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Carcinogenicity

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Description of key information

Key: Literatue data on 1,3,2-Dioxathiolane, 2,2-dioxide:

In the paper of Van Duuren et al.(1974), ESA (glycol sulfate) was tested in female ICR/Ha Swiss mice for carcinogenic activity.

Routes of administration

No of mice / group

Dose or volume / solution

Application site

Treatment frequency / duration

Outcome

skin

n = 30

0.1 mg/0.1 mL acetone

interscapular region (shaved skin)

3 times a week / 456 days

No papilloma / no carcinoma

Summary: 0/30

sc injection

n = 30

0.5 mg/0.05 mL tricaprylin

left flank

once a week /

413 days

21 sarcomas /

1 squamous cell carcinomas /

0 adenocarcinomas

(P for total malignant tumors < 0.01 : significant tumorogenic activity)

Summary: 22/30

ip injection

n = 30

0.05 mg/0.05 mL tricaprylin

lower abdomen

once a week /

450 days

9 papillary tumors of lung / 5 local sarcomas

Summary: 6/30

The authors carefully regarded the test item solubility and stability before testing: ESA was diluted in acetone or tricaprylin. ESA diluted in acetone showed no more than 1% degradation during a month.

ESA tested though subcutaneous (sc) injection showed significant local malignant tumor incidence (P < 0.01) of sarcomas at the injection site. Authors assumed that the sulfate reacting with nucleophiles in neutral media undergoes C-O scission. In these instances, one requirement for biologic activity seems to be ready cleavage of the carbon-oxygen bond.

In the described test, no local and distant tumours were observed after the mouse skin application with 0.1 mg ESA/ 0.1 mL acetone 3 times a week during 456 days. In addition, no skin tumours after similar exposure were observed in an open chain analogue dimethyl sulfate. It can therefore be assumed that dermal exposure to ESA at the indicated level was the Non Observed Effect Level (NOEL) related to the absence of tumour incidence. However, no other information related to the other adverse toxicity in mice after ESA exposure was available.

Supporting literature data on structurally similar substances:

1,3-propanesultone (EC 214-317-9, CAS 1120-71-4):

Druckrey et al, 1970:

According to the literature (Druckrey et al, 1970), 1,3-propanesultone is highly reactive and is rapidly destroyed by heterolysis (half-life of hydrolyse t1/2was 110 min at 37 °C in phosphate buffer with pH 7.4). When given sc at weekly dosages of 15 and 30 mg/kg bw respectively, and even as single dose, it produces a high yield of sarcomas at the site of injection. After oral or intravenous (iv) administration only a limited number of malignant tumours in remote organs is observed, 10 of them in the nervous system. When given to pregnant rats on the 15thday of gestation as a single iv injection of 20 and 60 mg/kg respectively, malignant and mainly neurogenic tumours occurred in 7 out of 39 rats of the offspring. According to these results, 1,3-propanesultone is a potent carcinogen. The next higher homologue, 1,4-butanesultone is much less carcinogenic and may account for this difference in the structure and biological activity.

Weisburger et al, 1981:

Fourteen chemicals, including propane sultone, were tested for carcinogenicity by oral administration in male and female Charles River CD rats.

Propane sultone induced significant increases in malignant gliomas and mammary adenocarcinomas, and the incidences of leukemia, cancer of the small intestine, and squamous cell carcinoma of the ear duct were increased over those in controls.

Under the conditions of the test, propane sultone, in addition to the positive control (N-2-fluorenylacetamide), were carcinogenic.

Methyl methanesulphonate (EC 200-625-0, CAS 66-27-3):

Sekkakumar et al, 1987:

Inhalation exposure was conduct on water reactive compound, methylmethane sulfonate (MMS), on male Sprague-Dawley rats. The comound was administered for 30 days (6 hr/day x 5 days/wk) with the use of exposure concentrations that were inversely proportional to hydrolysis rate: t1/2: 580 min, exposure concentraiton 50 ppm.

Within this protocol, MMS produced nasal cancer in rats. The concentration of MMS employed in the studies produced similar nasal cancer yields, indicating that the carcinogenic potency of this compound in rat nasal mucosa was proportional to this hydrolysis rate.

Dimethyl sulfate (EC 201-058-1, CAS 201-058-1)

According to literature, subcutaneous injections once a week of dimethyl sulfate produced local sarcomas in BD-strain rats, the yield corresponding to dosage. However, given by oral route or by intravenous injections dimethyl sulfate was inactive. Inhalation of dimethyl sulfate vapours, 3 and 10 ppm respectively for one hour five times per week, however, produced squameous carcinomas of the nascal cavity or neurogenic tumours in 8 out of 27 exposed rats.

The substances used for supporting data are all classified for carcinogenicity and are described as alkylating agents.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed

Mode of Action Analysis / Human Relevance Framework

The substance has been identified as a possible alkylating agent in available literature data and by QSAR structural alerts. However, the mode of action is not able to be definitively concluded from the available data.

Additional information

ESA QSAR modelling: carcinogenicity and carcinogenic potency TD50:

Further investigation of ESA carcinogenic properties by means of (Q)SAR modelling was performed.

