Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics

Endpoint summary

Description of key information

Skin Irritation

Not irritating to the skin

 

Ocular Irritation

Not irritating to eyes

 

Respiratory Irritation

No studies were located to indicate that Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics, is a respiratory irritant.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

2000/4/12-2000/6/22

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: According to OECD test guideline 404. GLP

Justification for type of information:

The justification for read across is provided as an attachment in IUCLID Section 13

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Source:Harlan UK Ltd
Number of Animals: Three
Age at study initiation: Approximately 13 weeks
Weight at study initiation: 2.7-3.2 kg
Housing: Individually
Diet (e.g. ad libitum): Special Diet Service STANRAB SQC (pellets); ad libitum
Water (e.g. ad libitum): Automatic watering system, ad libitum
Acclimation period: 22d

ENVIRONMENTAL CONDITIONS
Temperature (°C): 18-21
Humidity (%): 53-65%
Photoperiod (hrs dark / hrs light): 12/12
Monitored at least once a day

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

Amount(s) applied (volume or weight): 0.5 ml
Concentration (if solution): neat

Duration of treatment / exposure:

Test material was administered to the clipped backs as a single dose introduced under a gauze patch (secured with non-irritating tape) and held in contact with the skin by means of a semi-occlusive dressing for 4 hours. Residual test material was then removed.

Observation period:

24, 48, and 72h post application and once per day until Day 14

Number of animals:

Three females

Details on study design:

SCORING SYSTEM: Draize scale for dermal irritation

Irritation parameter:

erythema score

Basis:

mean

Time point:

24 h

Score:

ca. 2

Max. score:

2

Reversibility:

fully reversible within: 13 days

Irritation parameter:

erythema score

Basis:

mean

Time point:

48 h

Score:

ca. 1.7

Max. score:

2

Reversibility:

fully reversible within: 13 days

Irritation parameter:

erythema score

Basis:

mean

Time point:

72 h

Score:

ca. 2

Max. score:

2

Reversibility:

fully reversible within: 13 days

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

1.9

Max. score:

2

Reversibility:

fully reversible within: 13 days

Irritation parameter:

edema score

Basis:

mean

Time point:

24 h

Score:

ca. 1.3

Max. score:

1

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

mean

Time point:

48 h

Score:

ca. 1

Max. score:

2

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

mean

Time point:

72 h

Score:

ca. 1

Max. score:

2

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

1.1

Max. score:

2

Reversibility:

fully reversible

Irritant / corrosive response data:

Topical application of Petrepar 134 (50/50) elicited dermal responses in all animals. Well defined erythema and slight edema followed exposure and was resolved by day 13.

Interpretation of results:

other: R38 under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations. Not classified under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The average erythema score (24,48, and 72 hours) was 1.9, with 2 out of 3 animals having a mean (24-72 hour) erythema score of 2.0. The average edema score (24,48, and 72 hours) was 1.1. Based on the individual animal dermal irritation scores, the test substance warrants classification of the test material as a skin irritant (R38) under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations. Classification as a dermal irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Executive summary:

In this study, 3 rabbits were subjected to a 4h dermal (shaved) exposure of 0.5 ml of Petrepar 134 (50/50) via a semi-occluded patch. Dermal responses were evaluated at 1, 24, 48, and 72h post-dosing and once a day for a total of 14 days according to the Draize method of scoring. Topical application of Petrepar 134 (50/50) elicited dermal responses in all animals. Well defined erythema and slight oedema followed exposure and was resolved by day 13. The average erythema score (24,48, and 72 hours) was 1.9, with 2 out of 3 animals having a mean (24-72 hour) erythema score of 2.0. The average edema score (24,48, and 72 hours) was 1.1. Based on the individual animal dermal irritation scores, the test substance warrants classification of the test material as a skin irritant (R38) under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations. Classification as a dermal irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

1997/04/27- 1997/07/23

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented study report equivalent or similar to OECD guideline 404: GLP.

Justification for type of information:

The justification for read across is provided as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

six animals

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan UK Ltd
- Age at study initiation: adult
- Housing: individually
- Diet (e.g. ad libitum): Special Diets Services
- Water (e.g. ad libitum): ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16-19
- Humidity (%): 50-53
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5ml

Duration of treatment / exposure:

4 hours

Observation period:

Dermal responses were evaluated approximately 60 minutes, 24, 48, and 72 hours following patch removal.

