Propanoic acid, 2-(4-hydroxyphenoxy)-, sodium salt (1:1), (2R)-

Endpoint summary

Description of key information

Skin Irritation: [(R)-2-(4-hydroxyphenoxy)-propanoic acid]: non-irritating, rabbit, Liggett 1991
Eye Irritation: [(R)-2-(4-hydroxyphenoxy)-propanoic acid]: severe ocular lesions, rabbit, Liggett 1991

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

1991-07-30 to 1991-08-02

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP study on structural analogue (free acid) according to guideline: EEC Directive 84/449/EEC Method B.4. The fact that the study is used for read-across purposes triggers reliability rating 2.

Qualifier:

according to guideline

Guideline:

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

Deviations:

yes

Remarks:

Observation terminated after 72 hours (no observable effects)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Froxfield Farms (U.K.) Ltd., Petersfield, Hampshire, England
- Age at study initiation: 10 - 12 weeks
- Weight at study initiation: 2.3 - 2.7 kg
- Housing: individually in metal cages with perforated floors
- Diet: SDS Stanrab (P) Rabbit Diet ad libitum
- Water: ad libitum
- Acclimation period: yes, duration not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19°C
- Humidity (%): 30 - 70%
- Air changes (per hr): 19
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 1991-07-30 To: 1991-08-02

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

water

Remarks:

distilled

Controls:

not required

Amount / concentration applied:

0.5 g

Duration of treatment / exposure:

4 hours
washing with water after removal of the semiocclusive dressing and gauze

Observation period:

30 min after removal of dressings, 24, 48, and 72 hours

Number of animals:

3 females

Details on study design:

TEST SITE
- Area of exposure: 2.5 cm square, approximately 6cm2
- Type of wrap if used: gauze pad (moistened with 0.5 mL distilled water), Elastoplast elastic adhesive dressing, semiocclusive
- Animals not restrained

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with water, to remove any residual test substance
- Time after start of exposure: 4 hours

SCORING SYSTEM:
-According to EU Method B.4, Table 1: Grading of Skin Reactions

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no signs of edema at any time, reversibility could therefore not be assessed

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no signs of edema at any time, reversibility could therefore not be assessed

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no signs of edema at any time, reversibility could therefore not be assessed

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no signs of eryhtema at any time, reversibility could therefore not be assessed

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no signs of eryhtema at any time, reversibility could therefore not be assessed

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no signs of eryhtema at any time, reversibility could therefore not be assessed

Irritant / corrosive response data:

No dermal response to treatment in any animal at any time point

Other effects:

No signs of toxicity or ill health throughout the observation period

No signs of skin irritation were observed with the source substance, the free acid (R)-2-(4-hydroxyphenoxy)-propanoic acid (CAS 94050-90-5), which has pH 1.8 in concentrated aqueous solution, in any animal at any time.

The skin irritation potential of the target substance propanoic acid, 2-(4-hydroxyphenoxy)-, sodium salt (2R) (CAS 133647-88-8) is determined by read-across from the test with the free acid. The analogue approach is based on the facts that source and target contain the identical molecular structure and the same functional groups (except the Na+ counterion), and that the Na+ salt is expected to have a next-to-neutral pH, below 8.5. The additional amount of sodium applied to the skin is not expected to permeate the skin due to its ionic nature, therefore it is not taken up and will not elicit systemic adverse effects.

As a conclusion, propanoic acid, 2-(4-hydroxyphenoxy)-, sodium salt (2R) is not expected to be a skin irritant.

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Sodium (2R)-2-(4-hydroxyphenoxy)propanoate is not expected to be a skin irritant derived from read-across.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

1991-08-05 until 1991-10-30

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP study on structural analogue (free acid) according to guideline: EEC Directive 84/449/EEC Method B.5. Termination of initial test for humane reasons (severe ocular lesions) after 1 hour is unlikely to have compromised the result. The fact that the study is used for read-across purposes triggers reliability rating 2.

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Froxfield Farms (U.K.) Ltd., Petersfield, Hampshire, England
- Age at study initiation: 12 weeks
- Weight at study initiation: 2840 g
- Housing: individually in metal cages with perforated floors
- Diet: SDS Stanrab (P) Rabbit Diet ad libitum
- Water: ad libitum
- Acclimation period: yes, duration not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19°C
- Humidity (%): 30 - 70%
- Air changes (per hr): 19
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 1991-08-05 To: 1991-08-05 (terminated on same day)

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): approx. 77 mg, corresponding to 0.1 mL volume
- Concentration: 100%, finely ground powder
- placed into the lower everted lid of one eye, lids held together for 1 second
- Untreated eye serves as control

Duration of treatment / exposure:

1 hour, until dense corneal opacity (grade 4) was detected, and the experiment was terminated for humane reasons

Observation period (in vivo):

1 hour, until dense corneal opacity (grade 4) was detected, and the experiment was terminated for humane reasons (in accordance with EU Method B.5, sequential testing strategy, initial test)

Number of animals or in vitro replicates:

