5H-1,2-oxathiole 2,2-dioxide

Endpoint summary

Description of key information

The substance 1,3-Propenesultone is an organic mono-constituent solid with a purity of 99.5 - 100% (w/w), with a typical concentration of 99.9% (w/w).

A full ADME toxicokinetic study in the rat is not available. The toxicokinetic analysis is based on the physicochemical and in vivo toxicological data. In vivo studies covering the oral route (acute oral toxicity study in rats, combined repeated dose toxicity study with reproduction/developmental toxicity screening test in rats), the dermal route (LLNA in mice) and the inhalation route (acute inhalational toxicity study in rats) are available. Further details on endpoints are available in the IUCLID 6 registration dossier.

Based on the physicochemical data and available in vivo toxicological data, absorption of 1,3-Propenesultone is expected to be moderate via the oral route, low via the dermal and inhalation routes. 1,3-Propenesultone is hydrolysed and the breakdown products are expected to be excreted in the urine.

The absorption rates of 50% (oral), 50% (dermal) and 100% (inhalation) are accepted for chemical risk assessment purposes.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

1. Physicochemical properties

In accordance with the ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C Section R.7.12 (Endpoint Specific Guidance), the physicochemical properties can provide an insight into the potential behaviour of 1,3-Propenesultone in the body.

Absorption - oral

The molecular weight of 1,3-Propenesultone is 120.13 g/mol which is in the range for favourable oral absorption (<500 g/mol). The log Kow (-0.49 at 22.5°C) indicates it is poorly lipophilic and the water solubility (23.4 g/L at 20°C) indicates it is very soluble in water. Oral absorption is expected to occur via aqueous pores or across membranes with the bulk passage of water.

Absorption – dermal

Due to the high hydrophilicity (very water soluble, log Kow<0), uptake of of 1,3-Propenesultone via the dermal route is expected to be low.

Absorption – inhalation

The particle size distribution report for 1,3-Propenesultone indicated a range of 2.884μm – 831.764μm (D(10): 38.277μm; D(50): 192.582μm; D(90): 450.225μm), therefore it is considered to have medium dustiness. As at least 10% of the particles are available in the inhalable fractions of air (<100 μm), some exposure via inhalation is expected to occur via aqueous pores.

Distribution/Metabolism/Excretion

Based on the molecular weight, water solubility and log Kow, 1,3-Propenesultone is likely to be widely distributed, but is unlikely to accumulate, due to poor lipophilicity. 1,3-Propenesultone was predicted by QSAR to be hydrolysed to 3-hydroxyprop-1-ene-1-sulfonic acid. However, an OECD 111/GLP test was conducted and although it was noted that PST is hydrolysed (t½ = approximately 4 days at ph 4/7/9 @25°C), no specific hydrolysis products were observed, using the HPLC method (1). 1,3-Propenesultone is hydrolysed and the breakdown products are expected to be excreted in the urine.

(1) Refer to IUCLID6 dossier Section 5.1.2

2. Information from other studies in the dossier

Absorption – oral

In an acute oral toxicity test in female Wistar rats (OECD 423/GLP), the LD50 was > 50 mg/kg - 300 mg/kg bw.

In a combined repeated dose and reproduction/developmental toxicity screening test (OECD 422/GLP), 1,3-Propenesultone (99.90%) in 0.5% w/v Carboxy Methyl Cellulose was administered to 4 main groups ((G1, G2, G3 and G4; 12/sex/group) and 2 recovery groups (G1R, G4R; 5/sex/group) of Sprague Dawley rats by oral gavage. The animals in the G1/G1R, G2, G3 and G4/G4R groups were administered the test item at the dose levels of 0, 22.5, 45 and 90 mg/kg bw/day (based on a 14-day DRF study), respectively, 7 days per week, for 48-71 days.

There were no mortalities at any dose during the study. In groups G2 and G3, there were no indications of test item-related effects in any of the parameter/endpoints assessed for systemic toxicity. In groups G4/G4R, the animals from these dose groups were noted with test item-related reduction in body weight gain (outside historical control data) and feed consumption in both sexes. However, a recovery in both mean body weight and percent change in mean body weight was noted in G4R animals of both sexes during the recovery period. The changes outside historical control data in hematological values (absolute reticulocytes only) showed a trend towards recovery during the recovery period. The clinical chemistry, urinalysis and ophthalmoscopic examinations did not reveal any test item-related changes. There was no test item-related organ weight, gross pathological or histopathological changes noted at these dose levels.