Number of animals:

3 females

Details on study design:

TEST SITE
- Area of exposure: dorsal surface from the shoulder region to the lumbar region
- % coverage: N/A
- Type of wrap if used: under a gauze patch secured with tape, the patch was loosely held in contact with the skin by means of a semi-occlusive dressing


REMOVAL OF TEST SUBSTANCE
- Washing (if done): removed residual test material using reverse osmosis water and paper towels.
- Time after start of exposure: 4 hours


SCORING SYSTEM: Draize

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

ca. 0.55

Max. score:

1

Reversibility:

fully reversible within: 72 hours

Remarks on result:

other: based on scores of three animals

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0.66

Max. score:

2

Reversibility:

fully reversible within: 72 hours

Irritation parameter	Basis	Time Point	Score	Reversibility
erythema score	animal #1	24 hours	1	Fully reversible by 72 hours
erythema score	animal #2	24 hours	1	Fully reversible by 72 hours
erythema score	animal #3	24 hours	1	Fully reversible by 72 hours
erythema score	animal #1	48 hours	1	Fully reversible by 72 hours
erythema score	animal #2	48 hours	1	Fully reversible by 72 hours
erythema score	animal #3	48 hours	0	Fully reversible by 72 hours
erythema score	animal #1	72 hours	0	Fully reversible by 72 hours
erythema score	animal #2	72 hours	0	Fully reversible by 72 hours
erythema score	animal #3	72 hours	0	Fully reversible by 72 hours
erythema score	mean	24 hour mean	1	Fully reversible by 72 hours
erythema score	mean	48 hour mean	0.66	Fully reversible by 72 hours
erythema score	mean	72 hour mean	0	Fully reversible by 72 hours
erythema score	mean	24-72 hour mean	0.55	Fully reversible by 72 hours
edema score	animal #1	24 hours	2	Fully reversible by 72 hours
edema score	animal #2	24 hours	1	Fully reversible by 72 hours
edema score	animal #3	24 hours	1	Fully reversible by 72 hours
edema score	animal #1	48 hours	1	Fully reversible by 72 hours
edema score	animal #2	48 hours	1	Fully reversible by 72 hours
edema score	animal #3	48 hours	0	Fully reversible by 72 hours
edema score	animal #1	72 hours	0	Fully reversible by 72 hours
edema score	animal #2	72 hours	0	Fully reversible by 72 hours
edema score	animal #3	72 hours	0	Fully reversible by 72 hours
edema score	mean	24 hour mean	1.3	Fully reversible by 72 hours
edema score	mean	48 hour mean	0.66	Fully reversible by 72 hours
edema score	mean	72 hour mean	0	Fully reversible by 72 hours
edema score	mean	24-72 hour mean	0.66	Fully reversible by 72 hours

Interpretation of results:

other: Not irritating

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The mean erythema and edema scores for the test material were 0.55 and 0.66 respectively. Classification as a dermal irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Executive summary:

The test material was administered  via semi-occlusive patch for four hours to three rabbits (3 female) to assess dermal irritation  Dermal responses were evaluated at 1, 24, 48, and 72h post-dosing according to the Draize method of scoring.  Application of the test material elicited responses in all animals. Erythema scores decreased as the study progressed.  Effects continued to subside until all animals were free of adverse clinical signs by study termination (Day 7). Classification as a dermal irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Reference 3

Endpoint:

skin irritation: in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

1991/03/05-1991/03/07

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: In accordance with sound scientific principles and performed with good laboratory standards.

Justification for type of information:

The justification for read across is provided as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Guideline:

other:

Principles of method if other than guideline:

Fifteen panelists entered and completed the study. Each subject received one exposure to the test materials. The exposure was for a 24 hour period. Dermal irritation scores were recorded 60 min after test material application and 24 hours after test material application.

GLP compliance:

yes

Species:

human

Strain:

other: general population

Details on test animals or test system and environmental conditions:

Ethical approval confirmed, but no further information available. The technique involved the use of 15 volunteer subjects, 14 females and 1 male, with the age range from 18 to >60. Approximately 15 healthy adult male/female panelists were enrolled for this study. Informed consent and demographic data were obtained from subjects prior to their participation in the study. Subjects with acne, skin diseases (e.g. psoriasis or eczema), abrasions, scar tissue, or tattoos at the test sites were excluded from participating in this study. Also anyone using antihistamines and/or corticosteroids was excluded.

Type of coverage:

semiocclusive

Preparation of test site:

other: examined for defects prior to application of test material

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

0.1 to 0.3 mL

Duration of treatment / exposure:

A single 24 hour contact application of the test material to sites on the outer surface of the upper arms.

Observation period:

All skin sites were scored 60 minutes after removal of the 24 hour application and again 24 hours following patch removal.