1 female

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: No

SCORING SYSTEM:
- According to EU Method B.5, Table 1: Grading of Ocular Lesions

TOOL USED TO ASSESS SCORE: handheld light

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

other: 1 hour

Score:

4

Max. score:

4

Reversibility:

other: no reversibility to be expected

Remarks on result:

other: dense corneal opacity covering the entire corneal surface

Irritation parameter:

iris score

Basis:

animal #1

Time point:

other: 1 hour

Max. score:

2

Reversibility:

other: experiment terminated for humane reasons

Remarks on result:

other: Assessment of iridial inflammation impossible due to corneal opacity

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

other: 1 hour

Score:

1

Max. score:

3

Reversibility:

other: experiment terminated for humane reasons

Remarks on result:

other: whitening (blanching) of eyelids

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

other: 1 hour

Score:

2

Max. score:

4

Reversibility:

other: experiment terminated for humane reasons

Other effects:

Slight ocular discharge
No signs of toxicity or ill health observed during the (very short, 1 h) exposure period.

Severe ocular lesions (dense corneal opacity) were observed with the source substance, the free acid (R)-2-(4-hydroxyphenoxy)-propanoic acid (CAS 94050-90-5), which has pH 1.8 in aqueous solution; the study was terminated for humane reasons after 1 hour. From the data, it cannot be decided whether this severe ocular response reflects effects of low pH or structural properties common to the source and the target molecule, e.g. the phenolic group.

It cannot be excluded by read-across that propanoic acid, 2-(4-hydroxyphenoxy)-, sodium salt (2R) (CAS 133647-88-8) may be irritant with the risk of serious damage to the eye.

Interpretation of results:

Category 1 (irreversible effects on the eye)

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

It cannot be excluded by read-across that sodium (2R)-2-(4-hydroxyphenoxy)propanoate may cause serious eye damage.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation/ corrosion and eye irritation of sodium (2R)-2-(4-hydroxyphenoxy)propanoate, (CAS 133647-88-8) were determined by read-across from skin irritation/ corrosion and eye irritation studies conducted with the free acid, namely (R)-2-(4-hydroxyphenoxy)propanoic acid (CAS 94050-90 -5).

Skin Irritation:

Only a single study conducted according to a guideline (EEC Directive 84/449/EEC Method B.4) and under GLP is available for the source substance (R)-2-(4-hydroxyphenoxy)-propanoic acid (CAS 94050-90-5). The study is considered to be complet, reliable and adequate for the purposes of risk assessment, classification and labelling. No irritating effect was observed in any of the three rabbits tested.

The skin irritation potential of the target substance propanoic acid, 2-(4-hydroxyphenoxy)-, sodium salt (2R) (CAS 133647-88-8) is determined by read-across from the test with the free acid. The analogue approach is based on the facts that source and target contain the identical molecular structure and the same functional groups (except the Na+ counterion), and that the Na+ salt is expected to have a next-to-neutral pH, below 8.5. The additional amount of sodium applied to the skin is not expected to permeate the skin due to its ionic nature, therefore it is not taken up and will not elicit systemic adverse effects.

As a conclusion, propanoic acid, 2-(4-hydroxyphenoxy)-, sodium salt (2R) is not expected to be a skin irritant.

Eye Irritation:

Only a single study conducted according to European guideline (EEC Directive 84/449/EEC Method B.4) and under GLP is available for the source substance (R)-2-(4-hydroxyphenoxy)-propanoic acid (CAS 94050-90-5). The study is considered to be complete, reliable and adequate for the purposes of risk assessment, classification and labelling. An initial test with one animal revealed severe ocular lesions (dense corneal opacity on entire surface) after 1 hour; the study was terminated one hour after application, for humane reasons.

From the data, it cannot be decided whether this severe ocular response reflects effects of low pH or structural properties common to the source and the target molecule, e.g. the phenolic group.

It cannot be excluded by read-across that the target substance, propanoic acid, 2-(4-hydroxyphenoxy)-, sodium salt (2R) (CAS 133647-88-8) may be irritant with the risk of serious damage to the eye.

Justification for selection of skin irritation / corrosion endpoint:
Only one study was available, which was carried out according to guidelines and under GLP.

Justification for selection of eye irritation endpoint:
Only one study was available, which was carried out according to guidelines and under GLP.

Effects on eye irritation: highly irritating

Justification for classification or non-classification

Skin Irritation/Corrosion

With a mean score of 0 the substance is considered to be non-irritating to skin based on the criteria as outlined in Regulation (EC) No. 1272/2008, Annex I, Part 3, 3.2.2.7. Therefore the substance is not classified, according to the criteria in Regulation (EC) No. 1272/2008, Annex I, Part 3, 3.2.2.

Eye Irritation

With a cornea score of 4 the substance is considered to cause serious damage to eyes based on the criteria as outlined in Regulation (EC) No. 1272/2008, Annex I, Part 3, 3.3.2.6.1. Therefore the substance is classified for serious eye damage, Category 1 (H318), according to the criteria in Regulation (EC) No. 1272/2008, Annex I, Part 3, 3.3.2.