4,4-dimethyloxazolidine

Endpoint summary

Description of key information

Skin irritation/corrosion:

In vivo skin irritation/corrosion: irritant (rabbits, 4h exposure)

In vivo skin irritation: irritant (rabbits, 24 and 58h exposure)

In vivo skin irriation: irritant (humans, 24h application, repeated exposure)

 

Eye irritation/corrosion:

Two studies for in vivo eye irritation/corrosion: damaging to the eye (rabbits, 1s and 1 min exposure)

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation / corrosion, other

Remarks:

Skin corrosion: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

27 - 29 May 1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Remarks:

No observation after 72 hours

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Skin Corrosion Test in Rabbits to evaluate corrosive potential of a chemical or a product to the skin
- Short description of test conditions: The test material (0.5g or 0.5 ml) will be applied to a hair free area one the back. The test material will be left in contact with the skin for four hours. After exposure, the skin sites will be wiped clean and left exposed to the air for the duration of the study. The treated skin site will be visually examined for erythema, edema or any irreversible tissue destruction at 4, 24 and 48 hours after the initial application of the material.

GLP compliance:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: IMC, Terre Haute, Indiana / Lot 94
- Purity:
P-1952 - Lot 94
Oxidine (Oxazolidine A) 82.01 w/w %
TMO (Trimethyl oxazolidine) 2.90 w/w %
Water 15.00 w/w %
ox APD (Oxazolidine from 2-amino-1,3-propanediol) 0.01 w/w %
ox E (Oxazolidine E) 0.05 w/w %

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Kuiper Rabbit ranch, Gary, Indiana
- Age at study initiation: At least 9 weeks
- Weight at study initiation: 2.8 ± 0.2 kg
- Housing: Individually caged during and after exposure
- Diet: Purina Certified Rabbit Chow #5322 ad libitum. Each utilized lot was identified and dated. The diet was certified free of contaminants and the analysis was performed by the supplier.
- Water: Tap water will ad libitum. Every quarter the animals' drinking water was analyzed to ensure that the levels of contaminants are equal to or less than the recommended levels as per the Primary Drinking Water Regulations (40 CFR. 141.11, 141.12, 141.14).
- Acclimation period: at least 7 days

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.5 ml
- Concentration: as supplied

Duration of treatment / exposure:

4 hours

Observation period:

- Skin examination: 4, 24 and 48 hours after application of the test material
- Body weights: At 0 and 48 hours after application

Number of animals:

6

Details on study design:

TEST SITE
- Area of exposure: 1 sq inch
- Type of wrap if used: covered with gauze and a "Dermicel" cloth tape. The animal trunk was then loosely wrapped with an impervious rubberized cloth and a flexible stainless steel protective screen held in place by tape.

REMOVAL OF TEST SUBSTANCE
The patches were removed and the treated skin sites were gently cleaned.

OBSERVATION TIME POINTS
- Skin examination: 4, 24 and 48 hours after application of the test material
- Body weights: At 0 and 48 hours after application

EVALUATION:
The sites were visually evaluated for erythema, edema and tissue destruction after stated time points.

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 4h

Score:

ca. 1

Max. score:

1

Reversibility:

not specified

Remarks on result:

probability of weak irritation

Irritation parameter:

erythema score

Basis:

mean

Time point:

24 h

Score:

ca. 1.5

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

mean

Time point:

48 h

Score:

ca. 1.3

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 4h

Score:

1.2

Max. score:

2

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

edema score

Basis:

mean

Time point:

24 h

Score:

ca. 0.7

Max. score:

2

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

edema score

Basis:

mean

Time point:

48 h

Score:

ca. 0.2

Max. score:

1

Reversibility:

not specified

Remarks on result:

probability of weak irritation

Irritant / corrosive response data:

The material applied easily on the skin. At 4, 24, and 48 hour observation period all the animals showed erythema and five animals showed edema. At 48 hours four animals still showed from mild to strong erythema, but none of the treated skin sites showed any tissue destruction.