Number of animals:

15 human subjects

Details on study design:

Procedure:

Each test patch received 0.1 to 0.3 ml. of the test material. The final volume was dependent upon the nature of each sample and was determined prior to initiation of the study. Each sample was dispensed 15 minutes prior to application to allow evaporation of volatile components. A group of 15 subjects received a single 24 hour contact application of the test material to sites on the outer surface of the upper arms. All applications and patch removal was conducted by a technician at the laboratory.

The panelists remained at the test location for a maximum of 4 hours following sample application. In the event that the test materials elicited severe burning, stinging, erythema, edema, or other cutaneous reaction during this time period, the patch(es) were removed and the test site gently rinsed with warm water. If no such clinical events occurred during the monitoring period, the patches were worn for the duration of the 24 hours.

The basic schedule for the test will be as follows:

Day 1 - Score test sites and apply samples for 24 hours. Wait 2-4 hours following sample application.
Day 2 - Remove sample patches, wait 60 minutes, score test site
Day 3 — Score test sites (24 hours post-removal).

As shown above, all skin sites will be scored 60 minutes after removal of the 24 hour application and again 24 hours following patch removal.

Evaluation:
Panelists will be screened for abnormalities of the outer surface of the right and/or left arms on Day 1 before being accepted on the study. Dermatological examination will be made prior to the sample application. The primary measurement will be the evaluation of irritation.

Scoring of irritation will be conducted by an experienced staff member using a 100 watt incandescent blue bulb lamp as the artificial light source to illuminate the patch areas. The scorer will be blinded as to treatment assignments and any previous scores. The same individual will do all scoring of reactions to the test materials during the course of the study. The following modified Draize scale will be used:
0 - No evidence of irritation
1 - Minimal erythema, barely perceptible
2 - Definite erythema, readily visible, or minimal edema; or minimal papular response
3 - Erythema and papules
4 - Definite edema
5 - Erythema, edema and papules
6 - Vesicular eruption
7 - Strong reaction spreading beyond test site

Effects of superficial layers of the skin should be scored as follows:
A - Slight glazed appearance
B - Marked glazing
C - Glazing with peeling and cracking
F - Glazing with fissures
G - Film of dried serous exudate covering all or portion of the patch site .
H - Small petechial erosions and/or scabs

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: 60 min

Score:

1.6

Max. score:

2

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

24 h

Score:

2.13

Max. score:

5

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

other: Only overall irritation score at 24 hours provided

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

other: Only overall irritation score at 24 hours provided

Panelist	Day 2	Day 3
1	2	5
2	0	0
3	1	2
4	2	5
5	2	5
6	1	0
7	2	1
8	1	1
9	2	1
10	2	5
11	0	1
12	1	1
13	2	3
14	2	2
15	0	0

Interpretation of results:

other: Irritating

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The average irritation score after 24 hours was 2.13. Four of the 15 subjects were noted with dermal irritation scores of 5. MRD-89-519 would be classified as a Category 2 dermal irritant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP). The test material would be classified as an R38 dermal irritant under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Executive summary:

Fifteen panelists entered and completed the study. Each subject received one exposure to the test materials under semi-occlusive conditions. The exposure was for a 24 hour period and dermal irritation scores were recorded at 60 minutes and 24 hours after test material application.  The average irritation score after 24 hours was 2.13.  Four of the 15 subjects were noted with dermal irritation scores of 5.  MRD-89-519 would be classified as a Category 2 dermal irritant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).  The test material would be classified as an R38 dermal irritant under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Reference 4

Endpoint:

skin irritation: in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

1990/1/22 - 1990/3/05

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Similar to OECD test guideline 404. GLP

Justification for type of information:

The justification for read across is provided as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Source: Hazleton Research Products, Denver, PA
Number of Animals: six males
Age at study initiation: Approximately 17 weeks
Weight at study initiation: 2.0-3.0 kg
Housing: Individually
Diet (e.g. ad libitum): Pelleted Agway Certified Diet R.C.A. Rabbit; Animals were fed a restricted diet based on the recommendation of the supplier and not ad lib as required by protocol. This deviation did not adversely affect study results
Water (e.g. ad libitum): Automatic watering system, ad libitum
Acclimation period: 50 days

ENVIRONMENTAL CONDITIONS
Temperature (°F): 65 - 70
Humidity (%): 40-70%
Photoperiod (hrs dark / hrs light): 12/12
Monitored at least once a day

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

Amount(s) applied (volume or weight): 0.5 ml
Concentration (if solution): undiluted, administered as received

Duration of treatment / exposure:

Test material was administered to the clipped backs as a single dose introduced under a gauze patch (secured with non-irritating tape) and held in contact with the skin by means of a semi-occlusive dressing for 4 hours. Residual test material was then removed using distilled water and paper towels.

