Potassium 3-sulphopropyl methacrylate

Skin sensitisation

Administrative data

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

03 Aug - 08 Sep 2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

GLP

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
see target record

Cross-reference

Reason / purpose for cross-reference:

read-across source

Remarks:

link to target

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

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

Adequacy of study:

key study

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
[Please provide information for all of the points below. Indicate if further information is included as attachment to the same record, or elsewhere in the dataset (insert links in 'Cross-reference' table)]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The rational for the analogue approach is the high structural similarity between the source and the target substance. 2-Propenoic acid, 3-sulfopropyl ester, potassium salt (source) and 2-Propenoic acid, 2-methyl-,3-sulfopropylester, potassium salt (target) are structurally identical except an additional methyl group on position 2 of the target substance. Despite the fact that a methyl group may alter the toxicological behaviour of a substance, this effect is considered very minor as there are three common groups in the molecules which are considered more relevant for their toxicological behaviour, i.e. the sulfo-group, the ester and the Michael-acceptor system. Due to the similarities in structure, similar physico-chemical properties of the substances are to be expected, which would result in a similar toxicokinetic behaviour and most likely also in very similar toxicodynamic and toxicological behaviour.

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

Source Chemical: 2-Propenoic acid, 3-sulfopropyl ester, potassium salt, CAS 31098-20-1, EC 250-465-0, SMILES [K+].[O-]S(=O)(=O)CCCOC(=O)C=C, MW 232.30

Target Chemical: 2-Propenoic acid, 2-methyl-,3-sulfopropylester, potassium salt, CAS 31098-21-2, EC 250-466-6, SMILES [K+].CC(=C)C(=O)OCCCS(=O)(=O)O, MW 247.33

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
Comparing the actually available information on the substances with regard to their physico-chemical properties, the minor influence of the additional methyl group of the target chemical becomes obvious. So the molecular weight is in the same range, i.e. approx. 240 g/mol, indicating per se the potential for absorption. Both substances are solids which either do not melt or decompose at or above 300°C, and have hence a negligible vapour pressure. Both compounds are very soluble in water, and their logPow is in a negative range, < -3.
In general, absorption of a chemical is possible, if the substance crosses biological membranes. In case where no transport mechanisms are involved, this process requires a substance to be soluble, both in lipid and in water, and is also dependent on its molecular weight (substances with molecular weights below 500 are favourable for absorption). Relevant for the endpoint skin sensitisation is the absorption resp. retention in the skin. In order to cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the epidermis, the dermis and the vascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the epidermis is most resistant to penetration by highly lipophilic compounds. Substances with a molecular weight below 100 are favourable for penetration through the skin and substances above 500 are normally not able to penetrate. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility is below 1 mg/L, dermal uptake is likely to be low. Additionally logPow values between 1 and 4 favour dermal absorption. In the case of both the target and source chemical, due to their high water solubility and very low logPow, their absorption is very likely to be hindered in the stratum corneum. Nevertheless, once reaching the epidermis, i.a. due to their common small size, their absorption is favoured.
Besides the common physico-chemical and toxicokinetic properties, they exhibit a similar toxicological behaviour. Both substances are relatively non-toxic, with oral LD50 values >5000 mg/kg bw, and are non-irritating the skin and eyes.
Hence, due to the above-mentioned similarities of the source and target chemical, with regard to their structure, functional groups, toxicokinetic and toxicological behaviour, it can be reasonably concluded that a similar behaviour of the target chemical regarding its skin-sensitizing properties compared to the source chemical can be expected. In summary, the target chemical 2-Propenoic acid, 2-methyl-,3-sulfopropylester, potassium salt, needs to be regarded as skin sensitizer, too.


4. DATA MATRIX
The following table shows the available data relevant to justify the read-across from the source to the target chemical for the endpoint skin sensitization:

Endpoint Source: SPA Target: SPM
Molecular weight 232.30 g/mol 247.33 g/mol
Physical state solid solid
Partition coefficient logPow = -3.63 logPow = -3.1 (EpiSuite estimation)
Water solubility 3329 g/L 2570 g/l
Acute toxicity oral LD50 > 5000 mg/kg (rat) LD50 > 5000 mg/kg (rat)
Acute toxicity dermal LD50 > 2000 mg/kg (rat) n/a
Skin irritation Not irritating (in vivo, rabbit) Not irritating (in vivo, rabbit)
Eye irritation Not irritating (in vivo, rabbit) Not irritating (in vivo, rabbit)
Skin sensitization Skin sens 1A (GPMT) n/a

