4,4-dimethyloxazolidine

Skin sensitisation

Administrative data

Endpoint:

skin sensitisation, 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

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Reference

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.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1979

Report date:

1979

Materials and methods

Test guideline

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-blin
d 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 h
ours 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

Type of study:

patch test

Justification for non-LLNA method:

The study was conducted before the OECD Guideline 429: Skin Sensitisation Local Lymph Node Assay came into force in 2002.

Test material

Test material information

Constituent 1

Reference substance name:

4,4-dimethyloxazolidine

EC Number:

257-048-2

EC Name:

4,4-dimethyloxazolidine

Cas Number:

51200-87-4

Molecular formula:

C5H11NO

IUPAC Name:

4,4-dimethyl-1,3-oxazolidine

Test material form:

liquid

Specific details on test material used for the study:

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

In vivo test system

Test animals

Species:

other: human

Sex:

male/female

Details on test animals 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 eli
minate 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.

Results and discussion

In vivo (non-LLNA)

Results

Results 1

Key result

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

3% w/v solution

No. with + reactions:

1

Total no. in group:

101

Remarks on result:

no indication of skin sensitisation

Results 2

Key result

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

3% w/v solution

No. with + reactions:

1

Total no. in group:

100

Remarks on result:

no indication of skin sensitisation

Results 3

Key result

Reading:

other: 3rd reading

Hours after challenge:

72

Group:

test chemical

Dose level:

3% w/v solution

No. with + reactions:

0

Total no. in group:

101

Remarks on result:

no indication of skin sensitisation

Results 4

Key result

Reading:

rechallenge

Hours after challenge:

24

Group:

other: Rechallenge of two individuals that showed positive reaction on first challenge

Dose level:

0.1 % w/v

No. with + reactions:

0

Total no. in group:

2

Remarks on result:

no indication of skin sensitisation

Results 5

Key result

Reading:

other: rechallenge 2nd reading

Hours after challenge:

48

Group:

other: Rechallenge of two individuals that showed positive reaction on first challenge

Dose level:

0.1% w/v

No. with + reactions:

0

Total no. in group:

2

Remarks on result:

no indication of skin sensitisation

Results 6

Key result

Reading:

other: rechallenge 3rd reading

Hours after challenge:

72

Group:

other: Rechallenge of two individuals that showed positive reaction on first challenge

No. with + reactions:

0

Total no. in group:

2

Remarks on result:

no indication of skin sensitisation

Any other information on results incl. tables

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 tes

ted 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.

Challenge period: 0.3% w/v emulsion in water

The test material, tested at 0.3% w/v emulsion in water was well tolerated by all but two panelists.

Additional Challenge period: 0.1% w/v emulsion in water

The absence of any significant reaction in the two panelists indicate that this dilution of the test material, 0.1% w/v solution in water, was incapable of eliciting a response wich could be interpreted as evidence that sensitization has occured.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The results indicate that, though a 3.05 w/v dilution of the test material was capable of irritating the skin of 70.3% of the test panel, it was not capable of eliciting a state of hypersensitivity in any of the individuals.
The 95 percentile confidence limits, where CS-1135 will not elicite any sensitization reactions are 96.41 to 100%, for n = 101.

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.