Observation period:

The animals were examined for viability twice daily on Monday through Friday, and once daily on Saturday, Sunday and holidays. Dermal responses were evaluated approximately 45 minutes, 24, 48, and 72h following patch removal, and on Day 7.

Number of animals:

Six males

Details on study design:

SCORING SYSTEM: Draize scale for dermal irritation

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

2

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0.94

Interpretation of results:

other: Category 3 (mild irritant)

Remarks:

R38 Criteria used for interpretation of results: EU

Conclusions:

The average erythema score (24,48, and 72 hours) was 2. The average edema score (24,48, and 72 hours) was 0.94. This finding warrants classification of the test material as a skin irritant (R38) under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations. This finding warrants classification of the test material as a Category 3 mild dermal irritant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Executive summary:

A primary dermal irritation study was conducted to evaluate the dermal irritation potential of a single dose of MRD-89 -519 in the rabbit. All animals survived the study. One animal (JEH743) was noted to vocalize at patch removal.

Topical application of MRD-89 -519 elicited dermal responses in all animals. At the 45 minute observation, four animals displayed well defined erythema, one animal dislayed very slight erythema, and one animal displayed no erythema. The average erythema score (24,48, and 72 hours) was 2. At study termination, four animals displayed well-defined erythema, one animal displayed moderate/severe erythema, and one animal displayed severe erythema.

At the 45 minute obervation, three animals displayed very slight edema, two animals displayed slight edema, and one animals displayed moderate edema. The average edema score (24,48, and 72 hours) was 0.94. At study termination, one animal showed no edema, two animals showed very slight edema, and three animals showed slight edema.

This finding warrants classification of the test material as a skin irritant (R38) under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations. This finding warrants classification of the test material as a Category 3 mild dermal irritant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

 

Reference 5

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1989-12-13 to 1990-02-05

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented study report equivalent or similar to OECD guideline 404: GLP

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

six test animals

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hazleton Research Products, Denver, PA
- Age at study initiation: ca. 15 weeks
- Weight at study initiation: ca 2.0-3.0 kg
- Housing: individual
- Diet (e.g. ad libitum): restricted diet based on the recommendation of the supplier
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 37 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 65-70
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5ml

Duration of treatment / exposure:

ca. 4 hours

Observation period:

Dermal responses were evaluated approximately 45 minutes, 24, 48 and 72 hours following patch removal, and on Day 7.

Body weights were recorded on the day of dosing.

Number of animals:

6

Details on study design:

TEST SITE
- Area of exposure: back
- Type of wrap if used: gauze patch which was secured with tape, patch was loosely held in contact with the skin by means of semi-occlusive dressing


REMOVAL OF TEST SUBSTANCE
- Washing (if done): residual test material was removed using reverse osmosis water and paper towels.
- Time after start of exposure: 4h


SCORING SYSTEM: Draize

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

ca. 1.56

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Interpretation of results:

other: Not irritating

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The mean erythema and edema scores for the test material were 1.56 and 0 respectively. Classification as a dermal irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Executive summary:

MRD-89-520 was administered  via semi-occlusive patch for four hours to six male rabbits to assess dermal irritation.  Dermal responses were evaluated at 1, 24, 48, and 72h post-dosing and on Day 7 according to the Draize method of scoring. Dermal responses were observed in all animals.  At the 45 minute, 48 hour and 72 hour observations, three animals displayed well-defined erythema and three displayed very slight erythema.  Four animals were noted with well-defined erythema and two were noted with very slight erythema at the 24 hour observations.  At study termination (Day 7), four animals showed very slight erythema   No other dermal observations were noted during the study.  The mean erythema and edema scores for MRD-89-520 were 1.56 and 0 respectively.  Classification as a dermal irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Reference 6

Endpoint:

skin irritation: in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

1989/5/23 - 1989/5/30

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Similar to OECD test guideline 404. GLP

Justification for type of information:

The justification for read across is provided as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Source:Hazleton Research Products, Denver, PA
Number of Animals: Six males
Age at study initiation: Approximately 10-16 weeks
Weight at study initiation: 2.0-3.6 kg
Housing: Individually
Diet (e.g. ad libitum): Purina Rabbit Chow HF (pellets); ad libitum
Water (e.g. ad libitum): Automatic watering system, ad libitum
Acclimation period: 50d

ENVIRONMENTAL CONDITIONS
Temperature (°F): 65-70
Humidity (%): 40-60%
Photoperiod (hrs dark / hrs light): 12/12
Monitored at least once a day

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

Amount(s) applied (volume or weight): 0.5 ml
Concentration (if solution): undiluted, administered as received

Duration of treatment / exposure:

Test material was administered to the clipped backs as a single dose introduced under a gauze patch (secured with non-irritating tape) and held in contact with the skin by means of a semi-occlusive dressing for 4 hours. Residual test material was then removed using distilled water and paper towels.

