Sodium 3-(2-propyn-1-yloxy)-1-propanesulfonate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1993-06-03 - 1993-06-23

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

under GLP, sufficiently documented

Justification for type of information:

see target record

Cross-reference

Reason / purpose for cross-reference:

read-across source

Remarks:

target record

Reference

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1993-06-03 - 1993-06-23

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

Klimisch 1 source record, but performed on read-across substance

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The rational for the analogue approach is the high structural similarity between the source and the target substance. Propargyl 3-sulfopropyl ether, potassium salt, and Propargyl 3-sulfopropyl ether, sodium salt, are structurally identical except the inorganic counterion, potassium resp. sodium. This difference is considered very minor as both cations are ubiquitously present in the body fluids, and the organic moieties are identical containing three functional groups in the molecules which are considered more relevant for their toxicological behaviour, i.e. the alkine, ether and sulfo group.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

Source Chemical: Propargyl 3-sulfopropyl ether, potassium salt, EC 618-959-4, CAS 93637-00-4, SMILES Code C#CCOCCCS(=O)(=O)[O-].[K+], molecular formula C6H9O4KS, Mol. Weight 216.2994 g/mol

Target Chemical: Propargyl 3-sulfopropyl ether, sodium salt, EC 608-454-7, CAS 30290-53-0, SMILES Code C#CCOCCCS(=O)(=O)[O-].[Na+], molecular formula C6H9O4NaS, Mol. Weight 200.19 g/mol

Both substances do not contain impurities to an extent which is expected to alter the outcome of the experimental results or read-across approach.

3. ANALOGUE APPROACH JUSTIFICATION
According to REACH Annex XI, chapter 1.5, “Substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or "category" of substances.”… “The similarities may be based on:
1) a common functional group;
2) the common precursors and/or the likelihood of common breakdown products via physical and biological processes, which result in structurally similar chemicals…”.
Hence, Propargyl 3-sulfopropyl ether, sodium salt was analyzed regarding these criteria in the order as stated above:
1) Propargyl 3-sulfopropyl ether, sodium salt, is an organic salt with a sodium cation as inorganic counterion. The inorganic cation sodium (Na+) is widely distributed throughout the body and a normal constituent in the electrolyte system of vertebrates. Hence, it suggests itself to predominantly focus on the organic anion and regard it unchanged as a first step. So, the complete organic cation shall serve as a ‘functional group’ in this case. Further analogues can therefore be easily found by exchanging the inorganic counterion into a similar one of a similar size and low or no intrinsic toxic properties. Obvious here are e.g. potassium, hydrogen or ammonium.
2) Due to the ionic structure of all above mentioned salts, they all dissociate readily into the respective ions when getting into contact with water, which can be scientifically concluded. Propargyl 3-sulfopropyl ether, sodium salt, is distributed as a 50% aqueous solution and hence very soluble in water; the registered substance containing water is fully miscible in water. A similar behaviour can be assumed for POPS-K. In consequence, both substances can be reasonably expected to be present completely dissociated in the body fluids predominantly consisting of water. So, the organic moiety is identical in both substances and can be regarded as common breakdown product according to the Regulation. The substances structurally only differ in their inorganic cation, which can be considered as a very minor difference as both cations are ubiquitously present in the body fluids.
The data matrix displays exemplarily the chlorides of the inorganic counterions in question, sodium and potassium. Both salts show mild to moderate irritating effects, data available on POPS-K indicate very minor irritating effects not sufficient for classification. In general, the observed effects can be considered as rather consistent given the magnitude of effects, ionic structure of the cations, the content of the cations in the actual source and target chemical and the available data quality.
In both RTECS and GESTIS Substance Database of the German IFA providing various information on hazardous substances at the workplace, no information is given that NaCl or KCl are sensitizing which is comprehensible out of the following reasons: both sodium and potassium are ubiquitously present in the body and no information is given on autoimmune diseases associated with these ions. Further, these cations are not capable to act as (pre-)haptene or allergen. Immune responses are associated with proteins, and those ion are neither a protein nor capable of binding on them or modify them in a manner that the immune system is capable of recognizing them. Hence, a immune response could maximally be caused by the organic anion, which is identical in both source and target substance.
With regard to acute toxicity, also here possible differences may only arise from the cation. As displayed in the data matrix, potassium is in general of higher toxicity compared to sodium. Hence, a read-across is unlikely to underestimate the actual hazard of the registered substance, and more likely to overestimate it. Hence, read-across does not pose a potential risk and can be justified.