Interpretation of results:

GHS criteria not met

Conclusions:

The results obtained in this in vivo Skin Corrosion Test of 4,4-dimethyloxazolidine (CAS 51200-87-4) showed erythema and edema after exposure to the substance, but no tissue destruction. The test item 4,4-dimethyloxazolidine (CAS 51200-87-4) is considered to be non-corrosive to skin.

Executive summary:

The material applied easily on the skin. At 4, 24, and 48 hour observation period all the animals showed erythema and five animals showed edema. At 48 hours four animals still showed from mild to strong erythema, but none of the treated skin sites showed any tissue destruction.

Amine CS-1135 was noncorrosive to the skin and did not induce tissue damage.

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

according to guideline

Guideline:

other: Federal Register , Title 21, Part 191

Deviations:

not specified

Principles of method if other than guideline:

- Short description of test conditions: The test material was applied, undiluted, to the shaved skin by introducing 0.5 ml under a gause pad. Readings were made of the treated areas after 24 hours of exposure. Following the 24-hour observation, the wrappings were re-applied and the animals were held in restraint for an additional 48 hours after which the skin reposes were observed again.
- Parameters analysed / observed: Erythema, Eschar Formation; Edema Formation

GLP compliance:

not specified

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Lot No.of test material: 575916
- Purity test date: 87.4 %
- Final dilution: undiluted

Species:

rabbit

Strain:

other: New Zealand (color not specified)

Remarks:

Male

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: 2300 to 2700 grams

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.5 ml
- Concentration: undiluted

Duration of treatment / exposure:

24 and 48 hours

Observation period:

24 and 72 hours

Number of animals:

6

Details on study design:

TEST SITE
- Area of exposure: 1 sq inch
- Type of wrap if used: gause pad affixed by adhesive tape to each side. The skin under one pad (on the right side) was abraded by
scoring the epidermis, using light, horizontal strokes with a pointed scalpel blade; the skin of the contralateral side rernained unabraded.
The trunks of the animals were wrapped with an impervious material and the animals were placed in a restraining rack for the duration of the exposure
period.

REMOVAL OF TEST SUBSTANCE
not specified

OBSERVATION TIME POINTS
- After 24 hours of exposure
- After 72 hours of exposure; wrappings were re-applied and the animals were held restraint for an additional 48 hours.

SCORING SYSTEM:
- Method of calculation: The skin responses were evaluated according to a table and instructions contained in the Federal Register, Title 21, Part 191, apra. 191.11, p.244.

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2.5

Max. score:

4

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Remarks:

48h was not reported

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

1

Reversibility:

not specified

Remarks on result:

probability of mild irritation

Remarks:

48h was not reported

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Remarks:

48h was not reported

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Remarks:

48h was not reported

Irritation parameter:

erythema score

Basis:

animal #5

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Remarks:

48h was not reported

Irritation parameter:

erythema score

Basis:

animal #6

Time point:

24/48/72 h

Score:

2

Max. score:

2

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Remarks:

48h was not reported

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1.5

Max. score:

2

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Remarks:

48h was not reported

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

2

Reversibility:

not specified

Remarks on result:

probability of mild irritation

Remarks:

48h was not reported

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Remarks:

48h was not reported

Irritation parameter:

edema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

2.5

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Remarks:

48h was not reported

Irritation parameter:

edema score

Basis:

animal #5

Time point:

24/48/72 h

Score:

2.5

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Remarks:

48h was not reported

Irritation parameter:

edema score

Basis:

animal #6

Time point:

24/48/72 h

Score:

2.5

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Remarks:

48h was not reported

Irritant / corrosive response data:

Subjective observations:
1. Erythema/eschar formation: Erythema appeared not only at the application sites, but also as a border surrounding the whole area covered by the wrapping. High scores on the 72-hour readings are due primarily to evidence of deep-tissue damage -- a blanched, gray appearance of the skin immediately surrounding the site of treatment and scab formation at the treatment site; especially where the tape adhered to the skin.
2. Edema formation: As with erythema, the edema encompassed the whole area under the wrapping. In a majority of the animals, edema subsided significantly by the time of the 72-hour observation.

