Sodium 2-[[4-[3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl]phenyl]sulphonyl]ethanesulphonate

Endpoint summary

Description of key information

Not skin irritating

Not eye irritating

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:

September from 03 to 12, 2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

adopted July 17, 1992

GLP compliance:

no

Remarks:

in accordance with SN EN 45001 (incl. certificate)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Elevage Scientifique des Dombes F-01400 Chatillon sur Chalaronne / France
- Age at study initiation: males 12 weeks, females 11 weeks.
- Diet: pelleted standard Provimi Kliba 3418 rabbit maintenance diet, ad libitum (batch no.39/02) provided by Provimi Kliba AG, CH-4303 Kaiseraugst.
- Water: community tap water from Füllinsdorf, ad libitum.
- Acclimatization: under laboratory conditions after health examination. Only animals without any visual signs of illness were used for the study.
- Animals selection: four days before treatment, one flank was clipped with an electric clipper, exposing an area of approximately 100 cm2 (10 cm x 10 cm). The skin of the animals was examined one day before treatment, and regrown fur of all animals was again clipped. Animals with overt signs of skin injury or marked irritation which may have interfered with the interpretation of the results were not used in the test.

ENVIRONMENTAL CONDITIONS
- Temperature: 17 - 23 °C
- Relative humidity: between 30-70 %
- Air changes: 10-15 air changes per hour.
- Photoperiod: 12 hours fluorescent light/12 hours dark.
- Other: music during the light period.

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

water

Controls:

yes, concurrent no treatment

Amount / concentration applied:

- Amount: 0.5 g (per animal), moistened with approximately 0.1 ml of purified water before application
- pH: the pH of the test item was measured before the study initiation date. A formulation of 1 % in water was prepared and the pH was found to be 7.

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

1 male and 2 females

Details on study design:

TEST SITE
- Area of exposure: on the day of treatment, test item was placed on a surgical gauze patch (ca. 4 cm x 4 cm). This gauze patch was applied to the intact skin of the clipped area.
- Type of wrap if used: the patch was covered with a semi-occlusive dressing. The dressing was wrapped around the abdomen and anchored with tape.

REMOVAL OF TEST SUBSTANCE
- Washing: the dressing was removed and the skin was flushed with lukewarm tap water to clean the application site so that any reactions (erythema) were clearly visible at that time.
- Time after start of exposure: 4 hours

OBSERVATIONS
- Viability/Mortality: daily from delivery of the animals to the termination of test.
- Clinical signs: daily from delivery of the animals to the termination of test.
- Body weights: at start of acclimatization, on the day of application and at termination of observation.

OBSERVATION TIME POINTS
Approximately 1, 24, 48 and 72 hours after the removal of the dressing, gauze patch and test item.

SCORING SYSTEM
The skin reaction was assessed according to the numerical scoring system listed in the EEC Commission Directive 92/69/EEC, July 31, 1992.
lf evident, corrosive or staining properties of the test item were described and recorded.

ERYTHEMA AND ESCHAR FORMATION
No erythema 0
Very slight erythema 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beet redness) or eschar formation (injuries in depth preventing erythema) reading 4

OEDEMA FORMATION
No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well-defined by definite raising) 2
Moderate oedema (edges raised approximately 1 mm) 3
Severe oedema (raised more than 1 mm and extending beyond the area of exposure) 4

Irritation parameter:

erythema score

Basis:

animal: 3/3

Time point:

24/48/72 h

Score:

< 2.3

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal: 3/3

Time point:

24/48/72 h

Score:

< 2.3

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

The test item did not elicit any skin reactions at the application site of any animal at any of the observation times (all scores 0). The individual mean score for erythema/eschar and oedema for each of the three animals was therefore 0.
No staining by the test item of the treated skin was observed.
No irreversible alterations of the treated skin were observed nor were corrosive effects evident on the skin.

Other effects:

VIABILTTY/MORTALITY/CLINICAL SIGNS
No clinical signs of systemic toxicity were observed in the animals during the study and no mortality occurred.

BODY WEIGHTS
The body weights of all rabbits were considered to be within the normal range of variability.

Interpretation of results:

other: not classified, according to the CLP Regulation ((EC) No 1272/2008)

Conclusions:

Not irritating

Executive summary:

The primary skin irritation potential of test item was investigated by topical semiocclusive application of 0.5 g to the intact left flank of each of three young adult New Zealand White rabbits. The method and procedures followed were in accordance with those outlined into the OECD guideline 404. The duration of treatment was four hours. The scoring of skin reactions was performed 1, 24, 48 and 72 hours after removal of the dressing.