Reason / purpose for cross-reference:

read-across source

Positive control results:

Historical data on two positive control substances (2-mercapobenzothiazole and alpha-hexylcinnamaldehyde) show that they induced positive reactions in control animals, thus meeting the reliability criteria for the GPMT. In four independent studies performed in 1999 and 2000, 2-mercapobenzothiazole induced sensitisation in 90-100% of the animals. A 5% solution was used for intradermal induction, 50% solution for topical induction, and 50% and 25% for topical challenge. In two independent studies performed in 2000 and 2001, alpha-hexylcinnamaldehyde induced sensitisation in 40% and 50% of the animals, respectively. A 5% solution was used for intradermal induction, 100% solution for topical induction, and 100% and 75% for topical challenge. See results table under 'Attached background material' (Positive control historical data).

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

50%

No. with + reactions:

9

Total no. in group:

9

Remarks on result:

positive indication of skin sensitisation

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

75%

No. with + reactions:

9

Total no. in group:

9

Remarks on result:

positive indication of skin sensitisation

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

50%

No. with + reactions:

0

Total no. in group:

5

Remarks on result:

no indication of skin sensitisation

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

75%

No. with + reactions:

0

Total no. in group:

5

Remarks on result:

no indication of skin sensitisation

Key result

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

50%

No. with + reactions:

9

Total no. in group:

9

Remarks on result:

positive indication of skin sensitisation

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

75%

No. with + reactions:

9

Total no. in group:

9

Remarks on result:

positive indication of skin sensitisation

Reading:

2nd reading

Hours after challenge:

48

Group:

negative control

Dose level:

50%

No. with + reactions:

0

Total no. in group:

5

Remarks on result:

no indication of skin sensitisation

Reading:

2nd reading

Hours after challenge:

48

Group:

negative control

Dose level:

75%

No. with + reactions:

0

Total no. in group:

5

Remarks on result:

no indication of skin sensitisation

Reading:

other: historical data

Group:

positive control

Remarks on result:

other: see attachment "positive control historical data"

Interpretation of results:

Category 1A (indication of significant skin sensitising potential) based on GHS criteria

Conclusions:

CLP: Skin sens 1A, H317 The skin sensitisation classification category 1 for sulfopropyl acrylate (SPA) is based on the challenge results that all test animals (9/9) gave a positive response. The classification was further specified to be 1A, based on the intradermal induction concentration. The concentration tested at intradermal induction was 0.5% SPA. As the percentage of animals with positive reaction at challenge is 100% and thus above the 60% cut-off point for classification as skin sensitiser 1A, the classification criteria are met. Therefore, classification for skin sens 1A is justified.

Executive summary:

The study was performed to assess the contact sensitisation potential of the test material in the albino guinea pig. The method was designed to meet the requirements of the following:

- OECD Guidelines for the Testing of Chemicals No. 406 "Skin Sensitisation" (adopted 17 July 1992)

- Commission Directive 96/54/EC Method B6 Acute Toxicity (Skin Sensitisation)

 

Ten test and five control animals were used for the study. Two phases were involved in the main study; an induction of a response by intradermal injection and topical application and a topical challenge of that response.

 

Based on the results of sighting tests, the concentrations of test material for the induction and challenge phases were selected as:

Intradermal Induction: 0.5% w/w in distilled water

Topical Induction: 75% w/w in distilled water

Topical Challenge: 75% and 50% w/w in distilled water

 

Under the conditions of the test, the test material produced a 100% (9/9) sensitisation rate and was classified as an extreme sensitiser to guinea pig skin.

The test material was classified as a sensitiser. The test material requires labelling with the symbol "Xi", indication of danger 'irritant' and the risk phrase R 43 "May Cause Sensitisation by Skin Contact" according to EU labelling regulations Commission Directive 93/21/EEC. According to GHS criteria / CLP, this corresponds to Skin sens 1A.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2001

Report date:

2001

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.6 (Skin Sensitisation)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

The Department of Health of the Government of the United Kingdom

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

Test was conducted for another regulatory purpose, other than and prior to REACH registration.