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Remarks:

Observation was done only for 72 h

Conclusions:

The Primary Irritation Scores, representing the combined ratings on the effects of the test materials in producing erythema and edema, inadicate that in this experiment, Oxazolidine-A exerted marked, localized effects on the skin of the test animals.

Executive summary:

Treatment of rabbits' skin with Oxazolidine-A caused slight to severe erythema in 4 of 6 rabbits at 24 hours. The erythema persisted in most cases until the 72-hour reading and was, by then, accompanied by signs of deeper tissue involvement.

Treatment with Oxazolidine-A produced slight to severe edema in all test animals at 24 hours. The edema was transitory in that it had subsided by the time of the 72-hour readings.

The Primary Irritation Scores, representing the combined ratings on the effects of the test materia1s in producing erythema and edema, inadicate that in this experiment, Oxazolidine-A exerted marked, localized effects on the skin of the test animals.

Reference 3

Endpoint:

skin irritation / corrosion, other

Type of information:

experimental study

Adequacy of study:

key study

Study period:

16 April - 08 June 1979

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

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

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

other: Shelanski (Combination method)

Deviations:

not specified

Principles of method if other than guideline:

- Principle of test: Shelanski (Combination method)
- Short description of test conditions:
A total of 105 individuals was selected to participate in this evaluation. The procedure is a double-blind evaluation of the test material in a randomy selected group from the local population.
Induction was done through a series of twelve consecutive daily applications, each of twenty-four hours duration, was scheduled to be carried out during the induction period (weeks #1, 2 and 3). In week #1 and #2 the test material was applied in a concentration of 3.0 % w/v in water; in week #3 the test material was applied in a concentration of 0.3 % w/v in water.
Challenge was done through one application with a concentration of 0.3 % w/v of the test material in water on virgin sites during the challenge week (week #6).
An additional challenge application was done with 2 individuals with a concentration 0.1 % w/v of the test substance in water (week #8).
Site definition: A site on the arm of each individual was selected and identified for contact with the test material.
Patch definition: Specially prepared Parke-Davis Readi-Bandages werde used in this procedure. 0.2 ml of the test material was applied to the webril pads of occlusive Readi-Bandages. The patches were then applied to the sites.
- Parameters analysed / observed:
Direct effects: Immediate Primary Irritation and/or Fatigue or Cumulative Primary Irritation
Indirect effects (Hypersensitivity): Immediate Reaction Type (Histamine release, phenomenon, wheal and flare, urticaria, Arthus penomenon), Delayed Reaction Type (Macular or maculo-papular eruptions, induration, itching)

GLP compliance:

not specified

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Name: Amine CS-1135
- Source and lot No: Received from International Minerals and Chemical Corporation at 16 April 1979, Lot No. 55
- Description: clear liquid
- Purity: 78%

PREPARATION OF THR TEST MATERIAL
3 g of the original test material was diluted to 100 ml in water to form a 3 % v/v emulsion in water.
300 mg of the original test material was diluted to 100 ml in water to form a 0.3 % w/v emulsion in water.
100 mg of the original test material was diluted to 100 ml in water to form a 0.1 % w/v emulsion in water.

Species:

other: human

Details on test animals or test system and environmental conditions:

TESTED POPULATION
- Source: Randomly selected group from the local population
Adults (18 years and older) from local population were recruited to participate.

Criteria for initial qualification:
1. Willingness to cooperate
2. Dependability and perserverance.
3. Ability to understand the purpose of the procedure and what was required of him or her.
4. Ability to understand the risks involved and to make a reasonable judgment to participate.
5. Ability to understand the items in the consent form which he or she was required to sign before the start of the study.

