Imidazolium compounds, 1-[2-(2-carboxyethoxy)ethyl]-1(or 3)-(2-carboxyethyl)-4,5-dihydro-2-norcoco alkyl

Endpoint summary

Description of key information

Based on an in vivo skin irritation test in rabbits, the registered substance is not be classified as a skin irritant according to CLP and GHS UN criteria.

Based on the absence of reversibility of ocular effects

in two vivo eye irritation tests in rabbits, the registered substance is classified as a severe eye irritant (Eye Damage 1, H318) according to CLP and GHS UN criteria.

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:

no specified (1978)

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

Occlusive dressing instead of non-occlusive. Half of the treated area was abraded. The animals were exposed for 24 hours instead of 4 hours and observed for 72 hours instead of 14 days.

GLP compliance:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Batch No.of test material: 4324D78
- Expiration date of the lot/batch: not specified
- Purity test date: not specified

Species:

rabbit

Strain:

other: albino rabbit

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: not specified
- Age at study initiation: not specified
- Weight at study initiation: not specified
- Housing: in racks
- Diet (e.g. ad libitum): not specified
- Water (e.g. ad libitum): not specified
- Acclimation period: not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): not specified
- Humidity (%): not specified
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): not specified

IN-LIFE DATES: not specified

Type of coverage:

occlusive

Preparation of test site:

other: clipped and abraded areas

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL on each area (scarified and unscarified)

Duration of treatment / exposure:

24 hours

Observation period:

72 hours

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure:
- % coverage: 10% of the total body area was clipped free of hair the day prior the exposure. The test article was applied to a 2.0 x 2.0 cm clipped area of both intact and abraded skin
- Type of wrap if used: The 2 x 2 patch area was covered with Webril patches and the entire experimental area sealed with Blenderm Surgical Tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no washing
- Time after start of exposure: 24 hours

OBSERVATION TIME POINTS : 24 and 72 jours

SCORING SYSTEM:
- Method of calculation: Draize

Irritation parameter:

erythema score

Remarks:

Intact skin

Basis:

mean

Remarks:

mean score of the 3 animals (individual scores of each animal were not reported in the study report)

Time point:

24 h

Score:

2

Reversibility:

not specified

Remarks:

Skin reactions were still observed after the 72-hours observation period.

Remarks on result:

probability of mild irritation

Irritation parameter:

erythema score

Remarks:

intact skin

Basis:

mean

Remarks:

mean score of the 3 animals (individual scores of each animal were not reported in the study report)

Time point:

72 h

Score:

1

Reversibility:

not specified

Remarks:

Skin reactions were still observed after the 72-hours observation period.

Remarks on result:

probability of weak irritation

Irritation parameter:

erythema score

Remarks:

abraded skin

Basis:

mean

Remarks:

mean score of the 3 animals (individual scores of each animal were not reported in the study report)

Time point:

24 h

Score:

2

Reversibility:

not specified

Remarks:

Skin reactions were still observed after the 72-hours observation period.

Remarks on result:

probability of mild irritation

Irritation parameter:

erythema score

Remarks:

abraded skin

Basis:

mean

Remarks:

mean score of 3 animals (individual scores of each animal were not reported in the study report)

Time point:

72 h

Score:

1

Reversibility:

not specified

Remarks:

Skin reactions were still observed after the 72-hours observation period.

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Remarks:

intact skin

Basis:

mean

Remarks:

mean score of the 3 animals (individual scores of each animal were not reported in the study report)

Time point:

24 h

Score:

1

Reversibility:

not specified

Remarks:

Skin reactions were still observed after the 72-hours observation period.

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Remarks:

intact skin

Basis:

mean

Remarks:

means score of the 3 animals (individual scores of each animal were not reported in the study report)

Time point:

72 h

Score:

0

Reversibility:

not specified

Remarks:

Skin reactions were still observed after the 72-hours observation period.

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Remarks:

abraded skin

Basis:

mean

Remarks:

mean score of the 3 animals (individual scores of each animal were not reported in the study report)

Time point:

24 h

Score:

1

Reversibility:

not specified

Remarks:

Skin reactions were still observed after the 72-hours observation period.

