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

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1993-06-14 - 1993-06-18 (experimental phase)

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:

skin irritation: in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

1993-06-14 - 1993-06-18 (experimental phase)

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 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

OECD guideline for the testing of chemicals no. 404 (May 12, 1981)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Version / remarks:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

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:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harald Schriever, Kaninchenfarm, 27432 Bremervörde, Neuendamm 88
- Housing: individual housing (50 x 45 x 40 cm, L x B x H) in a battery of cages, each equipped with a paper roll disposal system
- Diet (e.g. ad libitum): Ssniff K - Haltung (Alleindiät fur Zuchtkaninchen), pellets, 1.0-1.5 cm long, 0.5 cm diameter, by Ssniff Spezialdiäten GmbH, 59494 Soest/Westfalen, ad libitum
- Water (e.g. ad libitum): drinking water as for human consumption via drinking nipples ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20±3°C
- Humidity (%):30-70%
Measurement: twice daily
- Photoperiod (hrs dark / hrs light): artificial lighting (120 lux) from 7.00 a.m. - 7.00 p.m.

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

water

Remarks:

The test article was moistened sufficiently with aqua ad iniectabilia to ensure a good contact with the skin.

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5g
- Concentration (if solution): The test article was moistened sufficiently with aqua ad iniectabilia to ensure a good contact with the skin.

VEHICLE
- Amount(s) applied (volume or weight with unit): water

Duration of treatment / exposure:

4h

Observation period:

Animals were examined for signs of erythema and oedema at 30-60 min, 24, 48 and 72 h after patch removal.

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: 24 h before treatment, fur was removed with electric clippers from an area of roughly 8 x 15 cm on the back of each animal. The skin was examined for abrasions and only animals with healthy, intact skin were used in the test.
- Type of wrap if used: A gauze patch (Ypsiplast®, Holthaus Medical, Remscheid-Luttringhausen) with 0.5 g of the test article was applied to the test site, an adjacent area of untreated skin was covered only with a gauze patch and served as a control. The gauze patches were held in place with a semi-occlusive dressing consisting of non-irritating tape (Elastoplast®, Beiersdorf AG, Hamburg), and Stiilpa® (P. Hartmann AG, Heidenheim-Brenz), which enveloped the whole of the animal's trunk.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): patch was removed
- Time after start of exposure: 24h

OBSERVATION TIME POINTS
Animals were examined for signs of skin reactions at 30-60 min, 24,48 and 72 h after patch removal.

SCORING SYSTEM: as indicated in the guideline

Erythema and Eschar Formation
Value
No erythema 0
Very slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beet redness) to slight eschar formation (injuries in depth) 4
Maximum possible = 4

Oedema Formation
Value
No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well defined by definite raising) 2
Moderate oedema (raised approximately 1 mm) 3
Severe oedema (raised more than 1 mm and extending beyond area of exposure) 4
Maximum possible = 4

- Method of calculation: Skin reactions were classified with special consideration of the EEC directive 91/325/EEC of March 1, 1991 and GefStoffV, 1987 (BGBL I, p. 2721), i.e. Mean values of skin reactions at 24, 48 and 72 h after patch removal were calculated.

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.3

Max. score:

1

Reversibility:

fully reversible within: 48h

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal: 1, 2, 3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

Clinical observations: Slight erythema of the test site was apparent up to 24 h after patch removal.
Reversibility: The observed findings were reversible within 48 h.
Serious lesions and toxic effects other than dermal irritation: No other serious lesions or toxic effects were observed.

Other effects:

No other serious lesions or toxic effects were observed.

Interpretation of results:

GHS criteria not met

Conclusions:

The study was conducted according to OECD 404 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 scoring data allows classification acc. GHS.
According to Regulation (EC) 1272/2008 table 3.2.2, a substance must be classified as Irritating to skin (Category 2), if the following criteria are met:
1) Mean value of ≥ 2,3 - ≤ 4,0 for erythema/ eschar or for oedema in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after patch removal or, if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions; or
(2) Inflammation that persists to the end of the observation period normally 14 days in at least 2 animals, particularly taking into account alopecia (limited area), hyperkeratosis, hyperplasia, and scaling; or
(3) In some cases where there is pronounced variability of response among animals, with very definite positive effects related to chemical exposure in a single animal but less than the criteria above.
The mean grades of dermal reactions at 24, 48 and 72 h were lower than the ones triggering classification as irritating to the skin. Slight erythema of the test site was apparent up to 24 h after patch removal in one of three animals, leading to an erythema score of 0.3 in one animal. All other animals revealed scores of zero. The observed findings were reversible within 48 h. No other serious lesions or toxic effects were observed. Hence, the substance does not need to be classified as irritating to the skin.

Executive summary:

The potential toxicity of "POPS" was assessed in an acute dermal irritation/corrosion test on 3 albino rabbits in an OECD 404 study under GLP. The skin was exposed to 0.5 g of the test article for 4 h (semi-occlusive). Animals were examined for signs of erythema and oedema at 30-60 min, 24, 48 and 72 h after patch removal.

Clinical observations: Very slight erythema of the test site was observed in one animal (no. 2) which was reversible within 48 h after patch removal, leading to an erythema score of 0.3. All other animals revealed scores of zero, Oedema score was zero in all animals.

Assessment: The mean grades of skin reactions at 24, 48 and 72 h after patch removal were lower than the value classified as irritant by the EEC directive 91/325/EEC of March 1, 1991, the Gefahrstoffverordnung (GefStoffV), 1987 (BGB1. I, p. 2721), and Regulation (EC) 1272/2008. When applied to the skin for 4 h, the test article "POPS" might therefore be considered to be non-irritant.