Exclusion Criteria:
A history of past and present health status and medication intake was obtained from each of the individuals being considered a brief physical examination was performed in order to detect and eliminate any who evidenced any finding which could be considered a basis for exclusion.
Candidates were exeluded for any one of the following reasons:
1. Systemic illnes which might have contra-indicated participation.
2. Skin disease with manifestions wich might be confused with effects of the test material.
3. Intake of medications which might augment or impede the irritant effects of the test material.

Type of coverage:

occlusive

Preparation of test site:

not specified

Vehicle:

water

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.2 ml of solution
- Concentration:
3.0 % v/v of solution (diluted with water) on weeks #1 and #2
0.3 % v/v of solution (diluted with water) on week #3

Duration of treatment / exposure:

- Induction was done through a series of twelve consecutive daily applications, each of twenty-four hours duration, four applications per week, four applications per week, was scheduled to be carried out during the induction period (weeks #1, 2 and 3).
- Challenge was done through one application on virgin sites during the challenge week (week #6)

Observation period:

6 weeks

Number of animals:

101

Details on study design:

TEST SITE :
- Type of wrap: Parke-Davis Readl-Bandages
REMOVAL OF TEST SUBSTANCE
- Washing: no
OBSERVATION TIME POINTS
After every 24 h application
SCORING SYSTEM:
- Area of exposure: Arm
- Type of wrap if used: Parke-Davis Readi-Bandages. 0.2 ml of the test material was applied to the webril pads of occlusive Readi-Bandages. The adhesive was pressed all around to assure firm contact of the test material against the skin and to form a seal against loss of moisture.

Irritation parameter:

primary dermal irritation index (PDII)

Remarks:

3% w/v solution

Basis:

other: 101 human volunteers

Time point:

other: 24 h after repeated application

Score:

ca. 70.3

Reversibility:

fully reversible

Remarks on result:

positive indication of irritation

Remarks:

Presence of visible irritation after two or more consecutive 24h applications

Irritation parameter:

other: Primary irritant effect of the cumulative type (% individuals showing irritation)

Remarks:

0.3% w/v solution

Basis:

other: 101 human volunteers

Time point:

other: 24 h after four 24h application

Score:

0

Remarks on result:

no indication of irritation

Remarks:

Presence of visible irritation after two or more consecutive 24h applications

Irritant / corrosive response data:

No significant irritation was recorded as a result of the first application.
The presence of visible irritation after two or more applications indicates that the sample material tested at 3.0% w/v emulsion in water did excert a primary irritant effect of the cumulative type in 70.3 % of the individuals under test.
The presence of visible irritation after two or more applications on week #3 indicates that the sample material tested at 0.3 w/v emulsion in water did excert a primary irritant effect of the cumulative type in 6.9 % of the individuals under test.

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

CS-1135 is a skin irritant.

Executive summary:

Amine CS-1135 (P-1952, 4,4-dimethyl-1,3-oxazolidine or Oxazolidine A 78% plus Water 22% by weight) Lot No. 55, was submitted to Product Investigations, Inc., Conshohocken, PA, for potential assessment of dermal irritation and sensitization hazard in human volunteers.

A series of twelve, 24 hr applications, four applications per week of Amine CS-1135 were applied to the intact skin. Each application consisted of 0.2 m1 solution of Amine CS-1135 under an occlusive patch. Initially, a 3.0 % solution of Amine CS-1135 was applied but by the end of the second week, 60% of the subjects were exhibiting irritation at the application site. Thus, for the third week repeat applications of the concentration of CS-1135 was reduced to 0.3%.

After two weeks of rest a virgin site was challenged with 0.3% CS-1135 solution. Only two subjects out of 101 showed any skin reaction within the four-day observation period. The same two subjects upon rechallenge with a 0.1% CS-1135 solution at a virgin site showed no skin reaction.