According to the RTECS database, for both NaCl and KCl, there are positive effects noted in various assays related to mutagenicity. According to the GESTIS database however, „There are no indications that NaCl has any mutagenic effects. NaCl solutions of very low concentrations have been used as solvents for test substances in a variety of mutagenicity tests (because of their inactivity). Positive reactions found in isolated cases on cultivated mammalian cells or in microorganisms were probably caused by osmotic effects and are not attributable to mutagenicity. There are no indications that NaCl has any carcinogenic effects.“ (http://gestis-en.itrust.de/nxt/gateway.dll/gestis_en/000000.xml?f=templates$fn=default.htm$vid=gestiseng:sdbeng$3.0). For KCl, that information is not given, but expectable, as also potassium is contained in cell culturing media, and the same osmotic effects in higher concentrations are expectable. Summarizing, there is no indication given that the exchange of the cation (Na+ or K+) would result in a different outcome of gene mutation testing in bacteria, hence, read-across is justified.
An obvious difference is that the potassium salt may be isolated as solid, whereas the sodium salt undergoes slight changes during isolation, can hence not be isolated as such and so the water must be considered as stabilizer in its identification. However, when being dissolved resp. diluted in the body fluids predominantly consisting of water, this difference can be neglected.

4. DATA MATRIX
There is not sufficient data on both complete, non-dissociated substances available to allow a direct comparison. Further, QSAR estimation revealed identical phys.-chem. properties, as e.g. for EpiSuite (US EPA) estimations, the inorganic ion is not regarded. However, as stated above, both organic salts immediately dissociate into the respective ions. Hence, the toxicity of the more relevant organic anion, Propargyl 3-sulfopropyl ether, does not need to be regarded for depicting possible differences or similarities, as it is identical in both molecules, and it is sufficient to compare the different cations only. Exemplarily, sodium and potassium chloride are compared, data is derived from RTECS (http://ccinfoweb.ccohs.ca/rtecs/search.html)

For the table, please refer to the attached justification

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

OECD guideline for the testing of chemicals OECD 401 (February 24, 1987)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Version / remarks:

EEC directive 84/449 EEC (September 19, 1984)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: sponsor

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: ambient, protected from light

Species:

rat

Strain:

Wistar

Remarks:

Bor: WISW (SPF Cpb)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Fa. Harlan Winkelmann, Versuchstierzucht GmbH & Co. KG, Gartenstr. 27, 33178 Borchen
- Weight at study initiation: m: 230 - 272 g, f: 183 - 198 g
- Fasting period before study: The animals were fasted from 16 h before until 3 - 4 h after administration of the test article.
- Housing: collective housing up to a maximum of 5 animals per cage (Makrolon® type III)
- Diet (e.g. ad libitum): Ssniff-R Alleindiät, by Ssniff Spezialdiäten GmbH, 59494 Soest/Westfalen, pellets, 2.5 cm long, 1.0 cm diameter, ad libitum
- Water (e.g. ad libitum): drinking water as for human consumption via drinking bottles ad libitum
- Acclimation period: Prior to study initiation, the animals were acclimatized to laboratory conditions for at least 5 days. Only healthy animals were used in the test.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3°C
- Humidity (%): 30 - 70 %
Measurement: with thermohygrometer twice daily
- Photoperiod (hrs dark / hrs light): artificial lighting (120 lux) from 7.00 a.m. - 7.00 p.m.

IN-LIFE DATES: From: May 12,19 and 26,1993

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 20%
- Amount of vehicle (if gavage): 10 ml/kg

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

- Rationale for the selection of the starting dose: A preliminary range finding test with a dose of 2000 mg/kg body weight was conducted using two female rats. There were no deaths in the preliminary study.