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 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

OECD guideline for the testing of chemicals no. 404 (May 12, 1981)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Version / remarks:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

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:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harald Schriever, Kaninchenfarm, 27432 Bremervörde, Neuendamm 88
- Housing: individual housing (50 x 45 x 40 cm, L x B x H) in a battery of cages, each equipped with a paper roll disposal system
- Diet (e.g. ad libitum): Ssniff K - Haltung (Alleindiät fur Zuchtkaninchen), pellets, 1.0-1.5 cm long, 0.5 cm diameter, by Ssniff Spezialdiäten GmbH, 59494 Soest/Westfalen, ad libitum
- Water (e.g. ad libitum): drinking water as for human consumption via drinking nipples ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20±3°C
- Humidity (%):30-70%
Measurement: twice daily
- Photoperiod (hrs dark / hrs light): artificial lighting (120 lux) from 7.00 a.m. - 7.00 p.m.

Test system

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

water

Remarks:

The test article was moistened sufficiently with aqua ad iniectabilia to ensure a good contact with the skin.

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5g
- Concentration (if solution): The test article was moistened sufficiently with aqua ad iniectabilia to ensure a good contact with the skin.

VEHICLE
- Amount(s) applied (volume or weight with unit): water

Duration of treatment / exposure:

4h

Observation period:

Animals were examined for signs of erythema and oedema at 30-60 min, 24, 48 and 72 h after patch removal.

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: 24 h before treatment, fur was removed with electric clippers from an area of roughly 8 x 15 cm on the back of each animal. The skin was examined for abrasions and only animals with healthy, intact skin were used in the test.
- Type of wrap if used: A gauze patch (Ypsiplast®, Holthaus Medical, Remscheid-Luttringhausen) with 0.5 g of the test article was applied to the test site, an adjacent area of untreated skin was covered only with a gauze patch and served as a control. The gauze patches were held in place with a semi-occlusive dressing consisting of non-irritating tape (Elastoplast®, Beiersdorf AG, Hamburg), and Stiilpa® (P. Hartmann AG, Heidenheim-Brenz), which enveloped the whole of the animal's trunk.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): patch was removed
- Time after start of exposure: 24h

OBSERVATION TIME POINTS
Animals were examined for signs of skin reactions at 30-60 min, 24,48 and 72 h after patch removal.

SCORING SYSTEM: as indicated in the guideline

Erythema and Eschar Formation
Value
No erythema 0
Very slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beet redness) to slight eschar formation (injuries in depth) 4
Maximum possible = 4

Oedema Formation
Value
No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well defined by definite raising) 2
Moderate oedema (raised approximately 1 mm) 3
Severe oedema (raised more than 1 mm and extending beyond area of exposure) 4
Maximum possible = 4

- Method of calculation: Skin reactions were classified with special consideration of the EEC directive 91/325/EEC of March 1, 1991 and GefStoffV, 1987 (BGBL I, p. 2721), i.e. Mean values of skin reactions at 24, 48 and 72 h after patch removal were calculated.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Results 2

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.3

Max. score:

1

Reversibility:

fully reversible within: 48h

Results 3

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Results 4

Irritation parameter:

edema score

Basis:

animal: 1, 2, 3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

Clinical observations: Slight erythema of the test site was apparent up to 24 h after patch removal.
Reversibility: The observed findings were reversible within 48 h.
Serious lesions and toxic effects other than dermal irritation: No other serious lesions or toxic effects were observed.

Other effects:

No other serious lesions or toxic effects were observed.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The study was conducted according to OECD 404 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 scoring data allows classification acc. GHS.
According to Regulation (EC) 1272/2008 table 3.2.2, a substance must be classified as Irritating to skin (Category 2), if the following criteria are met:
1) Mean value of ≥ 2,3 - ≤ 4,0 for erythema/ eschar or for oedema in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after patch removal or, if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions; or
(2) Inflammation that persists to the end of the observation period normally 14 days in at least 2 animals, particularly taking into account alopecia (limited area), hyperkeratosis, hyperplasia, and scaling; or
(3) In some cases where there is pronounced variability of response among animals, with very definite positive effects related to chemical exposure in a single animal but less than the criteria above.
The mean grades of dermal reactions at 24, 48 and 72 h were lower than the ones triggering classification as irritating to the skin. Slight erythema of the test site was apparent up to 24 h after patch removal in one of three animals, leading to an erythema score of 0.3 in one animal. All other animals revealed scores of zero. The observed findings were reversible within 48 h. No other serious lesions or toxic effects were observed. Hence, the substance does not need to be classified as irritating to the skin.

Executive summary:

The potential toxicity of "POPS" was assessed in an acute dermal irritation/corrosion test on 3 albino rabbits in an OECD 404 study under GLP. The skin was exposed to 0.5 g of the test article for 4 h (semi-occlusive). Animals were examined for signs of erythema and oedema at 30-60 min, 24, 48 and 72 h after patch removal.

Clinical observations: Very slight erythema of the test site was observed in one animal (no. 2) which was reversible within 48 h after patch removal, leading to an erythema score of 0.3. All other animals revealed scores of zero, Oedema score was zero in all animals.

Assessment: The mean grades of skin reactions at 24, 48 and 72 h after patch removal were lower than the value classified as irritant by the EEC directive 91/325/EEC of March 1, 1991, the Gefahrstoffverordnung (GefStoffV), 1987 (BGB1. I, p. 2721), and Regulation (EC) 1272/2008. When applied to the skin for 4 h, the test article "POPS" might therefore be considered to be non-irritant.