activity and death, following oral administration of 3-methylsulfolane. Furthermore, in an OECD TG 422 a reversible increase of liver enzymes ALAT, and slightly increased biochemical values such as potassium and inorganic phosphate were observed. These findings confirm that systemic absorption of the substance via the gastrointestinal tract takes place.

Dermal: The physico chemical properties of the substance, its liquid state and molecular weight would not exclude dermal uptake. As the water solubility of the test substance is between 100-10,000 mg/l dermal uptake is expected to be moderate to high, however the high hydrophilicity of the substance (Log Kow <0) can limit penetration into the stratum corneum and hence dermal absorption (ECHA guidance, 7.12, Table R.7.12-3).

Acute dermal toxicity was examined in rabbits. Some clinical signs occurred: one dosed animal was found dead, and on day 1 and 2 hunched posture, piloerection, chromodacryorrhoea (snout or nose) and ptosis were noted, but no irritation. These results support that systemic absorption of the substance via the skin can take place.

Inhalation: As moderate log P values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion, 3-methylsulfolane may be absorbed though inhalation. However, the high water-solubility of the substance (andhigh hydrophilicity) may result in (part of) the substance being retained within the mucus. Furthermore, the low vapour pressure indicates that the substance may only be available for inhalation as a vapour to a very low extent.

Distribution

Distribution of 3-methylsulfolane is expected based on the relatively low molecular weights. Also, distribution throughout the body through aqueous channels and pores would be possible due to the moderate water solubility, and the low Log Kow suggest a higher extracellular concentration.

Metabolism

The metabolism of 3-methylsulfolane is not known. However, based on its structure it is expected that the methyl group would biotransformed by phase-I metabolism via oxidation and the subsequent formation of a carboxyl group. Followed by phase-II conjugation and successive excretion. Observed increased ALAT values in the OECD TG 422 study also suggest that the substance is metabolised by the liver.

Elimination

Based on the molecular eight of the substance excretion is likely to occur via the kidneys. Excretion via bile is not likely, as in the rat it has been found that substances with molecular weights below ~300 do not tend to be excreted into the bile (Renwick, 1994). Excretion via breast milk is unlikely, since the substance is not lipophilic. The excretion in saliva and sweatwould be possible based on the high hydrophilicity.

Accumulation

Accumulation of this substance is expected to be low, its high water-solubility and low lipophilicity will prevent 3-methylsulfolane from accumulating in adipose tissue, lung or stratum corneum.

Data from Toxicity studies

	3-methylsulfolane
Oral toxicity data	OECD TG 401: Acute Tox. 3, H301
Dermal toxicity data	OECD TG 402: Not classified (CLP), Category 5 (GHS)
Skin irritation / corrosivity	OECD TG 439: Not classified
Eye irritation	OECD TG 437: Eye Irrit. 2, H319
Skin sensitisation data	OECD TG 429: Not classified
Repeated dose toxicity	OECD TG 422: NOAEL > 50 mg/kg bw

 

Conclusion

Oral uptake is expected based on information from the available studies (acute and repeated dose oral toxicity) and the favourable physico chemical parameters. Dermal absorption would be possible based on information from available studies (acute oral toxicity) and physicochemical parameters. Relatively wide distribution and excretion through urine is expected based on the moderate water solubility, low molecular weight and hydrophilic nature of the substance. The absorption values to be used for hazard assessment are therefore taken as 100% for the inhalation route, 50% for the oral route and 50% for the dermal route.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100