2-Propenoic acid, methyl ester, reaction products with 2-ethyl-1-hexanamine and sodium hydroxide

Endpoint summary

Description of key information

Skin irritation:

- Experimental in vivo study (OECD 404) on the analogue substance "Sodium 3-[(2-carboxyethyl)(2-ethylhexyl)amino]propanoate", CAS 94441 -92-6.

Eye irritation:

- Experimental in vivo study (OECD 405) on the analogue substance "Sodium 3-[(2-carboxyethyl)(2-ethylhexyl)amino]propanoate", CAS 94441-92-6.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

18-28 September 2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Elevage de Gérome, Linxe.
- Age at study initiation: 12 weeks
- Weight at study initiation:2.42-2.68 kg
- Housing: Individual box
- Diet (e.g. ad libitum): ad libitium
- Water (e.g. ad libitum): ad libitium
- Acclimation period: 5 days
- Other: Albino rabbits, female

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23 °C
- Humidity (%): 31-55 %
- Photoperiod (hrs dark / hrs light): (12/12)

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL

Duration of treatment / exposure:

4 hours

Observation period:

1, 24, 48 and 72 hours after removal of the patches

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: 6 cm2 on an undamaged skin area of one flank of each animal.
- Type of wrap if used: patch with strip of surgical adhesive tape.

REMOVAL OF TEST SUBSTANCE
- Washing: treated area was rinsed with distilled water
- Time after start of exposure: 4 hours

SCORING SYSTEM: scored in accordance with OECD404

Irritation parameter:

erythema score

Basis:

animal: Mean of animals 1, 2 and 3

Remarks:

Individual scores not specified in the report

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

edema score

Basis:

animal: Mean of animals 1, 2 and 3

Remarks:

Individual scores not specified in the report

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritant / corrosive response data:

No cutaneous reactions (erythema and oedema) were observed (1, 24, 48 and 72 hours).

Other effects:

No other effects were observed

Interpretation of results:

GHS criteria not met

Conclusions:

The skin irritating potential of the substance was investigated in a dermal skin irritating study which was performed in accordance with OECD404 and under GLP conditions. Based on the result the test item does not need to be classified in accordance with the criteria outlined in Annex I of 67/548/EEC and Annex VI of 1272/2008?EC, under the conditions of this study.

Executive summary:

The skin irritating potential of sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate was investigated in a dermal skin irritating study which was performed in accordance with OECD404 and under GLP conditions. The test material was applied to the shorn skin of 3 (female) New Zealand White albino rabbits at a dose of 0.5 mL under semi-occlusive dressing during 4 hours. No cutaneous reactions (erythema and oedema) were observed. Based on these results, the test substance does not need to be classified in accordance with the criteria outlined in Annex I of 67/548/EEC and Annex VI of 1272/2008?EC, under the conditions of this study.

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The read-across hypothesis is based on “different compounds which have similar properties”.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
- The source substance is identified as Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate, also known as Sodium 3-[(2-carboxyethyl)(2-ethylhexyl)amino]propanoate (CAS no. 94441-92-6 | EC no. 305-318-6). It is a UVCB substance whose major constituent is sodium 2-ethylhexylimino-di-propionate. Minor constituents are sodium 2-ethylhexylimino-mono-propionate, unreacted acrylic acid and unreacted 2-ethylhexylamine.
- The target substance is identified as Propenoic acid, methyl ester, reaction products with 2-ethyl-1-hexanamine and sodium hydroxide (methanol free) (CAS no. 68610-44-6| EC no. 271-865-1). It is a UVCB substance whose major constituents are sodium 2-ethylhexylimino-mono-propionate and sodium 2-ethylhexylimino-di-propionate. Minor constituents are unreacted acrylic acid and unreacted 2-ethylhexylamine.