Doses:

2000 mg/kg

No. of animals per sex per dose:

5 / sex / dose

Control animals:

no

Remarks:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: In each animal a number of clinical-toxicological signs were evaluated according to a modified Irwin-Screening procedure (Screening Methods in Pharmacology, R. A. Turner, 1965, p. 26). The animals were examined at the following post-treatment intervals: 10 min, 1 h, 2 h, 6 h, 24 h, and thereafter once daily up to day 14. Body weights were recorded immediately before treatment (day 0) and on days 7 and 14 p.a. (termination).
- Necropsy of survivors performed: yes, The animals were sacrificed by CO2 asphyxiation after 14 days and gross pathological examinations were subsequently performed.
- Other examinations performed: clinical signs, body weight, gross examinations

Preliminary study:

There were no deaths in the preliminary study.

Key result

Sex:

male/female

Dose descriptor:

LD50 cut-off

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no mortalities occurred at a dose of 2000 mg/kg

Key result

Sex:

male/female

Dose descriptor:

LD0

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no mortalities occurred at a dose of 2000 mg/kg

Mortality:

No animal died during the course of the main study.

Clinical signs:

No abnormal clinical signs were observed.

Body weight:

Weight gains were normal in all animals.

Gross pathology:

Gross pathological examinations at 14 days p. a. (terminal necropsy) revealed no test article-dependent findings. Those macroscopic changes observed were attributable to the sacrificing procedure or to minor variations which can occur spontaneously in rats of this strain and age.
Specific findings were:
urinary bladder: urinary retention (one male)
uterus: hydrometra (one female)
no specific findings (remaining 4 males / 4 females)

Interpretation of results:

GHS criteria not met

Remarks:

EU implementation

Conclusions:

The study was conducted according to OECD 401 under GLP and is sufficiently documented. Hence, the available study is sufficiently reliable to assess the skin irritating potential of propargyl-3-sulfopropyl ether, potassium salt, and the given data allows classification according to Regulation (EC) 1272/2008. The regulation sets the cut-off value for classification as acutely toxic Cat. 4 to LD50 > 2000 mg/kg. At this dose, none of the animals died, and hence, no classification as acutely toxic is triggered.

Executive summary:

The acute oral toxicity of "POPS" was investigated in 5 male and 5 female Wistar rats in a limit study acc. OECD 401 under GLP.

On the basis of the range finding results, the animals were given a single oral administration of "POPS" at a dose of 2000 mg/kg.

Clinical observations were conducted at regular intervals during the 14-day observation period. Body weights were measured at days 0, 7 and 14 p.a. Gross pathological examinations were performed on all animals 14 days p.a.

The following results were obtained:

1. No abnormal clinical signs were observed.

2. Weight gains were normal in all animals.

3. Gross pathological examinations at 14 days p.a, (terminal necropsy) revealed no test article-dependent findings.

4. According to the requirements of the limit test, the LD50 values after 24 h and 14 days were as follows: male and female > 2000 mg/kg

5. The above value is higher than the limit specified as harmful by the EEC directive 91/325/EEC, the Gefahrstoffverordnung (GefStoffV), 1987 (BGB1. I, p. 2721) and Regulation (EC) 1272/2008. When administered by the oral route, the test article "POPS" may therefore be classified as "non-toxic".

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1993

Report date:

1993

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

OECD guideline for the testing of chemicals OECD 401 (February 24, 1987)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Version / remarks:

EEC directive 84/449 EEC (September 19, 1984)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

potassium 3-(prop-2-yn-1-yloxy)propane-1-sulfonate

EC Number:

618-959-4

Cas Number:

93637-00-4

Molecular formula:

C6H9O4KS

IUPAC Name:

potassium 3-(prop-2-yn-1-yloxy)propane-1-sulfonate

Test material form:

solid: particulate/powder

Remarks:

yellowish

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: sponsor

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: ambient, protected from light

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Bor: WISW (SPF Cpb)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Fa. Harlan Winkelmann, Versuchstierzucht GmbH & Co. KG, Gartenstr. 27, 33178 Borchen
- Weight at study initiation: m: 230 - 272 g, f: 183 - 198 g
- Fasting period before study: The animals were fasted from 16 h before until 3 - 4 h after administration of the test article.
- Housing: collective housing up to a maximum of 5 animals per cage (Makrolon® type III)
- Diet (e.g. ad libitum): Ssniff-R Alleindiät, by Ssniff Spezialdiäten GmbH, 59494 Soest/Westfalen, pellets, 2.5 cm long, 1.0 cm diameter, ad libitum
- Water (e.g. ad libitum): drinking water as for human consumption via drinking bottles ad libitum
- Acclimation period: Prior to study initiation, the animals were acclimatized to laboratory conditions for at least 5 days. Only healthy animals were used in the test.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3°C
- Humidity (%): 30 - 70 %
Measurement: with thermohygrometer twice daily
- Photoperiod (hrs dark / hrs light): artificial lighting (120 lux) from 7.00 a.m. - 7.00 p.m.

