Propanoic acid, 2-[(ethoxythioxomethyl)thio]-, methyl ester

Endpoint summary

Description of key information

Skin: OECD 404 guideline study, exposure for 4h under semiocclusive dressing: irritating.

Eyes: OECD 405 guideline study: slightly irritating but no classification is required.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2000

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

The relative humidity and temperature of the animal room exceeded the limits mentioned in the guidelines. the body weight range ordered was 2000-2500 g instead of 1500-1900 g. These deviations had no impact on the study.

Qualifier:

according to guideline

Guideline:

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

Deviations:

yes

Remarks:

The relative humidity and temperature of the animal room exceeded the limits mentioned in the guidelines. the body weight range ordered was 2000-2500 g instead of 1500-1900 g. These deviations had no impact on the study.

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Remarks:

SPF bred

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Centre Lagro, France
- Age at study initiation: young adult
- Weight at study initiation: 2950-3363 g
- Housing: individually in stainless steel cages with perforated floor
- Diet (e.g. ad libitum): standard laboratory rabbit diet ad libitum. Each batch of this diet is analyzed by the supplier (SDS Special Diets services, Whitham, England) for the nutrients and contaminants and the results are available upon request.
- Water (e.g. ad libitum): Tap water (N.V. Waterleidingbedrijf Midden-Nederland) ad libitum. Results of routine physical, chemical and microbiological examination of drinking water as conducted by the supplier are available upon request.
- Acclimation period: 49 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 3°C. (On 13 June, the temperature was up to 26.2°C for a very short period of time due to a malfunction).
- Humidity (%): 56-99.9 % (incidentally the upper limit was higher !han 70%, because of wet cleaning of the animal room and/or meteorological circumstances).
- Air changes (per hr): ca 10 air changes/hour
- Photoperiod (hrs dark / hrs light): 12 h light/12 h dark cycle

OTHERS
Upon arrival, the rabbits were checked for overt signs of ill health and anomalies. Three days prior to the start of the study, the hair was removed from the back and flanks of the animals using electric clippers in a way as to avoid abrasions. The clipping was repeated if considered necessary.

IN-LIFE DATES: From: 25 April 2000 To: 4 July 2000

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml of the test substance

VEHICLE
No

NEGATIVE CONTROL
No

POSITIVE CONTROL
No

Duration of treatment / exposure:

4 hours

Observation period:

24, 48, 72 h and at 7, 14, and 21 days

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: 2.5 x 2.5 cm
- % coverage: Just prior to application. a skin site suitable for application was selected on the clipped back and flanks of the animal.
- Type of wrap if used: The patch loaded with the test substance was fixed to the selected application site by means of adhesive tape (Leukopor, BDF, Germany). Subsequently, the entire trunk of the rabbit was wrapped with a self-adhesive-gauze (F1Xomull, BDF, Germany) to maintain the patch in position and to retard evaporation of volatile substances. The gauze was additionally fastened with two strips of tape (Leukoflex, BDF, Germany).

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Yes
- Time after start of exposure: After a 4-hour exposure period, the test substance and patch were removed and the test site was cleaned with a tissue moistened with water.

OBSERVATION TIME POINTS
One hour after treatment, the resulting skin reactions were evaluated by the method of Draize et al. (J. Pharmacol. Exp. Ther. 82 (1944) 377-390). Further skin readings were made at approximately 24, 48, 72 h, and at 7, 14 and 21 days after treatment.

SCORING SYSTEM:
- Method of calculation: Grading system by Draize et al.

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

4

Max. score:

4

Reversibility:

fully reversible within: 14 days

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

4

Max. score:

4

Reversibility:

fully reversible within: 21 days

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

4

Max. score:

4

Reversibility:

fully reversible within: 21 days

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

fully reversible within: 14 days

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

4

Max. score:

4

Reversibility:

fully reversible within: 21 days

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

4

Max. score:

4

Reversibility:

fully reversible within: 21 days

Irritant / corrosive response data:

At l h after treatment, the dermal effects observed in the three rabbits consisted of well-defined erythema and moderate oedema. At 24, 48 and 72 h after treatment, the dermal effects observed in the three rabbits consisted of moderate or severe erythema and moderate or severe oedema. In addition, the three rabbits showed slight ischemic necrosis. At 7 days after treatment, the dermal effects observed in the three rabbits consisted of moderate or severe erythema and moderate oedema. ln addition, two rabbits showed slight incrustation and one rabbit severe scaliness. At 14 days after treatment, the dermal effects had cleared in one rabbit, while the two remaining rabbits showed well-defined erythema, moderate scaliness and slight oedema. At 21 days after treatment, no signs of dermal irritation were observed in any of the three rabbits.