Test material

Test material information

Constituent 1

Reference substance name:

Potassium 3-sulphonatopropyl acrylate

EC Number:

250-465-0

EC Name:

Potassium 3-sulphonatopropyl acrylate

Cas Number:

31098-20-1

Molecular formula:

C6H10O5S.K

IUPAC Name:

potassium 3-(acryloyloxy)propane-1-sulfonate

Details on test material:

- Name of test material (as cited in study report): SPA, sulfopropyl acrylate- Physical state: white powder- Analytical purity: no data- Lot/batch No.: 0200014/001- Storage condition of test material: room temperature, in the dark- pH: 5.4 in a 10% w/w aqueous solution

In vivo test system

Test animals

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

male

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: David Hall Limited, Burton-on-Trent, Staffordshire, UK
- Age at study initiation: approximately 8-12 weeks
- Weight at study initiation: 300-450 g
- Housing: animals were housed singly or in pairs in solid-floor polypropylene cages furnished with woodflakes
- Diet: Guinea Pig FD1 Diet (Special Diets Services Limited, Witham, Essex, UK), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23
- Humidity (%): 30-70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

Study design: in vivo (non-LLNA)

Induction

Induction 1

Route:

intradermal and epicutaneous

Vehicle:

water

Induction 2

Concentration / amount:

Intradermal induction: 0.5%Epicutaneous induction: 75%Challenge: 75% and 50%

Challenge

Challenge 1

Route:

epicutaneous, occlusive

Vehicle:

water

Challenge 2

Concentration / amount:

Intradermal induction: 0.5%Epicutaneous induction: 75%Challenge: 75% and 50%

No. of animals per dose:

10 in test group, 5 in control group

Details on study design:

RANGE FINDING TESTS:
In the range-finding study, intradermal injections were made on the shaved shoulder of 4 guinea pigs using concentrations of 0.1, 0.5, 1 and 5% w/w in distilled water. The degree of erythema was assessed 24, 48 and 72 hours, and 7 days after the injection. The highest concentration causing mild to moderate skin irritation was selected for the intradermal induction stage of the main study. Two guinea pigs (intradermally injected with Freund's complete adjuvant 9 days earlier) were each treated with 10, 25, 50 and 75% (w/w in distilled water) solutions of the test substance. The solution was applied to clipped flanks and covered with an occlusive dressing for 48 hours. The degree of erythema and edema was assessed 1, 24 and 48 hours after exposure ended. The highest concentration causing mild to moderate skin irritation was selected for the topical induction stage of the main study. Two guinea pigs were each treated with 10, 25, 50 and 75% (w/w in distilled water) solutions of the test substance. The solution was applied to clipped flanks and covered with an occlusive dressing for 24 hours. The degree of erythema and edema was assessed 1, 24 and 48 hours after exposure ended. The highest non-irritant concentration and one lower concentration were selected for the challenge stage of the main study.

MAIN STUDY

A. INDUCTION EXPOSURE
- No. of exposures: 2, intradermal and epicutaneous
- Exposure period: single injection (intradermal, left and right side) and 48 hours (epicutaneous)
- Test groups:Intradermal (3 pairs of injections, 0.1 mL):
Injection 1: a 1:1 mixture (v/v) FCA/water
Injection 2: 0.5% w/w test substance in distilled water
Injection 3: 0.5% w/w test substance in a 1:1 mixture (v/v) FCA/water
24 and 48 h after intradermal injection, the degree of erythema and edema was evaluated.
Epicutaneous: 75% w/w test substance in distilled water
On day 7 the animals were treated with a topical application of SPA. The occlusive dressing was kept in place for 48 h. The degree of erythema and edema was evaluated 1 and 24 h after removing the patch.
- Control group:
Intradermal (3 pairs of injections):
Injection 1: a 1:1 mixture (v/v) FCA/water
Injection 2: distilled water
Injection 3: distilled water in a 1:1 mixture (v/v) FCA/water
Epicutaneous: distilled water
- Site: approximately 40 mm x 60 mm area on the shoulder region
- Frequency of applications: once (intradermal and epicutaneous)
- Duration: day 0 (intradermal), day 7-9 (epicutaneous)
- Concentrations: 0.5% (intradermal), 75% (epicutaneous)

B. CHALLENGE EXPOSURE
- No. of exposures: one, topical
- Day(s) of challenge: 21
- Exposure period: 24 hours
- Test groups: test substance in distilled wate
r- Control group: test substance distilled water
- Site: approximately 50 mm x 70 mm, on both flanks of the animals
- Concentrations: 75% SPA on the right flank and 50% SPA on the left flank
- Evaluation (hr after challenge): 24 and 48 hours after exposure ended
OTHER: remaining test material was removed from the test site after epicutaneous exposure lasting 24 h