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Remarks:

abraded skin

Basis:

mean

Remarks:

mean score of the 3 animals (individual scores of each animal were not reported in the study report)

Time point:

72 h

Score:

0

Reversibility:

not specified

Remarks:

Skin reactions were still observed after the 72-hours observation period.

Remarks on result:

no indication of irritation

Interpretation of results:

GHS criteria not met

Conclusions:

Based on an in vivo skin irritation test in rabbits, the registered substance is not be classified as a skin irritant according to CLP and GHS UN criteria.

Executive summary:

The registered substance (product name = MIRANOL C2M Anhydrous Acid) has been tested for acute skin irritation in 3 New Zealand White rabbits. The test article, a liquid, was applied in a single dermal dose of 0.5 ml to a 2.0 x 2.0 cm clipped area of both intact and abraded skin, under an occlusive dressing for a 24-hour exposure period. Cutaneous examinations were performed at 24 hours, at removal of the dressing, and then at 72 hours.

 

Both on intact and abraded skin, the average score calculated over the 3 animals at 24 hours was 2.0 for erythema, and 1.0 at 72 hours. Oedema reaction was observed at 24 hours on both intact or abraded skin areas, but the reaction had cleared by 72 hours. The average score calculated over the 3 animals at 24 hours was 1.0 for both intact skin and abraded skin areas.

 

Considering the maximalized conditions of application (occlusive application during 24 hours), and the mild cutaneous reactions observed under these conditions, it can be concluded that the registered substance is not be classified as a skin irritant according to CLP and GHS UN criteria.

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:

key study

Study period:

from 15 to 29 June 1988

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

Animals were observed until Day 7 instead of Day 21

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Batch No.of test material: 8803149
- Expiration date of the lot/batch: not specified
- Purity test date: not specified

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Ace Animals, Boyer town, PA.
- Age at study initiation: not specified (young animals)
- Weight at study initiation: 2.48 to 2.61 kg
- Housing: in suspended wire mesh cages
- Diet (e.g. ad libitum): purina rabbit pellets ad libitum
- Water (e.g. ad libitum): water at libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 5°C
- Humidity (%): not specified
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 15 June 1988 To: 22 June 1988

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 sample of the test material was placed in the conjunctival sac of the right eye of each rabbit.
- Concentration (if solution): as such

Duration of treatment / exposure:

single adminstration on Day 0

Observation period (in vivo):

7 days

Number of animals or in vitro replicates:

3

Details on study design:

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

SCORING SYSTEM: recording of grade of ocular lesions (cornea, iris, conjunctivae)

Pre-screening: All rabbits used in this study received a pre-screening examination designed to detec pre-exicsting ocular irritation or corneal change.

Dose application: A 0.1 mL of test material was placed in the conjunctival sac of the right eye of each rabbit. The left eye served as control and was not treated. The lids of the treated eye were gently held together for 1 second before releasing them to prevent loss of the test material.

Observation: The ocular reactions were graded at 24, 48, 72 hours and on Days 4 and 7 using the grading system as the one described in the OECD 405 guideline.

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2

Max. score:

2

Reversibility:

not fully reversible within: 7 days

Remarks on result:

positive indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

2

Reversibility:

not reversible

Remarks on result:

positive indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2

Max. score:

2

Reversibility:

not reversible

Remarks on result:

positive indication of irritation

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

1

Reversibility:

fully reversible within: 7 days

Remarks on result:

positive indication of irritation

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.3

Max. score:

1

Reversibility:

not reversible

Remarks on result:

positive indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #1

Time point:

24/48/72 h

Score:

3

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Remarks on result:

positive indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

2

Reversibility:

not reversible

Remarks on result:

positive indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #3

Time point:

24/48/72 h

Score:

2

Max. score:

2

Reversibility:

not reversible

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2.7

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

2

Reversibility:

not reversible

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.3

Max. score:

2

Reversibility:

not reversible

Remarks on result:

positive indication of irritation

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

On the basis of the results of this in vivo study in rabbit, the registered substance is considered a severe eye irritant (Eye Damage 1, H318) according to criteria of CLP and GHS UN.