The test item did not elicit any skin reactions at the application site of any animal at any of the observation times (all scores 0). The individual mean score for erythema/eschar and oedema for each of the three animals was therefore 0. The test item caused no staining of the treated skin. No corrosive effects were noted on the treated skin of any animal at any of the measuring intervals.

Thus, the test item did not induce significant or irreversible damage to the skin.

Conclusion

Mean values from gradings at 24, 48 and 72 hours after patch removal were lower than 2.3 in all animals for both erythema/eschar and oedema reactions, thus the test item does not meet the criteria to be classified as irritating, according to the CLP Regulation ((EC) No 1272/2008).

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

June from 07 to 07, 1991

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

adopted 12 May 1981

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hoechst AG, Kastengrund.

Type of coverage:

semiocclusive

Amount / concentration applied:

0.5 g per animal

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

3 animals

Details on study design:

SCORING SYSTEM
According to the Draize system.

Irritation parameter:

erythema score

Basis:

animal: 3/3

Time point:

24/48/72 h

Score:

< 2.3

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal: 3/3

Time point:

24/48/72 h

Score:

< 2.3

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

On the basis of the numerically evaluated individual findings of erythema and oedema formation at observation times after 24, 48 and 72 hours, the following mean values were calculated:
animal 78: erythema 0, oedema 0
animal 79: erythema 0, oedema 0
animal 80: erythema 0, oedema 0

Interpretation of results:

other: not classified, according to the CLP Regulation ((EC) No 1272/2008)

Conclusions:

Not irritating

Executive summary:

The primary skin irritation potential of test item was investigated by topical semiocclusive application of 0.5 g of test item to three New Zealand White rabbits. The method and procedures followed were in accordance with those outlined into the OECD guideline 404 and EU method B4. The duration of treatment was four hours. The scoring of skin reactions was performed 1, 24, 48 and 72 hours after removal of the dressing, according to the Draize system.

On the basis of the numerically evaluated individual findings of erythema and oedema formation at observation times after 24, 48 and 72 hours, the following mean values were calculated: animal 78 erythema 0, oedema 0; animal 79 erythema 0, oedema 0; animal 80 erythema 0, oedema 0.

Therefore, the substance resulted to be not skin irritating.

Conclusion

Mean values from gradings at 24, 48 and 72 hours after patch removal were lower than 2.3 in all animals for both erythema/eschar and oedema reactions, thus the test item does not meet the criteria to be classified as irritating, according to the CLP Regulation ((EC) No 1272/2008).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

June from 11 to 25, 1991

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

adopted 12 May 1981

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Hoechst AG, Kastengrund.

Controls:

yes, concurrent no treatment

Amount / concentration applied:

100 mg per eye

Duration of treatment / exposure:

24 hours

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

3 animals

Details on study design:

SCORING SYSTEM
Draize test system.

Irritation parameter:

cornea opacity score

Basis:

animal: 3/3

Time point:

24/48/72 h

Score:

< 1

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal: 3/3

Time point:

24/48/72 h

Score:

< 1

Irritation parameter:

conjunctivae score

Basis:

animal: 2/3

Time point:

24/48/72 h

Score:

2.3 - 2.7

Irritation parameter:

chemosis score

Basis:

animal: 2/3

Time point:

24/48/72 h

Score:

< 2

Irritant / corrosive response data:

On the basis of the numerically evaluated individual findings at observation times after 24, 48 and 72 hours, the following mean values were calculated:
animal 58: corneal opacity 0, iris 0.3, conjuntival redness 2.3, conjunctival chemosis 2.0
animal 78: corneal opacity 0, iris 0, conjuntival redness 1.3, conjunctival chemosis 0.3
animal 80: corneal opacity 0, iris 0, conjuntival redness 2.7, conjunctival chemosis 1.0

Interpretation of results:

other: expected as not or weak irritating

Conclusions:

Expected as not or weak irritating

Executive summary:

The primary eye irritation potential of test item was investigated by the application of 100 mg of test item to three New Zealand White rabbits. The method and procedures followed were in accordance with those outlined into the OECD guideline 405 and EU method B5. The scoring of eye reactions was performed 1, 24, 48 and 72 hours after removal of the dressing, according to the Draize system.

