Imidazolium compounds, 2-C17-unsatd.-alkyl-1-(2-C18-unsatd. amidoethyl)-4,5-dihydro-N-methyl, Me sulfates

Endpoint summary

Description of key information

Degree of irritation / corrosivity was variable and depended on the test substance lot and chemical impurities. In essence, the substance class is irritating to the skin and the eye.

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:

2001-06-07 to 2001-06-21

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2500 (Acute Dermal Irritation)

Version / remarks:

1998

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

1992

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

1992

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Japanese Guideline 11 Nousan No. 6283 (October 1, 1999); First Revision: 12 Nousan 8628 (December 6, 2000)

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: Young adult
- Weight at study initiation: 3329 to 3867 grams
- Housing: individual housing in suspended wire mesh cages
- Diet: 150 g/day, standard laboratory rabbit diet PMI Nutrition International, Inc. Certified Rabbit LabDiet® 5322
- Water: ad libitum, municipal water
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 66-71
- Humidity (%): 50-75
- Air changes (per hr): no data
- Photoperiod: 12 hour light/dark cycle

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

other: Each animal served as its one control with adjacent area of untreated skin.

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.5 ml
- Concentration (if solution): undiluted

Duration of treatment / exposure:

4 h

Observation period:

14 days

Number of animals:

3

Details on study design:

PRE-EXPERIMENTAL PROCEDURE
On the day prior to dosing, the hair was removed from the backs and flanks of the rabbits using an electric clipper.

ADMINISTRATION OF THE TEST ARTICLE
Prior to use, the original container of the test article was agitated to insure a homogeneous mixture. A sufficient amount of test article was dispensed into a labeled storage vessel and a stir bar was added. The test article was stirred continuously throughout the dosing procedure. Each 0.5-ml was applied to an area of skin approximately 2.5 x 2.5 cm under a two-ply gauze patch secured in place with Micropore™ tape. The patches were overwrapped with a gauze binder and secured with Dermiform® tape. Plastic restraint collars were applied to the animals to prevent ingestion of the test article and/or bandages. The application sites were observed for erythema, edema and other dermal findings approximately 30-60 minutes and 24, 48 and 72 hours after patch removal and on study days 4, 7, 10 and 14.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes
- Time after start of exposure: 4 hours
At the end of four hours, the collars and bandages were removed and the sites wiped with disposable paper towels moistened with deionized water.

SCORING SYSTEM: Dermal irritation was graded in accordance with the method of Draize

Irritation parameter:

erythema score

Basis:

animal: #1, #2, #3

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

not fully reversible within: 14 days

Remarks on result:

other: Very slight erythema (score 1) in all animals at day 14

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 10 days

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1.33

Max. score:

4

Reversibility:

fully reversible within: 10 days

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.67

Max. score:

4

Reversibility:

fully reversible within: 14 days

Irritant / corrosive response data:

CLINICAL SKIN OBSERVATIONS
- All animals were noted with moderate to severe erythema and very slight to slight edema. Focal eschar was noted for two animals on study day 7, and desquamation was noted for all animals on study days 7 through 14.

REVERSIBILITY
- Very slight erythema was still present for all animals at study termination (study day 14).

Other effects:

TOXIC EFFECTS OTHER THAN SKIN IRRITATION
- There were no deaths during the study.
- Body weights: No remarkable body weight changes were noted during the study.

Irritant/corrosive response data for each animal at each observation time

Score at time point	Erythema	Edema
	Max. score: 4	Max. score: 4
0.5-1 hour	3/2/2	1/1/1
24 hours	3/3/3	1/2/2
48 hours	3/3/3	1/1/2
72 hours	3/3/3	1/1/1
4 days	3/3/3	1/1/1
7 days	2d/2dg/3dg	1/1/1
10 days	2d/2d/2d	0/0/1
14 days	1d/1d/1d	0/0/0

d=desquamation; g = focal eschar

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

Interpretation is based on erythema/eschar and edema calculated as mean scores for each animal following grading at 24, 48 and 72 hours after removal of the test material, in consideration of reversibility. The following mean scores were calculated for oleic-acid based IQAC, DMS quaternised: erythema 3/3/3 and edema 1/1.33/1.67. Edema were fully reversible within 14 days in all animals, whereas very slight erythema (score 1) was still present in all animals at study termination (day 14).