3. ANALOGUE APPROACH JUSTIFICATION
The target and source substances are essentially the same: both are UVCB substances composed of the exact same constituents with the exact same functional groups (i.e. carboxylic acid groups and secondary/tertiary amine groups). They are expected to have the same ADME profile and to share common mode of action and breakdown products. The target and source substances only differ in the overlapping ranges of their constituents, the content of sodium 2-ethylhexylimino-mono-propionate being especially higher in the target substance. This difference is expected to have no or very limited impact on the potency of effects exerted on exposed living organisms.

4. DATA MATRIX
Cf. read-across justification document attached in §13. Assessment reports.

Reason / purpose for cross-reference:

read-across source

Irritation parameter:

erythema score

Basis:

animal: Mean of animals 1, 2 and 3

Remarks:

Individual scores not specified in the report

Time point:

24/48/72 h

Score:

ca. 0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal: Mean of animals 1, 2 and 3

Remarks:

Individual scores not specified in the report

Time point:

24/48/72 h

Score:

ca. 0

Max. score:

4

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

24 September -02 October 2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Elevage de Gérome, Linxe
- Age at study initiation: 18 weeks
- Weight at study initiation: 3.20-3.84 kg
- Housing: Individual box
- Diet (e.g. ad libitum): ad libitium
- Water (e.g. ad libitum): ad libitium
- Acclimation period: 5 days
- Other: Albino rabbits (male)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25 °C
- Humidity (%): 36-70 %
- Photoperiod (hrs dark / hrs light): (12/12)

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

0,1 mL of test item was instilled into conjunctival sac of one eye, the other eye remained untreated as control.

Duration of treatment / exposure:

Single dose.

Observation period (in vivo):

1, 24, 48, and 72 hours following treatment and daily thereafter up to 8 days after treatment

Number of animals or in vitro replicates:

3

Details on study design:

SCORING SYSTEM: In accordance with OECD 405

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal: Mean of animals 1, 2 and 3 / Individual scores not specified in the report

Time point:

24/48/72 h

Score:

ca. 1.8

Max. score:

3

Reversibility:

fully reversible within: 8 days

Irritation parameter:

chemosis score

Basis:

animal: Mean of animals 1, 2 and 3 / Individual scores not specified in the report

Time point:

24/48/72 h

Score:

ca. 0.8

Max. score:

4

Reversibility:

fully reversible within: 6 days

Irritation parameter:

iris score

Basis:

animal: Mean of animals 1, 2 and 3 / Individual scores not specified in the report

Time point:

24/48/72 h

Score:

ca. 0

Max. score:

2

Reversibility:

other: not applicable

Irritation parameter:

cornea opacity score

Basis:

animal: Mean of animals 1, 2 and 3 / Individual scores not specified in the report

Time point:

24/48/72 h

Score:

ca. 0

Max. score:

4

Reversibility:

other: not applicable

Irritant / corrosive response data:

The conjunctiva reactions observed during the study have been moderate, and totally reversible in the three animals: a moderate redness, noted 24 hours after the test item instillation and totally reversible between day 6 and day 8, associated with a moderate chemosis, noted 1 hour after the test item instillation and totally reversible between day 3 and day 6.

Other effects:

No other effects were observed

Interpretation of results:

GHS criteria not met

Conclusions:

The eye irritating potential of Amphotensid EH was investigated in an acute eye irritation study, which was performed according to OECD 405 and under GLP conditions. Based on the results, the test item does not need to be classified according to the criteria outlined in Annex I of 67/548/EEC and Annex VI of 1272/2008, under the conditions of this study.

Executive summary:

The eye irritating potential of Amphotensid EH was investigated in an acute eye irritation study, which was performed according to OECD 405 and under GLP conditions. Three male albino New Zealand White rabbits were administered a single ocular dose of 0.1 ml of the test substance and observed up to eight days after instillation. Moderate conjunctiva reactions (redness and chemosis) were observed, which were totally reversible within 8 days. Based on these results, the test item does not need to be classified according to the criteria outlined in Annex I of 67/548/EEC and Annex VI of 1272/2008, under the conditions of this study.