On the basis of the numerically evaluated individual findings at observation times after 24, 48 and 72 hours, the following mean values were calculated: animal 58 corneal opacity 0, iris 0.3, conjuntival redness 2.3, conjunctival chemosis 2.0; animal 78 corneal opacity 0, iris 0, conjuntival redness 1.3, conjunctival chemosis 0.3; animal 80 corneal opacity 0, iris 0, conjuntival redness 2.7, conjunctival chemosis 1.0.

The substance was judged to be not irritating.

Discussion and conclusion

The mean values from gradings at 24, 48 and 72 hours were lower than 1 for corneal opacity, lower than 1 for iritis, lower than 2 for conjunctival oedema, in two out of three tested animals; the value for conjuntival redness resulted to be higher than 2 in two out of three animals.

Despite the conjunctival redness recorded, it should be considered that the tested substance is commonly in powder form. The effects observed are suspected to be attributable to the non specific effects due to the powder form of the substance, rather than to the substance chemical/toxicological properties. Due to the intrinsic irritating potential of dusty materials and considering that the reactions regards conjunctival redness, an overestimation of the effects seems to be likely. In addition, it should be considered that in the successive versions of the OECD guideline advise to rinse eye in case the solid substance has not been removed from the eye of the test animal by physiological mechanisms at the first observation time point of 1 hour after treatment. This indication was not provide in the OECD guidleine version here followed.

In conclusion, the substance is expected to be not or weak irritating.

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

March from 05 to 08, 1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Justification for type of information:

The read across approach is detailed into the document attached to the IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

adopted 12 May 1981

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Hoechst AG, Kastengrund, konventionelle Zucht.
- Age at study initiation: ca 3 - 5 months.
- Weight at study initiation: 2.5 - 3.1 kg
- Diet: Altromin 2123, ad libitum.
- Water: deionized, chlorinated water, ad libitum.
- Health check: 24 hours before the start of the experiment, the eyes of the animals to be treated were examined for any damage to the cornea, after instillation of a drop of fluorescein sodium solution (0.01 %) under UV light. Only animals whose eyes showed no findings were included in the experiment.

ENVIRONMENTAL CONDITIONS
- Temperature: 20 ± 3 °C
- Humidity: 50 ± 20 %
- Photoperiod: 12 hrs dark / 12 hrs light

Vehicle:

other: polyethylene glycol 400 (0.1 ml)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

100 mg per eye

Duration of treatment / exposure:

24 hours

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

3 animals

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: physiological saline (37 °C).
- Time after start of exposure: 24 hours after application of the test substance and at all other assessment times,i n those cases in which the treated eyes still showed secretions or on which a cornea examination with fluorescein-sodium solution took place, the treated eyes were thoroughly washed out with physiological saline (about 37 °C).

SCORING SYSTEM
Eyes were assessed 1, 24, 48 and 72 hours after application of the test substance. At the 24 and 72 hour evaluation periods, in addition to instillation of one drop of fluorescein sodium solution (0.01 %), the cornea was examined for damage under UV light. Damage to the cornea, iris and conjunctivae was assessed numerically. All other changes were recorded.
The scoring system was that proposed into the OECD guideline.

Irritation parameter:

cornea opacity score

Basis:

animal: 3/3

Time point:

24/48/72 h

Score:

< 1

Reversibility:

fully reversible within: 24 hours

Irritation parameter:

iris score

Basis:

animal: 3/3

Time point:

24/48/72 h

Score:

< 1

Reversibility:

fully reversible within: 24 hours

Irritation parameter:

conjunctivae score

Basis:

animal: 3/3

Time point:

24/48/72 h

Score:

< 2

Reversibility:

fully reversible within: 24 hours

Irritation parameter:

chemosis score

Basis:

animal: 3/3

Time point:

24/48/72 h

Score:

< 2

Reversibility:

fully reversible within: 24 hours

Irritant / corrosive response data:

1 hour after application, mild to clear swelling and a diffuse crimson staining of the conjunctiva occurred. One animal showed a slightly reddish iris. The irritation phenomena were accompanied by yellowing.
From 24 hours the animals were free of irritation symptoms.

Interpretation of results:

other: not classified, according to the CLP Regulation (EC) No 1272/2008

Conclusions:

Not irritating

Executive summary:

The primary eye irritation potential of test item was investigated by the application of 100 mg of test item to three New Zealand White rabbits. The method and procedures followed were in accordance with those outlined into the OECD guideline 405 and EU method B5. The scoring of eye reactions was performed 1, 24, 48 and 72 hours after removal of the dressing, according to the OECD guideline scoring system.