Observation period:

The animals were examined for viability twice daily on Monday through Friday, and once daily on Saturday and Sunday. Dermal responses were evaluated approximately 45 minutes, 24, 48, and 72h following patch removal, and on Day 7.

Number of animals:

Six Males

Details on study design:

SCORING SYSTEM: Draize scale for dermal irritation

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

2

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0.67

Interpretation of results:

other: Category 3 (mild irritant)

Remarks:

R38 Criteria used for interpretation of results: EU

Conclusions:

The average erythema score (24,48, and 72 hours) was 2. The average edema score (24,48, and 72 hours) was 0.67. This finding warrants classification of the test material as a skin irritant (R38) under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations. This finding warrants classification of the test material as a Category 3 mild dermal irritant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Executive summary:

A primary dermal irritation study was conducted to evaluate the dermal irritation potential of a single dose of MRD-89 -402 in the rabbit. All animals survived the study. Dermal application of MRD-89 -402 produced erythema in all test animals. At the 45 minute observation, five animals were noted with well-defined erythema and one animal was noted with very slight erythema. All animals were noted with well-defined erythema at the 24 hour and 48 hour observations. At the day 7 observations, one animal was noted with very slight erythema, four animals were noted with well-defined erythema, and one animal showed an increased erythema score of moderate/severe. Edema was also noted for all animals at the 45 minute observation, with two animals noted with moderate edema, while the remaining four animals exhibited slight edema. At the 24 hour observation, edema generally decreased with four animals noted with slight edema and two animals with very slight edema. At the 48 hour observation, very slight edema remained in two animals. At the 72 hour and day 7 observations, all animals were free of edema scores. These findings warrant the classification of the test material as a skin irritant (R38) under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.  This finding warrants classification of the test material as a Category 3 mild dermal irritant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Reference 7

Endpoint:

skin irritation: in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

1988/5/9 - 1988/5/23

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: According to OECD test guideline 404. GLP

Justification for type of information:

The justification for read across is provided as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Source:Kleintierfarm Madoerin AG, CH 4414 Fuellinsdorf, Switzerland
Number of Animals: three males, three females
Age at study initiation: Approximately 14-15 weeks
Weight at study initiation: 2.2-3.0 kg
Housing: Individually
Diet (e.g. ad libitum): Pelleted Standard Kliba 341; ad libitum
Water (e.g. ad libitum): Automatic watering system, ad libitum
Acclimation period: 4d under test conditions after veterinary examination

ENVIRONMENTAL CONDITIONS
Temperature (°C): 20 +/- 3
Humidity (%): 40-70%
Photoperiod (hrs dark / hrs light): 12/12
Monitored at least once a day

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

Amount(s) applied (volume or weight): 0.5 ml
Concentration (if solution): undiluted, administered as received

Duration of treatment / exposure:

Test material was administered to the clipped backs as a single dose introduced under a gauze patch (secured with non-irritating tape) and held in contact with the skin by means of a semi-occlusive dressing for 4 hours. Residual test material was then removed using distilled water and paper towels.

Observation period:

The skin reaction was assessed according to the OECD guidelines for testing chemicals, section 4, number 404, pp 3-4. The skin reaction was assessed at 1, 24, 48, and 72h and at day 7 and 14 days intervals after removal of the dressing, gauze patch and test article.

Number of animals:

Three males and three females

Details on study design:

SCORING SYSTEM: Draize scale for dermal irritation

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

2.58

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

1.72

Interpretation of results:

other: Category 2 (irritant)

Remarks:

R38 Criteria used for interpretation of results: EU

Conclusions:

The average erythema score (24,48, and 72 hours) was 2.58. The average edema score (24,48, and 72 hours) was 1.72. This finding warrants classification of the test material as a skin irritant (R38) under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations. This finding warrants classification of the test material as a Category 2 dermal irritant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Executive summary:

Under the conditions of this experiment, NAPPAR 10 was found to cause a primary irritation score of 4.3 when applied to intact rabbit skin. Local signs (mean 1 hour to 14 days) consisted of grade 1.8 erythema and grade 1.2 edema. They were reversible by day 14. In the area of application, no staining of the treated skin by pigment or coloring of the test article was observed.

If necessary prior to the first reading of the reactions, the skin was flushed with lukewarm water to clean the application site from staining produced by the test article so that the reactions (erythema) were clearly visible at that time. Slight to

severe scales were observed in animal nos. 7,8 (males), 10 and 12 (females) within 7 to 14 days of treatment.