A 3% CS-1135 solution produces fatiguing and irritation to the human skin but it does not elicite a sensitization reaction. The 95 percentile confidence limits, where CS-1135 will not elicite any sensitization reactions are 96.41 to 100%, for n = 101.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (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:

1973

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

according to guideline

Guideline:

other: The Federal Register, Title 21, Part 191

Deviations:

not specified

Principles of method if other than guideline:

- Principle of test: Eye Irritation in Rabbits by introduction to the eye
- Short description of test conditions: 0.1 ml of the test material was introduced topically into a cup formed by retracting the lower eyelid of the right eye only of each of six albino rabbits. After introduction of the test substance (Oxazolidine-A, Lot. No. 575916, 87.4%), the eyelids were held closed for one second. The test animals were then maintained without further treatment and their eyes were examined at 24, 48 and 72 hours after treatment.
- Parameters analysed / observed: Visualization of the treated eyes was accomplished through use of a hand-held slit lamp and spectacle loupes. Because of the severe reactions observed and the consequent risk of exacerbation of the responses, fluorescein sodium solution was not instilled into the eyes to aid the observations.

GLP compliance:

not specified

Specific details on test material used for the study:

- Lot No.of test material: 575916
- Concentration: 87.4% w/w

Species:

rabbit

Strain:

other:

Remarks:

Albino rabbits

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.1 ml of the test material

Duration of treatment / exposure:

After induction of the test substance, were hold closed for one second.

Observation period (in vivo):

The test animals were then maintained without further treatment and their eyes were examined at 24, 48 and 72 hours after treatment.

Number of animals or in vitro replicates:

6 Albino Rabbits

Details on study design:

SCORING SYSTEM: according to the method of Draize as described in the "Illustrated guide for grading eye irritation byhazardous substances" prepared by the U.S. Department of Health Education and Welfare, FDA

TOOL USED TO ASSESS SCORE: hand-slit lamp. Due to the severe reactions no fluorescein was instilled

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #4

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #5

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #6

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

inflamation

Basis:

animal #1

Time point:

24/48/72 h

Score:

>= 1 - <= 2

Max. score:

2

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

inflamation

Basis:

animal #2

Time point:

24/48/72 h

Score:

>= 1 - <= 2

Max. score:

2

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

inflamation

Basis:

animal #3

Time point:

24/48/72 h

Score:

>= 1 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

inflamation

Basis:

animal #4

Time point:

24/48/72 h

Score:

>= 1 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

inflamation

Basis:

animal #5

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

inflamation

Basis:

animal #6

Time point:

24/48/72 h

Score:

>= 1 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

3

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #4

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #5

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #6

Time point:

24/48/72 h

Score:

> 2 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

iris score

Basis:

animal:

Remarks:

all animals

Time point:

24/48/72 h

Remarks on result:

not determinable

Remarks:

Unable to observe the iris and bulbar conjunctivae because of corneal opacity and pronounced inflammation and edema

Irritant / corrosive response data:

Initial observation: All animals reacted with apparent pain within a few seconds after aplication of the test material. Excessive lacrymation of the treated eyes.
24-hour observation: Eyelids and palpebral conjunctivae edematous and inflamed; heavy, mucinous discharge. Corneas cloudy (evidence of corneal edema). Unable to observe the iris and bulbar conjunctivae because of corneal opacity and pronounced inflammation and edema.
48-hour observation: Increased severity of conjunctival edema and inflammation. Continued heavy, mucinous discharge
72-hour observation: Puriform discharge from treated eyes of all animals; increased degree of corneal opacity. Increase in edema and inflammation- conjunctivae pendulous; lid eversion in all animals.

No evidence of corneal ulceration at any observation period.

Interpretation of results:

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

Conclusions:

Topical treatment of rabbit eyes with Oxazolidine-A elicited a strong, positive reaction in 100 % (6 of 6 rabbits) of the test animals.

Executive summary:

The test procedure employed is discussed in The Federal Register, Title 21, Part 191, para. 191.12 amd was conducted as described briefly as follows: 0.1 ml of the test material was introduced topically into a cup formed by retracting the lower eyelid of the right eye only of each of six albino rabbits. After introduction of the test substance (Oxazolidine-A, Lot. No. 575916, 87.4%), the eyelids were held closed for one second. The test animals were then maintained without further treatment and their eyes were exaimned at 24, 48 and 72 hours after treatment.