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The read-across hypothesis is based on “different compounds which have similar properties”.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
- The source substance is identified as Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate, also known as Sodium 3-[(2-carboxyethyl)(2-ethylhexyl)amino]propanoate (CAS no. 94441-92-6 | EC no. 305-318-6). It is a UVCB substance whose major constituent is sodium 2-ethylhexylimino-di-propionate. Minor constituents are sodium 2-ethylhexylimino-mono-propionate, unreacted acrylic acid and unreacted 2-ethylhexylamine.
- The target substance is identified as Propenoic acid, methyl ester, reaction products with 2-ethyl-1-hexanamine and sodium hydroxide (methanol free) (CAS no. 68610-44-6| EC no. 271-865-1). It is a UVCB substance whose major constituents are sodium 2-ethylhexylimino-mono-propionate and sodium 2-ethylhexylimino-di-propionate. Minor constituents are unreacted acrylic acid and unreacted 2-ethylhexylamine.

3. ANALOGUE APPROACH JUSTIFICATION
The target and source substances are essentially the same: both are UVCB substances composed of the exact same constituents with the exact same functional groups (i.e. carboxylic acid groups and secondary/tertiary amine groups). They are expected to have the same ADME profile and to share common mode of action and breakdown products. The target and source substances only differ in the overlapping ranges of their constituents, the content of sodium 2-ethylhexylimino-mono-propionate being especially higher in the target substance. This difference is expected to have no or very limited impact on the potency of effects exerted on exposed living organisms.

4. DATA MATRIX
Cf. read-across justification document attached in §13. Assessment reports.

Reason / purpose for cross-reference:

read-across source

Irritation parameter:

conjunctivae score

Basis:

animal: Mean of animals 1, 2 and 3 / Individual scores not specified in the report

Time point:

24/48/72 h

Score:

ca. 1.8

Max. score:

3

Reversibility:

fully reversible within: 8 days

Irritation parameter:

chemosis score

Basis:

animal: Mean of animals 1, 2 and 3 / Individual scores not specified in the report

Time point:

24/48/72 h

Score:

ca. 0.8

Max. score:

4

Reversibility:

fully reversible within: 6 days

Irritation parameter:

iris score

Basis:

animal: Mean of animals 1, 2 and 3 / Individual scores not specified in the report

Time point:

24/48/72 h

Score:

ca. 0

Max. score:

2

Reversibility:

other: Not applicable

Irritation parameter:

cornea opacity score

Basis:

animal: Mean of animals 1, 2 and 3 / Individual scores not specified in the report

Time point:

24/48/72 h

Score:

ca. 0

Max. score:

4

Reversibility:

other: Not applicable

Interpretation of results:

GHS criteria not met

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irreversible damage)

Justification for classification or non-classification

No skin irritation effect were observed for both the analogue substance "Sodium 3-[(2-carboxyethyl)(2-ethylhexyl)amino]propanoate" (CAS 94441 -92 -6) and for Methanol.

Slight eye irritation and mild to moderate eye irritation were observed for the analogue substance "Sodium 3 -[(2 -carboxyethyl)(2 -ethylhexyl)amino]propanoate" (CAS 94441 -92 -6) and Methanol, respectively. These findings are not suffisient to trigger a classification.

However, families of Propionate and Surfactants substances with similar structure are known to induce moderate to severe skin and eye irritation (see the report "Final Amended Safety Assessment - Lauriminodipropionic Acid, Sodium Lauriminodipropionate, and Disodium Lauriminodipropionate as Used in Cosmetics - January 5, 2012" from CIR.

By category approach and as a precaution, the substance "2 -Propenoic acid, methyl ester, reaction products with 2-ethyl-1-hexanamine and sodium hydroxide" (water and Methanol free) is considered irritating for skin and causing seriuous eye damage, and classified skin irritating category 2, H315 and eye corrosion category 1, H318.