Positive control substance(s):

yes

Remarks:

historical data using 2-mercaptobenzothiazole and alpha-hexylcinnamaldehyde in arachid oil as positive controls was included

Results and discussion

Positive control results:

Historical data on two positive control substances (2-mercapobenzothiazole and alpha-hexylcinnamaldehyde) show that they induced positive reactions in control animals, thus meeting the reliability criteria for the GPMT. In four independent studies performed in 1999 and 2000, 2-mercapobenzothiazole induced sensitisation in 90-100% of the animals. A 5% solution was used for intradermal induction, 50% solution for topical induction, and 50% and 25% for topical challenge. In two independent studies performed in 2000 and 2001, alpha-hexylcinnamaldehyde induced sensitisation in 40% and 50% of the animals, respectively. A 5% solution was used for intradermal induction, 100% solution for topical induction, and 100% and 75% for topical challenge. See results table under 'Attached background material' (Positive control historical data).

In vivo (non-LLNA)

Results

Results 1

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

50%

No. with + reactions:

9

Total no. in group:

9

Remarks on result:

positive indication of skin sensitisation

Results 2

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

75%

No. with + reactions:

9

Total no. in group:

9

Remarks on result:

positive indication of skin sensitisation

Results 3

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

50%

No. with + reactions:

0

Total no. in group:

5

Remarks on result:

no indication of skin sensitisation

Results 4

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

75%

No. with + reactions:

0

Total no. in group:

5

Remarks on result:

no indication of skin sensitisation

Results 5

Key result

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

50%

No. with + reactions:

9

Total no. in group:

9

Remarks on result:

positive indication of skin sensitisation

Results 6

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

75%

No. with + reactions:

9

Total no. in group:

9

Remarks on result:

positive indication of skin sensitisation

Results 7

Reading:

2nd reading

Hours after challenge:

48

Group:

negative control

Dose level:

50%

No. with + reactions:

0

Total no. in group:

5

Remarks on result:

no indication of skin sensitisation

Results 8

Reading:

2nd reading

Hours after challenge:

48

Group:

negative control

Dose level:

75%

No. with + reactions:

0

Total no. in group:

5

Remarks on result:

no indication of skin sensitisation

Results 9

Reading:

other: historical data

Group:

positive control

Remarks on result:

other: see attachment "positive control historical data"

Applicant's summary and conclusion

Interpretation of results:

Category 1A (indication of significant skin sensitising potential) based on GHS criteria

Conclusions:

CLP: Skin sens 1A, H317 The skin sensitisation classification category 1 for sulfopropyl acrylate (SPA) is based on the challenge results that all test animals (9/9) gave a positive response. The classification was further specified to be 1A, based on the intradermal induction concentration. The concentration tested at intradermal induction was 0.5% SPA. As the percentage of animals with positive reaction at challenge is 100% and thus above the 60% cut-off point for classification as skin sensitiser 1A, the classification criteria are met. Therefore, classification for skin sens 1A is justified.

Executive summary:

The study was performed to assess the contact sensitisation potential of the test material in the albino guinea pig. The method was designed to meet the requirements of the following:

- OECD Guidelines for the Testing of Chemicals No. 406 "Skin Sensitisation" (adopted 17 July 1992)

- Commission Directive 96/54/EC Method B6 Acute Toxicity (Skin Sensitisation)

 

Ten test and five control animals were used for the study. Two phases were involved in the main study; an induction of a response by intradermal injection and topical application and a topical challenge of that response.

 

Based on the results of sighting tests, the concentrations of test material for the induction and challenge phases were selected as:

Intradermal Induction: 0.5% w/w in distilled water

Topical Induction: 75% w/w in distilled water

Topical Challenge: 75% and 50% w/w in distilled water

 

Under the conditions of the test, the test material produced a 100% (9/9) sensitisation rate and was classified as an extreme sensitiser to guinea pig skin.

The test material was classified as a sensitiser. The test material requires labelling with the symbol "Xi", indication of danger 'irritant' and the risk phrase R 43 "May Cause Sensitisation by Skin Contact" according to EU labelling regulations Commission Directive 93/21/EEC. According to GHS criteria / CLP, this corresponds to Skin sens 1A.