These findings warrant classification of the test material as a skin irritant (R38) under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.  This finding warrants classification of the test material as a Category 2 dermal irritant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Reference 8

Endpoint:

skin irritation: in vivo

Type of information:

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

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Similar to OECD test guideline 404. GLP

Justification for type of information:

The justification for read across is provided as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Source:Summit View Farm, Belvidere, New Jersey
Number of Animals: Two males, four females
Age at study initiation: Approximately 17 weeks
Weight at study initiation: 2.0-3.5 kg
Housing: Individually
Diet (e.g. ad libitum): Purina High Fiber Rabbit Chow (pellets); ad libitum
Water (e.g. ad libitum): Automatic watering system, ad libitum
Acclimation period: 48d

ENVIRONMENTAL CONDITIONS
Temperature (°F): 65-70
Humidity (%): 40-60%
Photoperiod (hrs dark / hrs light): 12/12
Monitored at least once a day

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

Amount(s) applied (volume or weight): 0.5 ml
Concentration (if solution): undiluted, administered as received

Duration of treatment / exposure:

Test material was administered to the clipped backs as a single dose introduced under a gauze patch (secured with non-irritating tape) and held in contact with the skin by means of a semi-occlusive dressing for 4 hours. Residual test material was then removed using distilled water and paper towels.

Observation period:

The animals were examined for viability twice daily on Monday through Friday, and once daily on Saturday and Sunday. Protocol deviation: the animals were examined twice on Sunday, October 16, 1988. Dermal responses were evaluated approximately 45 minutes, 24, 48, and 72h following patch removal, and on Day 7.

Number of animals:

two males, and four females

Details on study design:

SCORING SYSTEM: Draize scale for dermal irritation

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

2

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

1.55

Interpretation of results:

other: Irritating

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The average erythema score (24,48, and 72 hours) was 2. The average edema score (24,48, and 72 hours) was 1.55. The test substance warrants classification of the test material as a skin irritant (R38) under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations. Classification as a dermal irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Executive summary:

A primary dermal irritation study was conducted to evaluate the dermal irritation potential of a single dose of MRD-88 -275 in the rabbit. All animals survived the study. Topical application of MRD-88 -275 elicited well-defined erythema slight to moderate edema in all animals at the 45 minute observation. At 24 hours erythema increased to moderate/severe for one animal, while edema scores decreased for two animals and increased for one animal. The other scores remained the same as the 45 minute scores. Edema scores decreased to very slight to slight for all animals at 48 hours, while well-defined to moderate/severe erythema was noted for all animals at this interval. All animals exhibited well -defined erythema and very slight edema at the 72 hours and the Day 7 observations.

A thin line of severe erythema was noted for all animals bordering outside the dose site at the 45 minute observation. An area of eschar outside the dose site was noted for five animals from the 24 hour through the day 7 observations. Two animals also exhibited desquamation on Day 7. The test substance warrants classification of the test material as a skin irritant (R38) under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations. Classification as a dermal irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Reference 9

Endpoint:

skin irritation: in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

1988/7/12 - 1988/8/29

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Similar to OECD test guideline 404. GLP

Justification for type of information:

The justification for read across is provided as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Source:Summit View Farm, Belvidere, New Jersey
Number of Animals: Three males, three females
Age at study initiation: Approximately 11 weeks
Weight at study initiation: 2.0-3.2 kg
Housing: Individually
Diet (e.g. ad libitum): Purina Rabbit Chow HF (pellets); ad libitum
Water (e.g. ad libitum): Automatic watering system, ad libitum
Acclimation period: 14d

ENVIRONMENTAL CONDITIONS
Temperature (°F): 65-70
Humidity (%): 40-60%
Photoperiod (hrs dark / hrs light): 12/12
Monitored at least once a day

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

Amount(s) applied (volume or weight): 0.5 ml
Concentration (if solution): undiluted, administered as received

Duration of treatment / exposure:

Test material was administered to the clipped backs as a single dose introduced under a gauze patch (secured with non-irritating tape) and held in contact with the skin by means of a semi-occlusive dressing for 4 hours. Residual test material was then removed using distilled water and paper towels.

Observation period:

The animals were examined for viability twice daily on Monday through Friday, and once daily on Saturday and Sunday. Dermal responses were evaluated approximately 45 minutes, 24, 48, and 72h following patch removal, and on Day 7.

