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

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

read-across from similar mixture/product

Adequacy of study:

key study

Study period:

1995-08-21 until 1995-09-14

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP study on structural analogue (free acid) according to OECD guideline 406. The fact that the study is used for read-across purposes triggers reliability rating 2.

Qualifier:

according to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.6 (Skin Sensitisation)

Deviations:

no

GLP compliance:

yes

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

An appropriate guinea pig maximization test is available which would not justify conducting an additional LLNA due to animal welfare.

Species:

guinea pig

Strain:

Pirbright-Hartley

Sex:

male/female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Ciba-Geigy Ltd, Animal Production, CH-4332 Stein, Switzerland
- Strain: Pirbright White Strain (Tif: DHP)
- Age at study initiation: no data
- Weight at study initiation: 332 - 412 g
- Housing: individually in Macrolon cages (Type 3)
- Diet: standard guinea pig pellets NAFAG 845 ad libitum (NAFAG, Gossau, Switzerland)
- Water: fresh drinking water ad libitum
- Acclimation period: 5 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 1995-08-21 To: 1995-09-14

Route:

intradermal and epicutaneous

Vehicle:

physiological saline

Concentration / amount:

Pretest: 1, 5, 10, 20, 30 and 50% w/v
Intradermal induction: 5% (in saline and saline/adjuvant), 0.1 mL per injection
Epidermal induction: 50% in saline
Challenge: 1% in saline

Route:

epicutaneous, occlusive

Vehicle:

physiological saline

Concentration / amount:

Pretest: 1, 5, 10, 20, 30 and 50% w/v
Intradermal induction: 5% (in saline and saline/adjuvant), 0.1 mL per injection
Epidermal induction: 50% in saline
Challenge: 1% in saline

No. of animals per dose:

Pretest: 2 (1 male, 1 female, with two doses applied on each animal)
Main study: 10 males, 10 females in test group; 5 males, 5 females in control group

Details on study design:

RANGE FINDING TESTS:
- Six guinea pigs (3 males, 3 females) received two pairs of consecutive intradermal injections of adjuvant/ saline (50:50) in the neck. Seven days later, two different concentrations of the test substance were tested simultaneously (left and right flank, Hilltop chamber, occlusive) for 24 hours, to assess the primary irritation potential, scored 24 and 48 hours after removal of dressing.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: one intradermal (day 0), one epicutaneous (day 8)
- Exposure period: epicutaneous 48 hours
- Test groups: 1 (10 males + 10 females): intradermal: adjuvant/saline 1:1, test substance in saline, test substance in adjuvant/saline; epicutaneous: test substance in saline
- Control group: 1 (5 males + 5 females): intradermal: saline, adjuvant/saline 1:1; epicutaneous: saline
- Site: injections and epicutaneous application: shaved neck
- Frequency of applications: Day 0 + 8
- Concentrations: injection 5% (0.1 mL), epicutaneos 50% (approx. 0.4 g on a filter paper patch 2x4 cm, occlusive dressing)

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: 22
- Exposure period: epicutaneous 24 hours
- Test groups: 1% test substance in saline on one flank, saline on the other (epicutaneous, Hilltop chamber)
- Control group: 1% test substance in saline on one flank, saline on the other (epicutaneous, Hilltop chamber)
- Site: flanks
- Concentrations: 1% (approx. 0.35 mL per Hilltop chamber)
- Evaluation (hr after challenge): 24 and 48 hours after removal of dressing

Positive control substance(s):

yes

Remarks:

2-mercaptobenzothiazole

Positive control results:

2-mercaptobenzothiazole (intradermal induction: 5% in oleum arachidis, epidermal induction: 50% in vaseline, challenge: 10% in vaseline) caused 16/20 positive animals after 24 hours, 19/20 after 48 hours, with no irritation in the control.

Reading:

2nd reading

Hours after challenge:

48

Group:

positive control

Dose level:

10% in vaseline

No. with + reactions:

19

Total no. in group:

20

Reading:

1st reading

Hours after challenge:

24

Group:

positive control

Dose level:

10% in Vaseline

No. with + reactions:

16

Total no. in group:

20

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

1%

No. with + reactions:

0

Total no. in group:

20

Clinical observations:

no irritant skin reactions, no other findings

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 1%. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: no irritant skin reactions, no other findings.