Executive summary:

The registered substance (product name = Miranol C2M AA) has been tested for acute ocular irritation in 3 New-Zealand White rabbits according to Draize test, 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 the animal. The left eye remained untreated and served as a control. The eyes were not rinsed. Ocular examinations were performed at 24, 48, 72 hours after treatment, and at day 4 and 7.

 

Corneal opacity (score 2) was observed in all three rabbits at 24 hours. The reaction was still present in two animals at day 7 with grade 2, and with grade 1 in one animal. The mean scores (24-48-72 hours) calculated for each animal were 2.0 - 2.0 - 2.0. Iris reaction was observed between 24 hours and day 4 in one animal, and starting at day 3 in a second animal, whereas no reaction was observed in the third one. The mean scores (24-48-72 hours) calculated for each animal were 1.0 - 0.0 - 0.3.

Conjunctival redness (score 2 to 3) and chemosis (score 1 to 3) were observed and persisted until day 7 in all three animals. The mean scores (24-48-72 hours) calculated for each animal were 3.0 - 2.0 – 2.0 for redness, and 2.7 – 2.0 - 1.3 for chemosis.

In addition, ocular discharge was observed all three animals throughout the observation period.

 

On the basis of these results the registered substance is considered a severe eye irritant (Eye Damage 1, H318) according to criteria of CLP and GHS UN.

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

Animals were observed until Day 7 instead of Day 21

Principles of method if other than guideline:

Draize method

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Batch No.of test material: 4324D78
- Expiration date of the lot/batch: not specified
- Purity test date: not specified

Species:

rabbit

Strain:

other: albino rabbits

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
not specified
ENVIRONMENTAL CONDITIONS
not specified

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 sample of the test material was instilled into the right eye of each rabbit.
- Concentration (if solution): as such

Duration of treatment / exposure:

single adminstration on Day 0

Observation period (in vivo):

7 days

Number of animals or in vitro replicates:

3

Details on study design:

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

SCORING SYSTEM: recording of grade of ocular lesions (cornea, iris, conjunctivae) .

Dose application: A 0.1 mL of test material was instilled into the right eye of each rabbit. The left eye served as control and was not treated.

Observation: The ocular reactions were graded at 24, 48, 72 hours and on Days 4 and 7 using the grading system as the one described in the OECD 405 guideline.

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

1

Reversibility:

fully reversible within: 7 days

Remarks on result:

positive indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #2

Time point:

24/48/72 h

Score:

1.7

Max. score:

2

Reversibility:

not fully reversible within: 7 days

Remarks on result:

positive indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

1

Reversibility:

not fully reversible within: 7 days

Remarks on result:

probability of weak irritation

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.7

Max. score:

1

Reversibility:

fully reversible

Remarks on result:

probability of weak irritation

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

fully reversible within: 7 days

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.3

Max. score:

1

Reversibility:

fully reversible

Remarks on result:

probability of weak irritation

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

On the basis of the results of this in vivo study in rabbit (conjunctivae redness not fully reversible within 7 days), the registered substance is considered a severe eye irritant (Eye Damage 1, H318) according to criteria of CLP and GHS UN.

Executive summary:

The registered substance (product name = Miranol C2M AA) has been tested for acute ocular irritation in 3 albino rabbits according to Draize test. The test article, a liquid, was instillated as such in a single dose of 0.1 ml into the right eye of the animal. The left eye remained untreated and served as a control. The eyes were not rinsed. Ocular examinations were performed at 24, 48, 72 hours after treatment, and at and 7.

 

No corneal opacity nor iris reaction were reported in any animals.

Conjunctival redness (score 1 to 2) and chemosis (score 1 to 3) were observed in all three animals. Conjunctival redness persited until day 7 in one animal. The mean scores (24-48-72 hours) calculated for each animal were 1.0 - 1.7 – 1 for redness, and 0.7 – 2.0 - 0.3 for chemosis.

In addition, ocular discharge was observed all three animals but reversed at day 7.