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

Based on the results of the study, RHODIXAN A-1 was considered to be irritant to the skin.

Executive summary:

RHODIXAN A-1 was tested for primary dermal irritation in 3 male New Zealand White rabbits, according to O.E.C.D. guideline Nb.404/EEC Method B.4, and in compliance with Good Laboratory Practice. The test article, a liquid, was applied in a single dermal dose of 0.5 ml on a 2.5 x 2.5 cm2 clipped areas of intact skin, under a semi-occlusive dressing for a 4-hour exposure period. The cutaneous examinations were performed 24, 48, and 72 hours after removal of the dressing, then daily until day 21 for reversibility.

 

At 1 hour after treatment, well-defined erythema and moderate oedema were observed in the 3 rabbits. At 24, 48, and 72 hours, and at day 7, dermal effects observed in the 3 rabbits consisted of moderate or severe erythema, or severe oedema. In addition, the 3 rabbits showed slight ischemic necrosis at 48 and 72 hours, and at day 7, 2 rabbits showed slight incrustation and one rabbit severe scaliness. At day 14, dermal effects had cleared in one rabbit, while the two remaining animals showed well-defined erythema, moderate scaliness and slight oedema. The mean scores (24-48-72 hours) calculated for each animal were 4.0 - 4.0 and 4.0 for erythema and 3.0 - 4.0 and 3.7 for oedema.

 

Based on theses results, RHODIXAN A-1 is classified Skin irrit. 2, H315, irritant to the skin according to CLP and GHS criteria.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2000

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

The relative humidity and temperature of the animal room exceeded the limits mentioned in the guidelines. The body weigbt range ordered was 2000-2500 g instead of 1500-1900 g. These deviations had no impact on the study.

Qualifier:

according to guideline

Guideline:

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

Deviations:

yes

Remarks:

The relative humidity and temperature of the animal room exceeded the limits mentioned in the guidelines. The body weigbt range ordered was 2000-2500 g instead of 1500-1900 g. These deviations had no impact on the study.

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Remarks:

SPF bred

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Centre Lagro, France
- Age at study initiation: young adult
- Weight at study initiation: 3243-3421 g
- Housing: individually in stainless steel cages with perforated floor
- Diet (e.g. ad libitum): standard laboratory rabbit diet ad libitum. Each batch of this diet is analyzed by the supplier (SDS Special Diets services, Whitham, England) for the nutrients and contaminants and the results are available upon request.
- Water (e.g. ad libitum): Tap water (N.V. Waterleidingbedrijf Midden-Nederland) ad libitum. Results of routine physical, chemical and microbiological examination of drinking water as conducted by the supplier are available upon request.
- Acclimation period: 49 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 3°C. (On 13 June, the temperature was up to 26.2°C for a very short period of time due to a malfunction).
- Humidity (%): 58-80 % (incidentally the upper limit was higher !han 70%, because of wet cleaning of the animal room and/or meteorological circumstances).
- Air changes (per hr): ca 10 air changes/hour
- Photoperiod (hrs dark / hrs light): 12 h light/12 h dark cycle

IN-LIFE DATES: From: 25 April 2000 To: 16 June 2000

OTHERS
The non-GLP Chicken Enucleated Eye Test showed no signs of initation. Therefore, it was decided to proceed with the in vivo test, which was immediately started with three rabbits. Both eyes of the rabbits selected were examined just before testing. Only rabbits without observable eye defects were used.

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml

VEHICLE
No

Observation period (in vivo):

24, 48, and 72 h

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

An amount of ca 0.1 ml of the test substance was instilled in the conjonctival cul-de-sac of the right eye. After administration, the upper and lower eye lid were carefully closed and subsequently held together for at least one second before releasing, to prevent loss of material. The left eye remaining untreated, served as a control. The reactions of the test eyes were judged at circa one, 24, 48, and 72 h after treatment using the scoring scale.

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

3

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

3

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible

Irritant / corrosive response data:

One rabbit (no. 77) screamed for a very short period immediately after dosing. At I h after treatment, the eye effects observed in the three rabbits consisted of slight or moderate redness with or without slight swelling of the conjunctivae.
In addition, one rabbit showed moderate ocular discharge. At 24 h after treatment one rabbit still showed slight redness and slight swelling of the conjunctivae and slight ocular discharge.
At 48 and 72 h after treatment, no signs of eye irritation were observed in any of the three rabbits.