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

1%

No. with + reactions:

0

Total no. in group:

20

Clinical observations:

no irritant skin reactions, no other findings

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 1%. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: no irritant skin reactions, no other findings.

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

1%

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

no irritant skin reactions, no other findings

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 1%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no irritant skin reactions, no other findings.

Reading:

2nd reading

Hours after challenge:

48

Group:

negative control

Dose level:

1%

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

no irritant skin reactions, no other findings

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 1%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no irritant skin reactions, no other findings.

Pretest:

Primary Skin Irritation Potential, Erythema score

Concentration	24-hour	score	48-hour	score
%	M	F	M	F
50	+	-	+	+
30	+	-	-	-
20	+	+	+	+
10	+	-	-	-
5	-	+	-	-
1	-	-	-	-

No signs of edema were seen at any concentration.

Main Test:

On day 10 (after removal of the occlusive dressing used for epidermal induction), irritation of the application site was observed in all animals treated with the test substance (concentration 50% in saline). The body weight was not affected by the treatment.

Read-across: No signs of skin sensitisation were observed with the source substance, the free acid (R)-2-(4-hydroxyphenoxy)-propanoic acid (CAS 94050-90-5).

The sensitisation potential of the target substance propanoic acid, 2-(4-hydroxyphenoxy)-, potassium salt (2R) (CAS 1184648-08-5) is determined by read-across from the maximisation 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 K+ counterion), and that they form a pH-dependent equilibrium. Upon intradermal induction in the maximisation test, the free acid is neutralized to the Na⁺ salt (due to the buffer capacity of body fluids), whereas the K⁺counterion of the salt is exchanged to Na⁺(due to the sodium excess in body fluids), which makes the two forms indistinguishable. In the subsequent epidermal induction, the acid is more likely than the K+ salt to permeate the stratum corneum, so it is assumed to evoke a stronger effect, if any.

No signs of skin sensitisation were observed with the acid. As a conclusion, the target substance propanoic acid, 2-(4-hydroxyphenoxy)-, potassium salt (2R) is also unlikely to be a skin sensitiser.

Interpretation of results:

not sensitising

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

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

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Skin sensitisation of sodium (2R)-2-(4-hydroxyphenoxy)propanoate, (CAS 133647-88-8) was determined by read-across from a skin sensitisation study conducted with the free acid, namely (R)-2-(4-hydroxyphenoxy)propanoic acid (CAS 94050-90 -5).

Only a single skin sensitisation study conducted according to guideline OECD 406 and under GLP is available for the source substance, the free acid (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. The maximisation study in guinea pigs elicited no positive responses in any animal after 24 and 48 hours.

The sensitisation potential of the target substance propanoic acid, 2-(4-hydroxyphenoxy)-, sodium salt (2R) (CAS 133647-88-8) is determined by read-across from the maximisation 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 K+ counterion), and they form a pH-dependent equilibrium. Upon intradermal induction in the maximisation test, the free acid is neutralized to the Na⁺ salt (due to the buffer capacity of body fluids), which makes the two forms indistinguishable. In the subsequent epidermal induction, the acid is more likely than the Na+ salt to permeate the stratum corneum, so it is assumed to evoke a stronger effect, if any. No signs of skin sensitisation were observed with the source (free acid).

As a conclusion, the target substance propanoic acid, 2-(4-hydroxyphenoxy)-, sodium salt (2R) is also unlikely to be a skin sensitiser.

Migrated from Short description of key information:
Skin sensitisation: [(R)-2-(4-hydroxyphenoxy)-propanoic acid]: Not sensitising, OECD 406, Winkler 1995

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

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Skin sensitisation:

The results from Skin Sensitisation Test in the Guinea Pig, Maximisation test (OECD 406) indicate that the substance is not a skin sensitiser. As a result the substance does not meet the criteria for classification according to Regulation (EC) No. 1272/2008, Part 3, 3.4.2.2.

The conclusion given above only takes into consideration the properties of the constituent in this mono constituent substance. As indicated in the composition under section 1.2 one of the impurities is relevant for C&L of the substance. This is finally included in the Classification and Labelling section 2 where necessary based on the typical concentration value given and the harmonized classification and labelling that is available for this impurity both under CLP/GHS and DSD-DPD.