IN-LIFE DATES: From: May 12,19 and 26,1993

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 20%
- Amount of vehicle (if gavage): 10 ml/kg

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

- Rationale for the selection of the starting dose: A preliminary range finding test with a dose of 2000 mg/kg body weight was conducted using two female rats. There were no deaths in the preliminary study.

Doses:

2000 mg/kg

No. of animals per sex per dose:

5 / sex / dose

Control animals:

no

Remarks:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: In each animal a number of clinical-toxicological signs were evaluated according to a modified Irwin-Screening procedure (Screening Methods in Pharmacology, R. A. Turner, 1965, p. 26). The animals were examined at the following post-treatment intervals: 10 min, 1 h, 2 h, 6 h, 24 h, and thereafter once daily up to day 14. Body weights were recorded immediately before treatment (day 0) and on days 7 and 14 p.a. (termination).
- Necropsy of survivors performed: yes, The animals were sacrificed by CO2 asphyxiation after 14 days and gross pathological examinations were subsequently performed.
- Other examinations performed: clinical signs, body weight, gross examinations

Results and discussion

Preliminary study:

There were no deaths in the preliminary study.

Effect levels

Effect levels 1

Key result

Sex:

male/female

Dose descriptor:

LD50 cut-off

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no mortalities occurred at a dose of 2000 mg/kg

Effect levels 2

Key result

Sex:

male/female

Dose descriptor:

LD0

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no mortalities occurred at a dose of 2000 mg/kg

Mortality:

No animal died during the course of the main study.

Clinical signs:

No abnormal clinical signs were observed.

Body weight:

Weight gains were normal in all animals.

Gross pathology:

Gross pathological examinations at 14 days p. a. (terminal necropsy) revealed no test article-dependent findings. Those macroscopic changes observed were attributable to the sacrificing procedure or to minor variations which can occur spontaneously in rats of this strain and age.
Specific findings were:
urinary bladder: urinary retention (one male)
uterus: hydrometra (one female)
no specific findings (remaining 4 males / 4 females)

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Remarks:

EU implementation

Conclusions:

The study was conducted according to OECD 401 under GLP and is sufficiently documented. Hence, the available study is sufficiently reliable to assess the skin irritating potential of propargyl-3-sulfopropyl ether, potassium salt, and the given data allows classification according to Regulation (EC) 1272/2008. The regulation sets the cutt-off value for classification as acutely toxic Cat. 4 to LD50 > 2000 mg/kg. At this dose, none of the animals died, and hence, no classification as acutely toxic is triggered.

Executive summary:

The acute oral toxicity of "POPS" was investigated in 5 male and 5 female Wistar rats in a limit study acc. OECD 401 under GLP.

On the basis of the range finding results, the animals were given a single oral administration of "POPS" at a dose of 2000 mg/kg.

Clinical observations were conducted at regular intervals during the 14-day observation period. Body weights were measured at days 0, 7 and 14 p.a. Gross pathological examinations were performed on all animals 14 days p.a.

The following results were obtained:

1. No abnormal clinical signs were observed.

2. Weight gains were normal in all animals.

3. Gross pathological examinations at 14 days p.a, (terminal necropsy) revealed no test article-dependent findings.

4. According to the requirements of the limit test, the LD50 values after 24 h and 14 days were as follows: male and female > 2000 mg/kg

5. The above value is higher than the limit specified as harmful by the EEC directive 91/325/EEC, the Gefahrstoffverordnung (GefStoffV), 1987 (BGB1. I, p. 2721) and Regulation (EC) 1272/2008. When administered by the oral route, the test article "POPS" may therefore be classified as "non-toxic".