Executive summary:

In a primary skin irritation study according to US Guideline EPA OPPTS 870.2500 (1998), OECD Guideline 404 (1992), EU Guideline B.4 (1992) and Japanese Guideline Nousan No. 6283 (1999), revised Nousan 8628 (2000), three White New Zealand rabbits were semi-occlusive dermally exposed to 0.5 ml of oleic-acid based IQAC, DMS quaternised (according to sponsor information: 80 % of CAS No. 72749-55-4, 15 % of CAS No. 9004-96-0 (Oleic acid, ethoxylated) and 5 % of CAS No. 25322-68-3 (Poly(oxy-1,2-ethanediyl),α-hydro-ω-hydroxy- Ethane-1,2-diol, ethoxylated)) for 4 hours. Animals then were observed for 14 days. Irritation was scored by the method of Draize.

 

The oleic-acid based IQAC, DMS quaternised induced in all animals moderate to severe erythema and very slight to slight edema. Focal eschar was noted for two animals on study day 7, and desquamation was noted for all animals on study days 7 through 14. Very slight to slight erythema was still present for all animals at study termination (study day 14). Mean scores from gradings at 24, 48 and 72 hours after removal of the test material for erythema were for all animals >/=2.3 but < 4. Edema were less severe. Inflammation persisted to the end of the observation period (14 days) in all three animals.

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:

2001-06-14 to 2001-07-08

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

Version / remarks:

1998

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Japanese Guideline 11 Nousan No. 6283 (October 1, 1999); First Revision: 12 Nousan 8628 (December 6, 2000)

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Covance Research Products Inc. Denver, PA, USA
- Age at study initiation: Young adult
- Weight at study initiation: 2577 to 2758 grams
- Housing: individual housing in suspended wire mesh cages
- Diet: 150 g/day, standard laboratory rabbit diet PMI Nutrition International, Inc. Certified Rabbit LabDiet® 5322
- Water: ad libitum, municipal water
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 66-77
- Humidity (%): 48-80
- Air changes (per hr): no data
- Photoperiod: 12 hour light/dark cycle

Vehicle:

unchanged (no vehicle)

Controls:

other: Each animal served as its one control. The test article was introduced into the conjunctival sac of one eye, the untreated eye serving as a control.

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.1 ml
- Concentration: The test article was applied unchanged as received

Duration of treatment / exposure:

Eyes were not rinsed after treatment.

Observation period (in vivo):

21 days

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: no washing was done

SCORING SYSTEM: in accordance with Draize, as published in the guidelines in Subsection F. Hazard Evaluation: Human and Domestic Animals distributed in 1984 and the EPA-OPPTS Health Effects Test Guidelines (1998).

TOOL USED TO ASSESS SCORE: A direct ophthalmoscope was used during these observations to examine the corneal tissue. In addition, both eyes were further examined at 24 hours and at all subsequent observations with sodium fluorescein.

PREPARATION and SELECTION of ANIMALS: Both eyes of all rabbits were examined for ocular abnormalities prior to initiation of dosing. The pre-initiation examination included the use of sodium fluorescein and a direct ophthalmoscope for detection of corneal abnormalities. Only rabbits with no
pre-existing ocular abnormalities were assigned to study.
Both eyes of all rabbits were examined macroscopically for ocular irritation in accordance with the method of Draize at approx. 1, 24, 48, 72 h, 4, 7, 14 d

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

cornea opacity score

Basis:

other: #1, #2

Time point:

24/48/72 h

Score:

1.67

Max. score:

4

Reversibility:

fully reversible within: 21 days

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal: #1, #2

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

fully reversible within: 7 days

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

fully reversible within: day 14

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2.33

Max. score:

3

Reversibility:

fully reversible within: day 21

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

3

Max. score:

3

Reversibility:

fully reversible within: 17 days

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2.67

Max. score:

4

Reversibility:

fully reversible within: 14 days

Irritation parameter:

chemosis score

Basis:

animal: #1, #2

Time point:

24/48/72 h

Score:

3.67

Max. score:

4

Reversibility:

fully reversible within: 17 days

Irritant / corrosive response data:

Positive corneal, iridal and conjunctival findings were noted for all animals. Corneal neovascularization was noted for two animals on study days 7 through 14 or 17. Iridal irritation subsided by study day 7, and corneal and conjunctival irritation completely subsided by study termination (study day 21).
The Maximum Average Score for the test substance was 50.3 at 48 hours post-instillation.

Other effects:

There were no deaths or remarkable body weight changes during the study period.