In groups G2 and G3, there were no indication of test item-related effects in any of the parameter/endpoints assessed for reproductive and developmental toxicity. Also, there was no indication of test-item related effects on endocrine disruptor (ED) relevant endpoints in both parents (oestrus cyclicity in females, relative organ weight and histopathology of gonads and accessary sex organs, thyroid weights and serum T4 levels) and pups (development of external genital organs, measurement of anogenital distance, male pup nipple retention and serum T4 levels for PND 4/13 pups) at these dose levels. In group G4, test item-related reductions in live birth index per litter, male/female mating index, male/female fertility index, pregnancy and gestation index were noted. The increased post-implantation loss and postnatal loss were also evidenced as test item-related at this dose level. Test item-related reduced litter size, reduced live birth index per litter and increased number of dead pups at birth were also noted at this dose level. These noted effects on reproductive performances are considered as secondary effects related to stress due to noted treatment-related clinical signs of toxicity, reduced body weights, reduced body weight gain and reduced feed consumption. Also, there was no direct test item-related effects noted in any of the reproductive organs of both sexes, no gross or histopathological changes noted in the reproductive organs of both sexes and no effects were noted in serum T4 levels of both sexes. Based on the above considerations, these effects are concluded as secondary effects, but not direct treatment-related changes. In group G4, test item-related reduced mean male pup weight per litter was noted. However, no gross pathological changes were noted in any of the surviving pups of both sexes.  In group G4, there were no test item-related effects noted for ED relevant endpoints in both parental animals and F1 pups.

The NOAEL (reproduction; male/female) is determined as 45 mg/kg bw/day, due to noted secondary test item-related effects such as reduced mating and fertility performance of both sexes, reduced pregnancy and gestation indices, reduced live birth index, increased post-implantation and postnatal losses at the dose level of 90 mg/kg bw/day. The NOAEL (developmental) is determined as 45 mg/kg bw/day, due to noted reduced mean male pup weights at the dose level of 90 mg/kg bw/day.

Based on the physicochemical data and available in vivo toxicological data, the in vivo data indicates that moderate oral absorption may be expected. For chemical safety assessment purposes, an oral absorption rate of 50% is accepted.

Absorption – dermal

In a dermal sensitization study (OECD 429/GLP) with 0, 0.2, 2 and 20% w/v 1,3-Propenesultone (99.92%) in DAE 433 (40 % dimethylacetamide, 30 % acetone and 30 % ethanol), young adult female BALB/c mice (5/group) were tested using the local lymph node assay. The positive control item, Dinitrochlorobenzene (DNCB), as a known contact allergen (0.5% (w/v)) elicited the expected reaction pattern with a significant increase in the Stimulation Index (SI; 24.70) and ear weight. The value of the SI for groups treated at the 2% and 0.2% dose levels was below the threshold (2.06 and 1.09, respectively). The EC3 was calculated to be 17.96%. Under the given test conditions, the test item, 1,3 - Propenesultone, demonstrated a positive sensitising response in the LLNA assay.

As the substance is a dermal sensitiser, some dermal absorption occurs. The ECHA guidance criteria (Chapter R.7C) state that 10% dermal absorption is used when the molecular weight of the substance is >500 and the log Pow is <-1 or >4, otherwise 100% dermal absorption is used. In general, dermal absorption will not be higher than oral absorption, so for chemical safety assessment purposes a dermal absorption rate of 50% is accepted.

Absorption – inhalation

In an acute inhalation toxicity study (OECD 403/GLP), the LC50 male/female was > 2.08 mg/L (mean maximum achievable concentration) with no mortalities, treatment-related clinical signs or gross pathological findings observed. For chemical safety assessment purposes, an inhalation absorption rate of 100% is accepted

Distribution/Metabolism/Excretion

Based on the information provided from the in vivo studies, there is limited distribution throughout the body, no target organ for toxicity and any water-soluble metabolites will be excreted in the urine.