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the results of the study, RHODIXAN A-1 was considered to be slight irritant to the eyes.

Executive summary:

RHODIXAN A-1 was tested for acute eye irritation on 3 male New Zealand White albino rabbits, according to O.E.C.D. guideline Nb.405/EEC method B.5, and in compliance with Good Laboratory Practice. The test article, a liquid, was instillated as such, in a single dose of 0.1 ml into the conjunctival sac of the right eye of each animal. The left eye remained untreated and served as a control. The eyes were not rinsed. Ocular examinations were performed 1, 24, 48 and 72 hours after the instillation.

 

No corneal opacity or iritis was observed throughout the study.

Slight to moderate conjunctival redness was observed in all of the 3 animals,hour, which persisted at 24 hour in 1 animal. In addition, 1 animal displayed also slight chemosis and ocular dischargehour and 24 hours after instillation. Mean scores (24-48-72 hours) calculated for each animal were 0.0 - 0.0 - 0.3 for conjunctival redness, and 0.0 - 0.0 - 0.3 for chemosis. In addition, slight ocular discharge was observed in one animal and 24 hours.

Based on these results, RHODIXAN A-1 is not classified as an eye irritant according to CLP and GHS criteria.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

One klimisch score 1 study was available for dermal irritation and was used as a key study:

RHODIXAN A-1 was tested for primary dermal irritation in 3 male New Zealand White rabbits, according to O.E.C.D. guideline Nb.404/EEC Method B.4, and in compliance with Good Laboratory Practice. The test article, a liquid, was applied in a single dermal dose of 0.5 ml on a 2.5 x 2.5 cm2 clipped areas of intact skin, under a semi-occlusive dressing for a 4-hour exposure period. The cutaneous examinations were performed 24, 48, and 72 hours after removal of the dressing, then daily until day 21 for reversibility.

 At 1 hour after treatment, well-defined erythema and moderate oedema were observed in the 3 rabbits. At 24, 48, and 72 hours, and at day 7, dermal effects observed in the 3 rabbits consisted of moderate or severe erythema, or severe oedema. In addition, the 3 rabbits showed slight ischemic necrosis at 48 and 72 hours, and at day 7, 2 rabbits showed slight incrustation and one rabbit severe scaliness. At day 14, dermal effects had cleared in one rabbit, while the two remaining animals showed well-defined erythema, moderate scaliness and slight oedema. The mean scores (24-48-72 hours) calculated for each animal were 4.0 - 4.0 and 4.0 for erythema and 3.0 - 4.0 and 3.7 for oedema.

Based on the results of the study, RHODIXAN A-1 was considered to be irritant to the skin.

One klimisch score 1 study was available for eye irritation and was used as a key study:

RHODIXAN A-1 was tested for acute eye irritation on 3 male New Zealand White albino rabbits, according to O.E.C.D. guideline Nb.405/EEC method B.5, and in compliance with Good Laboratory Practice. The test article, a liquid, was instillated as such, in a single dose of 0.1 ml into the conjunctival sac of the right eye of each animal. The left eye remained untreated and served as a control. The eyes were not rinsed. Ocular examinations were performed 1, 24, 48 and 72 hours after the instillation.

 No corneal opacity or iritis was observed throughout the study.

Slight to moderate conjunctival redness was observed in all of the 3 animals,hour, which persisted at 24 hour in 1 animal. In addition, 1 animal displayed also slight chemosis and ocular dischargehour and 24 hours after instillation. Mean scores (24-48-72 hours) calculated for each animal were 0.0 - 0.0 - 0.3 for conjunctival redness, and 0.0 - 0.0 - 0.3 for chemosis. In addition, slight ocular discharge was observed in one animal and 24 hours.

Based on the results of the study, RHODIXAN A-1 was considered to be slight irritant to the eyes.

Justification for classification or non-classification

Harmonized classification:

No harmonized classification is available according to the Regulation (EC) No 1272/2008.

Self-classification:

Rhodixan A-1 is classified for skin irritation as Skin irrit. 2, H315 (irritating to skin) according to the Regulation (EC) 1272/2008 (CLP) considering the irritant effects observed in the dermal irritation study in rabbit.

Rhodixan A-1 is not classified for eye irritation according to the Regulation (EC) 1272/2008 (CLP).