Visualization of the treated eyes was accomplished through use of a hand-held split lamp and spectacle loupes. Because of the severe reactions observed and the consequent risk of excerbation of the responses, fluorescein sodium solution was not instilled into the eyes to aid the observations.

Initial observation: All animals reacted with apparent pain within a few seconds after aplication of the test material. Excessive lacrymation of the treated eyes.

24-hour observation: Eyelids and palpebral conjunctivae edematous and inflamed; heavy, mucinous discharge. Corneas cloudy (evidence of corneal edema). Unable to observe the iris and bulbar conjunctivae because of corneal opacity and pronounced inflammation and edema.

48-hour observation: Increased severity of conjunctival edema and inflammation. Continued heavy, mucinous discharge

72-hour observation: Puriform discharge from treated eyes of all animals; increased degree of corneal opacity. Increase in edema and inflammation- conjunctivae pendulous; lid eversion in all animals.

No evidence of corneal ulceration at any observation period.

Topical treatment of rabbit eyes with Oxazolidine-A elicited a strong, positive reaction in 100% (6 of 6 rabbits) of the test animals.

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

according to guideline

Guideline:

other: The Federal Register, Title 21, Part 191

Deviations:

not specified

Principles of method if other than guideline:

- Principle of test:
Eye Irritation of CS-1135 in Rabbits by introduction to the eye
- Short description of test conditions:
0.1 ml of the test material was introduced into a cup formed by retracting the lower eyelid of the right eye of each of six albino rabbits. Group 1 was treated by introducing 0.1 ml of a diluted solution of CS-1135 (1000pm in sterile water). After introduction of the test material, the eyelid was hold closed for one second.
Modified treatment of Group 2 was: 0.1 ml of undiluted CS-1135 was placed into the eye, the eyelid was held closed for one minute; the eye was then lavaged thoroughly with sterile 0.9% sodium chloride solution to remove all unabsorbed material. All test animals were maintained thereafter without further treatment and their eyes were examined at 24, 48 and 72 hours after treamtent
- Parameters analysed / observed: Examination of the treated eye was facilitated by use of a hand-held slit lamp and/or spectacle loupes. After the 24-hour examination, a drop of fluorescein sodium opthalmic solution was placed into each subject´s treated eye to aid in the visualisation of possible mechanical damage to the cornea.

GLP compliance:

no

Specific details on test material used for the study:

- Name: CS-1135
- Lot No.of test material: 575916
- Purity: 87.4 %

Species:

rabbit

Strain:

other:

Remarks:

Albino rabbits

Vehicle:

water

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.1 ml

Group 1: 1000 ppm of CS-1135 (diluted in sterile water)
Group 2: undiluted CS-1135

Duration of treatment / exposure:

Group 1: 1s while eyelid was held closed
Group 2: 1min while eyelid was held closed; the eye was lavaged with sterile 0.9% sodium chloride solution afterwards

Observation period (in vivo):

All test animals were maintained thereafter without further treatment and their eyes were examined at 24, 48 and 72 hours.

Number of animals or in vitro replicates:

6

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing:
Group 2: The eye was lavaged thoroughly with sterile 0.9 % sodium chloride solution to remove all unabsorbed material after treatment of 1 min.