1 hour after application, mild to clear swelling and a diffuse crimson staining of the conjunctiva occurred. One animal showed a slightly reddish iris. The irritation phenomena were accompanied by yellowing. From 24 hours the animals were free of irritation symptoms.

Conclusion

The mean values from gradings at 24, 48 and 72 hours were lower than 1 for corneal opacity, lower than 1 for iritis, lower than 2 for both conjunctival redness and oedema, in all the tested animals.

Therefore, the substance does not meet the criteria to be classified as eye irritating, according to the CLP Regulation (EC) No 1272/2008.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

SKIN IRRITATION

The primary skin irritation potential of Fluorescent Brightener 312 was investigated in two experiments, conducted by topical semiocclusive application of 0.5 g to the intact skin of three rabbits. In both the cases, the method and procedures followed were in accordance with those outlined into the OECD guideline 404.

In one experiment, the test item did not elicit any skin reactions at the application site of any animal at any of the observation times (all scores 0). The test item caused no staining of the treated skin. No corrosive effects were noted on the treated skin of any animal at any of the measuring intervals.

Also in the second experiment, on the basis of the numerically evaluated individual findings at observation times after 24, 48 and 72 hours, the mean values calculated for both erythema and oedema resulted to be 0, in all the treated animals. Therefore, the substance resulted to be not skin irritating.

EYE IRRITATION

The primary eye irritation potential of Fluorescent Brightener 312 was investigated by the application of 100 mg of test item to three New Zealand White rabbits. The method and procedures followed were in accordance with those outlined into the OECD guideline 405 and EU method B5.

On the basis of the numerically evaluated individual findings at observation times after 24, 48 and 72 hours, the mean values from gradings were lower than 1 for corneal opacity, lower than 1 for iritis, lower than 2 for conjunctival oedema, in two out of three tested animals; the value for conjuntival redness resulted to be higher than 2 in two out of three animals.

Despite the conjunctival redness recorded, it should be considered that the tested substance is commonly in powder form. The effects observed are suspected to be attributable to the non specific effects due to the powder form of the substance, rather than to the substance chemical/toxicological properties. Due to the intrinsic irritating potential of dusty materials and considering that the reactions regards conjunctival redness, an overestimation of the effects seems to be likely. In addition, it should be considered that in the successive versions of the OECD guideline advise to rinse eye in case the solid substance has not been removed from the eye of the test animal by physiological mechanisms at the first observation time point of 1 hour after treatment. This indication was not provide in the OECD guidleine version here followed. Therefore, the substance was judged to be not or weak irritating.

In order to clarify the test item irritating potential and in order to confirm the evaluation of the experiment abovementioned, the available data on the structural analogous Similar Substance 02 have been taken into consideration. The read across approach can be considered as appropriate and suitable to assess the property under investigation (details about the approach are reported into the IUCLID section 13).

The primary eye irritation potential of Similar Substance 02 was investigated by the application of 100 mg of test item to three New Zealand White rabbits. The method and procedures followed were in accordance with those outlined into the OECD guideline 405 and EU method B5. 1 hour after application, mild to clear swelling and a diffuse crimson staining of the conjunctiva occurred. One animal showed a slightly reddish iris. The irritation phenomena were accompanied by yellowing. From 24 hours the animals were free of irritation symptoms.

Justification for classification or non-classification

According to the CLP Regulation (EC) No 1272/2008, 3.2 Skin corrosion/irritation section, skin irritation means the production of reversible damage to the skin following the application of a test substance for up to 4 hours.

Mean values from gradings at 24, 48 and 72 hours after patch removal were lower than 2.3 in all animals for both erythema/eschar and oedema reactions, thus the test item does not meet the criteria to be classified as irritating, according to the CLP Regulation ((EC) No 1272/2008).

According to the CLP Regulation (EC) No 1272/2008, serious eye damage means the production of tissue damage in the eye, or serious physical decay of vision, following application of a test substance, which is not fully reversible within 21 days of application.

The mean values from gradings at 24, 48 and 72 hours were lower than 1 for corneal opacity, lower than 1 for iritis, lower than 2 for both conjunctival redness and oedema, in all the tested animals.

Therefore, the substance does not meet the criteria to be classified as eye irritating, according to the CLP Regulation (EC) No 1272/2008.