Irritant/corrosive response data for each animal at each observation time

Score at time point / Reversibility	Cornea opacity	Cornea - Area  involved	Iris	Conjunctivae Redness	Conjunctivae Chemosis	Conjunctivae Discharge	Fluorescein test (% of cornea retaining stain)
	Max. score: 4	Max. score: 4	Max. score: 2	Max. score: 3	Max. score: 4	Max. score: 3	Max.: 100 %
1 hour	1/1/1	1/1/1	1/1/1	2/2/1	3/2/3	3b/3b/3b	no
24 hours	1/1/1	4/4/1	1/1/0	3/2/2	4/3/3	3b,p/3b,p/3b,p	yes 75/65/10
48 hours	2/2/1	4/4/1	1/1/0	3/3/2	4/4/3	3b,p/3b/3b,p	yes 65/45/5
72 hours	2/2/1	4/3/1	1/1/0	3/2/2	3/4/2	3b,p/3b/1b,p	yes 50/30/0
4 days	2/2/1	4/3/1	1/1/0	3/2/2	3/3/2	2b,p/2b/1b,p	yes 50/20/0
7 days	2k/1k/0	2/1/0	0/0/0	2/2/1	2/2/1	1b/0/0	yes 15/5/0
10 days	1k/1k/0	1/1/0	0/0/0	1/2/1	1/1/1	0/0/0	yes 0/0/0
14 days	1k/1k/0	1/1/0	0/0/0	1/1/0	0/1/0	0/0/0	yes 0/0/0
17 days*	0/1k/-	0/1/-	0/0/-	0/1/-	0/0/-	0/0/-	yes 0/0/-
21days**	-/0/-	-/0/-	-/0/-	-/0/-	-/0/-	-/0/-	yes -/0/-

* only the two animals with responses at 14 days examined

** only the animal with responses at 17 days examined

b = clear discharge, p = purulent discharge in conjunctival sac, k = corneal neovascularization

Interpretation of results:

Category 2A (irritating to eyes) based on GHS criteria

Conclusions:

Interpretation is based on effects on the cornea, iris and conjunctiva calculated as mean scores following grading at 24, 48 and 72 hours after instillation of the test material, in consideration of reversibility. Slight to moderate effects of cornea and iris were observed and moderate to severe conjunctivae and chemosis scores. All symptoms were fully reversible within 21 days.

Executive summary:

In a primary eye irritation study according to US Guideline EPA OPPTS 870.2400 (1998), OECD Guideline 405 (1987), EU Guideline B.5 (1992) and Japanese Guideline Nousan No. 6283 (1999), revised Nousan 8628 (2000), 0.1 ml of oleic-acid based IQAC, DMS quaternised (according to sponsors information: 80 % of CAS No. 72749-55-4, 15 % of CAS No. 9004-96-0 (Oleic acid, ethoxylated) and 5 % of CAS No. 25322-68-3 (Poly(oxy-1,2-ethanediyl),α-hydro-ω-hydroxy- Ethane-1,2-diol, ethoxylated)) was instilled into the conjunctival sac of three White New Zealand rabbits. The eyes were not rinsed after substance application. Animals then were observed for 21 days. Irritation was scored by the method of Draize.

Positive corneal, iridal and conjunctival findings were noted for all animals. Corneal neovascularization was noted for two animals on study days 7 through 14 or 17. Iridal irritation subsided by study day 7, and corneal and conjunctival irritation completely subsided by study termination (study day 21).

The test substance induced a maximum mean total score of 50.3 (maximum possible mean total score of 110) at 48 hours post-instillation. Mean scores following grading at 24, 48 and 72 hours after instillation of the test material for corneal opacity were >/= 1but < 3, for iritis >/= 1 but < 1.5 and for conjunctival redness and oedema >/= 2. All effects were completely reversible in all animals within 21 days.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The degree of irritation / corrosivity was variable and most likely depends on undeclared chemical impurities in some of the test substances.

For the eye effects of an oleic-acid based IQAC, DMS quaternised, with by-products of approx. 10 % of nonylphenol ethoxilate, 1 % of free amine and 0.5 % of hydrogen peroxide, the corrosive effects can be attributed to the alkyl phenol, which causes severe damage to eyes. Though this substance contains the highest content of IQACs tested, its eye damaging potential is untypical for the substance class and can be rationalised as being due to its by-products.

Studies performed according to US Federal Hazardous Substances Act (FHSA) pointing to skin corrosion and serious eye damage had significant deficiencies in methodology regarding time of exposure, post-exposure observation time and reporting and are therefore not regarded as reliable data. In essence, the substance class is irritating to skin and eyes.

Justification for selection of skin irritation / corrosion endpoint:
Data from a GLP compliant study with reliability 1, according to acutal guidelines.

Justification for selection of eye irritation endpoint:
Data from a GLP compliant study with reliability 1, according to acutal guidelines.

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Justification for classification or non-classification

Skin irritation: Cat. 2 according to GHS/CLP; R38, Irritating to Skin according to Directive 67/548/EEC

Eye irritation: Cat. 2 according to GHS/CLP; R36, Irritating to Eyes according to Directive 67/548/EEC