Number of animals:

three males, and three females

Details on study design:

SCORING SYSTEM: Draize scale for dermal irritation

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

2.72

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0.72

Interpretation of results:

other: Category 2 (irritant)

Remarks:

R38 Criteria used for interpretation of results: EU

Conclusions:

The average erythema score (24,48, and 72 hours) was 2.72. The average edema score (24,48, and 72 hours) was 0.72. This finding warrants classification of the test material as a skin irritant (R38) under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations. This finding warrants classification of the test material as a Category 2 dermal irritant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Executive summary:

A primary dermal irritation study was conducted to evaluate the dermal irritation potential of a single dose of MRD-88 -275 in the rabbit. All animals survived the study. Topical application of MRD-88 -275 elicited very slight to well-defined erythema in all animals and very slight to slight edema in all animals at the 45 minute observation. There was little change in the severity of erythema at 24 hours, but at 48 hours erythema scores increased to severe for four animals and was very slight to well defined for two animals. Edema decreased slightly at the 24 hour observation and very slight edema was noted for five animals at 48 hours. The incidence and severity of dermal irritation remained generally unchanged at 72 hours and on Day 7.

Eschar was noted for five animals during the test period mainly at 48 and 72 hours and on day 7. Desquamation was noted for one animal on Day 7. This finding warrants classification of the test material as a skin irritant (R38) under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.  This finding warrants classification of the test material as a Category 2 dermal irritant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Reference 10

Endpoint:

skin irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available

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:

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

Adequacy of study:

key study

Study period:

2000/03/08

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented study report equivalent or similar to OECD guideline 405: GLP.

Justification for type of information:

The justification for read across is provided as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Harlan UK Ltd
- Age at study initiation: 13 weeks
- Weight at study initiation: 2.7 - 3.2 kg
- Housing: individual
- Diet (e.g. ad libitum): Special Diet Services STANRAB SQC pellet, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 25 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5 -23
- Humidity (%): 36-45
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

unchanged (no vehicle)

Controls:

other: contralateral eye

Amount / concentration applied:

0.1mL

Duration of treatment / exposure:

The eyelids were gently held together for one second before releasing.

Observation period (in vivo):

1, 24, 48, and 72 hours post-treatment

Number of animals or in vitro replicates:

3

Details on study design:

Test material was applied to the eyes and the eyelids were gently held together for one second before releasing. Irritation and toxicity were monitored at 1, 24, 48, and 72 hours post-treatment. Irritation was scored according to the Draize methodology.

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Irritant / corrosive response data:

No corneal damage or iridial inflammation was observed. Hyperaemia of blood vessels of the conjuctivae was seen in all animals. Ocular reactions had resolved in all instances by one day after instillation.

Irritation parameter	Basis	Time Point	Score
conjuctivae score	animal #1	24 hours	0
conjuctivae score	animal #2	24 hours	0
conjuctivae score	animal #3	24 hours	0
conjuctivae score	animal #1	48 hours	0
conjuctivae score	animal #2	48 hours	0
conjuctivae score	animal #3	48 hours	0
conjuctivae score	animal #1	72 hours	0
conjuctivae score	animal #2	72 hours	0
conjuctivae score	animal #3	72 hours	0
conjuctivae score	mean	24 hour mean	0
conjuctivae score	mean	48 hour mean	0
conjuctivae score	mean	72 hour mean	0
conjuctivae score	mean	24-72 hour mean	0
chemosis score	animal #1	24 hours	0
chemosis score	animal #2	24 hours	0
chemosis score	animal #3	24 hours	0
chemosis score	animal #1	48 hours	0
chemosis score	animal #2	48 hours	0
chemosis score	animal #3	48 hours	0
chemosis score	animal #1	72 hours	0
chemosis score	animal #2	72 hours	0
chemosis score	animal #3	72 hours	0
chemosis score	mean	24 hour mean	0
chemosis score	mean	48 hour mean	0
chemosis score	mean	72 hour mean	0
chemosis score	mean	24-72 hour mean	0
cornea score	mean	24-72 hour mean	0
iris score	mean	24-72 hour mean	0

Interpretation of results:

other: Not irritating

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The mean conjunctivae, chemosis, iris, and cornea scores for the Petrepar 134 (60/40) were 0.0, 0.0, 0.0, and 0.0 respectively. Classification as an ocular irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Executive summary:

Petrepar 134 (60/40) (0.1 mL, neat) was administered to the right eye of three rabbits to assess occular irritation. Irritation and toxicity were monitored at 1, 24, 48, and 72 hours post-treatment. Irritation was scored according to the Draize methodology. No corneal damage or iridial inflammation was observed. Hyperaemia of blood vessels of the conjuctivae was seen in all animals. Ocular reactions had resolved in all instances by one day after instillation. The mean conjunctivae, chemosis, iris, and cornea scores for the Petrepar 134 (60/40) were 0.0, 0.0, 0.0, and 0.0 respectively. Classification as an ocular irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented study report equivalent or similar to OECD guideline 405: GLP.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Hazleton Research Products
- Age at study initiation: ca. 12 weeks
- Weight at study initiation: 2.14-2.49 kg
- Housing: individually
- Diet (e.g. ad libitum): Agway restricted feeding regimen
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 65-70
- Humidity (%): 40-60%
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 1991-05-09 To: 1997-05-21

Vehicle:

unchanged (no vehicle)

Controls:

other: untreated eye of each animal served as the control

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1ml

Duration of treatment / exposure:

The test material was instilled into the lower conjunctival sac of the right eye of each animal. The upper and lower lids were gently held together for approximately 1 second to prevent loss of the material. The treated eyes remained unwashed.