 

On the basis of these results (absence of reversibility of conjunctival redness in one animal) the registered substance is considered a severe eye irritant (Eye Damage 1, H318) according to criteria of CLP and GHS UN.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

One study of Klimish score 2 is available to assess the skin irritation potential (Levenstein, 1978). In this study, the registered substance (product name = MIRANOL C2M Anhydrous Acid) has been tested for acute skin irritation in 3 New Zealand White rabbits. The test article, a liquid, was applied in a single dermal dose of 0.5 ml to a 2.0 x 2.0 cm clipped area of both intact and abraded skin, under an occlusive dressing for a 24-hour exposure period. Cutaneous examinations were performed at 24 hours, at removal of the dressing, and then at 72 hours.

 

Both on intact and abraded skin, the average score calculated over the 3 animals at 24 hours was 2.0 for erythema, and 1.0 at 72 hours. Oedema reaction was observed at 24 hours on both intact or abraded skin areas, but the reaction had cleared by 72 hours. The average score calculated over the 3 animals at 24 hours was 1.0 for both intact skin and abraded skin areas.

 

Considering the maximalized conditions of application (occlusive application during 24 hours), and the mild cutaneous reactions observed under these conditions, it can be concluded that the registered substance is not be classified as a skin irritant according to CLP and GHS UN criteria.

Two study of Klimish score 2 are available to asses the eye irritation potential (Terrell, 1988; Levenstein, 1978). Terrell study was selected as key study as it has been conducted following the Good Laboratory Practise. In this study, the registered substance (product name = Miranol C2M AA) has been tested for acute ocular irritation in 3 New-Zealand White rabbits according to Draize test. 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 the animal. The left eye remained untreated and served as a control. The eyes were not rinsed. Ocular examinations were performed at 24, 48, 72 hours after treatment, and at day 4 and 7. 

Corneal opacity (score 2) was observed in all three rabbits at 24 hours. The reaction was still present in two animals at day 7 with grade 2, and with grade 1 in one animal. The mean scores (24-48-72 hours) calculated for each animal were 2.0 - 2.0 - 2.0. Iris reaction was observed between 24 hours and day 4 in one animal, and starting at day 3 in a second animal, whereas no reaction was observed in the third one. The mean scores (24-48-72 hours) calculated for each animal were 1.0 - 0.0 - 0.3. Conjunctival redness (score 2 to 3) and chemosis (score 1 to 3) were observed and persisted until day 7 in all three animals. The mean scores (24-48-72 hours) calculated for each animal were 3.0 - 2.0 – 2.0 for redness, and 2.7 – 2.0 - 1.3 for chemosis. In addition, ocular discharge was observed all three animals throughout the observation period.

In the supporting study (Levenstein, 1978), the registered substance (product name = Miranol C2M AA) has been tested for acute ocular irritation in 3 albino rabbits according to Draize test. The test article, a liquid, was instillated as such in a single dose of 0.1 ml into the right eye of the animal. The left eye remained untreated and served as a control. The eyes were not rinsed. Ocular examinations were performed at 24, 48, 72 hours after treatment, and at and 7.

 No corneal opacity nor iris reaction were reported in any animals.

Conjunctival redness (score 1 to 2) and chemosis (score 1 to 3) were observed in all three animals. Conjunctival redness persited until day 7 in one animal. The mean scores (24-48-72 hours) calculated for each animal were 1.0 - 1.7 – 1 for redness, and 0.7 – 2.0 - 0.3 for chemosis. In addition, ocular discharge was observed all three animals but reversed at day 7.

 

On the basis of the results of these study and considering the absence of reversibility of ocular reaction 7 days after exposure, the registered substance is considered a severe eye irritant (Eye Damage 1, H318) according to criteria of CLP and GHS UN.

Justification for classification or non-classification

Based on an in vivo skin irritation test in rabbits, the registered substance is not be classified as a skin irritant according to CLP and GHS UN criteria.

Based on the absence of reversibility of ocular effects in two in vivo eye irritation tests in rabbits, the registered substance is classified as a severe eye irritant (Eye Damage 1, H318) according to CLP and GHS UN criteria.