The carcinogenicity of ESA was investigated by in silico modelling. From a qualitative point of view two highly reliable predictions were positive in RFMN/Antares and IRFMN/ISSCAN-CGX models. With low reliability, positive weight of evidence for carcinogenicity in rodents was predicted by TOPKAT.

The OECD QSAR Toolbox profiled the query compound according to oncologic primary classification as well as OncoLogic™ software for sultone reactive group alert. Sultones are direct-acting alkylating agents. However, in the OECD QSAR Toolbox there was not enough data to conduct the read across analysis with proposed structural similar compounds.

Performed (Q)SAR modelling with ESA hydrolysis product, hydroxyethyl sulphate, showed in the predictions less expressed carcinogenic properties. As for ESA, two out of four Vega carcinogenicity models predicted hydroxyethyl sulphate to be carcinogen showing high and moderate reliabilities. All negative predictions for hydroxyethyl sulphate were low reliable (Caesar, ISS; TOPKAT). In addition, no alert was triggered in the OECD QSAR Toolbox according to oncologic primary classification as well as in OncoLogic™ software.

In the TOPKAT modelling the TD50 standardized measure of carcinogenic potency was used. TD50 is the daily dose rate in mg/kg bw/day to induce tumors in half of test animals that would have remained tumor-free at zero dose. The carcinogenic potency TD50 for ESA was 3 and 7 times lower than for its hydrolysis product hydroxyethyl sulphate in mouse and rat, respectively. The reduction of carcinogenic potency in the hydrolysis product correlates with the lower evidence of carcinogenicity of hydroxyethyl sulphate in the carcinogenicity predictions of the (Q)SAR models.

This tendency is also observed by analogue structure 1,3‑propanesultone where the carcinogenic potency TD50 modelled with TOPKAT, for 1,3‑propanesultone was 2 and 6 times lower than for 3-hydroxypropane-sulophonic acid.

ESA (Q)SAR modelling

Carcinogenicity Model

Prediction

Reliability

VEGA

 

 

-Caesar

neg

low

-ISS

neg

low

-RFMN/Antares

pos

high

-IRFMN/ISSCAN-CGX

pos

high

Toxtree

no alert

-

OECD QSAR Toolbox

 

 

-Oncologic Primary Classification

Alert: sultone reactive functional group

-

-Carcinogenicity (gentox and nongenotox) alerts by ISS

no alert

-

OncoLogic

pos

low

TOPKAT

 

 

-Weight of evidence

pos

low

-Carc Potency TD50 mouse (mg/kg bw/day)

40.2

low

-Carc Potency TD50 rat (mg/kg bw/day)

28.8

low

Hydrolysis product: Hydroxyehtyl sulphate (Q)SAR modelling:

Carcinogenicity Model

Prediction

Reliability

VEGA

 

 

-Caesar

neg

low

-ISS

neg

low

-RFMN/Antares

pos

mod

-IRFMN/ISSCAN-CGX

pos

high

Toxtree

no alert

-

OECD QSAR Toolbox

 

 

-Oncologic Primary Classification

no alert

-

-Carcinogenicity (gentox and nongenotox) alerts by ISS

no alert

-

OncoLogic

N/A

low

TOPKAT

 

 

-Weight of evidence

neg

low

-Carc Potency TD50 mouse (mg/kg bw/day)

123.8

low

-Carc Potency TD50 rat (mg/kg bw/day)

207.6

low

QSAR modelling was also performed on 1,3-propanesultone (which has a harmonised classification for carcinogenicity) to compare against the QSAR modelling results for ESA.

Positive results for carcinogenicity were also obtained for 1,3 -propansultone.

1,3-propanesultone (Q)SAR modelling

Carcinogenicity Model

Prediction

Reliability

VEGA

 

 

-Caesar

neg

low

-ISS

pos

high

-RFMN/Antares

pos

high

-IRFMN/ISSCAN-CGX

pos

high

Toxtree

Alert: propiloactones/propiosultones

-

OECD QSAR Toolbox

 

 

-Oncologic Primary Classification

Alert: sultone reactive functional group

-

-Carcinogenicity (gentox and nongenotox) alerts by ISS

Alert: propioloactones or propiosultones (genotox)

-

OncoLogic

pos

-

TOPKAT

 

 

-Weight of evidence

pos

mod

-Carc Potency TD50 mouse (mg/kg bw/day)

40.1

low

-Carc Potency TD50 rat (mg/kg bw/day)

31.1

high

Lower evidence of carcinogenicity of 3-hydroxypropane-sulophonic acid (hydrolysis product) was observed when compared against 1,3 -propanesultone.

Justification for classification or non-classification

Based on the available data the substance, 1,3,2-Dioxathiolane, 2,2-dioxide is classified as Carc. Cat 2 (H351: Suspected of causing cancer).

No route of exposure is identified as the available literature data on ESA, showing significant local malignant tumor incidence, was by exposure through subcutaneous (sc) injection.

Insufficient data is available on oral, inhalation and dermal exposure routes on 1,3,2-Dioxathiolane, 2,2-dioxide

to conclusively prove that there is no hazard via any of these routes.