SCORING SYSTEM:
Cornea - examined for the detection of opacity (evidence of edema), ulceration and/or mechanical damage such as scratching or scoring.
Grade Coditions for grading
0 No opacity; no ulceration or mechanical damage
1 Scattered or diffuse opacity; iris clearly visible
2 Obvious areas; iris slightly obscured
3 Pearly areas; details of iris and size of pupil indistinct
4 Cornea completely opaque; iris not discernible

Iris - examined for congestion, reaction to bright light
Grade Conditions for grading
0 Normal appearance
1 Deepened folds, congestion; any degree of injection (engorgement) of circumcorneal vessels; still reacts to light
2 No reaction to light; hemorrhage; gross destruction

Chemosis/Redness - examination of conjuntivae for chemosis (edema, swelling) and injection of vessels

Chemosis
Grade Conditions for grading
0 No swelling
1 Detectable swelling
2 Obvious swelling; partial eversion of eyelids
3 Severe swelling; partial closure of eyelids
4 Severe swelling; eyelids more than half-closed

Redness
Grade Conditions for grading
0 Normal
1 Slight injection of some vessels
2 Diffuse, bright redness; individual vessels not discernible
3 Diffuse, deep, beefy redness


TOOL USED TO ASSESS SCORE: hand-slit lamp and/or spectacle loups / fluorescein

Irritation parameter:

cornea opacity score

Remarks:

1000 ppm CS-1135

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Remarks:

1000 ppm CS-1135

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Remarks:

1000 ppm CS-1135

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

1000 ppm CS-1135

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Remarks:

undiluted CS-1135

Basis:

animal #1

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritation parameter:

cornea opacity score

Remarks:

undiluted CS-1135

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

2

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

cornea opacity score

Remarks:

undiluted CS-1135

Basis:

animal #3

Time point:

24/48/72 h

Score:

>= 3 - <= 4

Max. score:

4

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritation parameter:

cornea opacity score

Remarks:

undiluted CS-1135

Basis:

animal #4

Time point:

24/48/72 h

Score:

>= 1 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritation parameter:

cornea opacity score

Remarks:

undiluted CS-1135

Basis:

animal #5

Time point:

24/48/72 h

Score:

>= 2 - <= 4

Max. score:

4

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritation parameter:

cornea opacity score

Remarks:

undiluted CS-1135

Basis:

animal #6

Time point:

24/48/72 h

Score:

>= 2 - <= 4

Max. score:

4

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritation parameter:

iris score

Remarks:

undiluted CS-1135

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

1

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritation parameter:

iris score

Remarks:

undiluted CS-1135

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

1

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritation parameter:

iris score

Remarks:

undiluted CS-1135

Basis:

animal #4

Time point:

24/48/72 h

Score:

>= 1 - <= 2

Max. score:

2

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritation parameter:

iris score

Remarks:

undiluted CS-1135

Basis:

animal #5

Time point:

24/48/72 h

Score:

2

Max. score:

2

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritation parameter:

iris score

Remarks:

undiluted CS-1135

Basis:

animal #6

Time point:

24/48/72 h

Score:

2

Max. score:

2

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritation parameter:

chemosis score

Remarks:

undiluted CS-1135

Basis:

animal #1

Time point:

24/48/72 h

Score:

>= 2 - <= 4

Max. score:

4

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritation parameter:

chemosis score

Remarks:

undiluted CS-1135

Basis:

animal #2

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritation parameter:

chemosis score

Remarks:

undiluted CS-1135

Basis:

animal #3

Time point:

24/48/72 h

Score:

>= 3 - <= 4

Max. score:

4

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritation parameter:

chemosis score

Remarks:

undiluted CS-1135

Basis:

animal #4

Time point:

24/48/72 h

Score:

2

Max. score:

2

Reversibility:

not specified

Remarks on result:

probability of moderate irritation

Irritation parameter:

chemosis score

Remarks:

undiluted CS-1135

Basis:

animal #5

Time point:

24/48/72 h

Score:

>= 2 - <= 4

Max. score:

4

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritation parameter:

chemosis score

Remarks:

undiluted CS-1135

Basis:

animal #6

Time point:

24/48/72 h

Score:

>= 2 - <= 4

Max. score:

4

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritation parameter:

conjunctivae score

Remarks:

undiluted CS-1135

Basis:

animal #1

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritation parameter:

conjunctivae score

Remarks:

undiluted CS-1135

Basis:

animal #2

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritation parameter:

conjunctivae score

Remarks:

undiluted CS-1135

Basis:

animal #3

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritation parameter:

conjunctivae score

Remarks:

undiluted CS-1135

Basis:

animal #4

Time point:

24/48/72 h

Score:

>= 1 - <= 2

Max. score:

2

Reversibility:

not specified

Remarks on result:

probability of moderate irritation

Irritation parameter:

conjunctivae score

Remarks:

undiluted CS-1135

Basis:

animal #5

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritation parameter:

conjunctivae score

Remarks:

undiluted CS-1135

Basis:

animal #6

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritant / corrosive response data:

There was no discernible effect upon the eyes nor upon the surrounding tissues following the application of CS-1135 which had been diluted to 1000 ppm in sterile water.
Moderate to severe effects were noted in the eyes of all rabbits treated with undiluted CS-1135.
No ulceration nor mechanical damage was detected on corneal surfaces following the instillation of fluorescein solution.

Interpretation of results:

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

Conclusions:

Dilution of CS-1135 to 1000 ppm with sterile water effectively reduced and, in fact, appears to have prevented entirely any adverse reaction in the eyes of test animals.
Introduction of undiluted CS-1135 into the test rabbits´ eyes produced significant effects even though material was washed out one minute after application. Adverse reactions were detected in all treated eyes and the reactions became more progressively more severe at the time of the later observations.
The results lead to the conclusion that even short-term exposure to an undiluted solution of CS-1135 is certain to cause serious adverse reactions on the eye.

Executive summary:

0.1 ml of the test material was introduced into a cup formed by retracting the lower eyelid of the right eye of each of six albino rabbits. Group 1 was treated by introducing 0.1 ml of a diluted solution of CS-1135 (1000pm in sterile water). After introduction of the test material, the eyelid was hold closed for one second.

Modified treatment of Group 2 was: 0.1 ml of undiluted CS-1135 was placed into the eye, the eyelid was held closed for one minute; the eye was then lavaged thoroughly with sterile 0.9% sodium chloride solution to remove all unabsorbed material. All test animals were maintained thereafter without further treatment and their eyes were examined at 24, 48 and 72 hours after treament.

Dilution of CS-1135 to 1000 ppm with sterile water effectively reduced and, in fact, appears to have prevented entirely any adverse reaction in the eyes of test animals.

Introduction of undiluted CS-1135 into the test rabbits´ eyes produced significant effects even though material was washed out one minute after application. Adverse reactions were detected in all treated eyes and the reactions became more progressively more severe at the time of the later observations.

The results lead to the conclusion that even short-term exposure to an undiluted solution of CS-1135 is certain to cause serious adverse reactions on the eye.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

Severe irritation of the eyes and respiratory system was observed in an acute inhalation toxicity study.

Justification for classification or non-classification

Skin Irritation:

Application of 4,4-dimethyloxazolidine (CAS 51200-87-4) to the skin of rabbits caused light to severe erythema and severe edema in most animals, that were partially reversible until 72 h observations, and no tissue destruction was observed.

Additionally, a study performed with human volunteers revealed visible immediate irritation to the human skin, and fatigue and cumulative primary irritation after repeated applications of the test item.

Therefore 4,4-dimethyloxazolidine has to be classified as irritant to the skin (UN GHS Category 2) according to the CLP regulation (EC) No 1272/2008.

 

Eye irritation/corrosion

Two in vivo studies show that application of 4,4-dimethyloxazolidine (CAS 51200-87-4) to the eye of rabbits causes serious adverse reactions on the eye.

Adverse reactions were detected in all treated eyes and the reactions became progressively more severe at later timepoints of observations. Severe corneal opacity was observed as well as pronounced inflammation and edema, which that was not completely reversed after the observation period.

Therefore, 4,4-dimethyloxazolidine has to be classified as damaging to the eyes (UN GHS Category 1) according to the CLP regulation (EC) No 1272/2008.