Observation period (in vivo):

Animals were observed for viability twice daily on Monday-Friday, and once daily on Saturday and Sunday. Observations of signs of ocular irritation were made 1, 24, 48, and 72 hours post-instillation and on Day 7.

Number of animals or in vitro replicates:

six males

Details on study design:

SCORING SYSTEM: Draize


TOOL USED TO ASSESS SCORE: 2% sodium fluorescein dye under UV light

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Remarks on result:

other: average of six animals

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Remarks on result:

other: average of six animals

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Remarks on result:

other: average of six animals

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Remarks on result:

other: average of six animals

Interpretation of results:

other: Not irritating

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The mean corneal opacity, iris lesion, conjunctivae redness, and chemosis scores for MRD-91-972 were all 0. Classification as an ocular irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Executive summary:

MRD-91-972 was administered to the right eye of six male rabbits to assess for ocular irritation. Ocular examinations occurred at 1h, 24h, 48h, 72h, and day 7 post instillation. Ocular damage was assessed and scored according to the Draize eye test. All animals survived the exposure. Ocular instillation of the test material elicited conjunctival irritation limited to redness noted in five of the six test animals at the 1 hour observation.  No other signs of ocular irritation were noted during the study.  The mean corneal opacity, iris lesion, conjunctivae redness, and chemosis scores for MRD-91-972 were 0, 0, 0, and 0 respectively. Classification as an ocular irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Reference 3

Endpoint:

eye irritation: in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented study report equivalent or similar to OECD guideline 405: GLP.

Justification for type of information:

The justification for read across is provided as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Kleintierfarm Madoerin AG
- Age at study initiation: ca. 14-15 weeks
- Weight at study initiation: 2.9-2.5 kg
- Housing: individually
- Diet (e.g. ad libitum): Pelleted standard Kliba 341, batch 34/88 rabbit maintenance diet, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 4 days under laboratory conditions after veterinary examination


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 3
- Humidity (%): 40-70%
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

unchanged (no vehicle)

Controls:

other: untreated eye of each animal (the right eye) served as the control

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1ml

Duration of treatment / exposure:

The test material was instilled into the lower conjunctival sac of the left eye of each animal. The upper and lower lids were gently held together for approximately 1 second to prevent loss of the material. The right eye remained untreated and served as the reference control.

Observation period (in vivo):

The eyes of each animal were examined 1, 24, 48, and 72 hours after administration. The irritation was assessed according to the OECD guidelines for testing of chemicals, section 4, number 405 "Acute eye irritation/corrosion" adopted February 24, 1987.

Number of animals or in vitro replicates:

3 males, 3 females

Details on study design:

SCORING SYSTEM: Draize

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Interpretation of results:

other: Not irritating

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The mean corneal opacity, iris lesion, conjunctivae redness, and chemosis scores for MRD-91-972 were all 0. Classification as an ocular irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/548/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Executive summary:

C9-C11, cyclic aliphatics was administered to the left eye of three male and three female rabbits to assess for ocular irritation. Ocular examinations occurred at 1h, 24h, 48h, 72h. Ocular damage was assessed and scored according to the Draize eye test. All animals survived the exposure. The mean corneal opacity, iris lesion, conjunctivae redness, and chemosis scores for C9-C11, cyclic aliphatics were 0, 0, 0, and 0 respectively. Classification as an ocular irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/548/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Reference 4

Endpoint:

eye irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study are available

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

There is data available for Hydrocarbons, C9-C11, isoalkanes, cyclics, >2% aromatics. This data is supported by information available for structural analogues, Hydrocarbons, C9-C11, cyclics, <2% aromatics; Hydrocarbons, C9-C11, n-alkanes, isoalkanes, cyclics, <2% aromatics; and Hydrocarbons, C11-C14, n-alkanes, < 2% aromatics; and presented in the dossier. This data is read across to Hydrocarbons, C9-C11, isoalkanes, cyclics, >2% aromatics based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

Isoparaffinic, normal paraffinic, and mixed C9-C14 aliphatic, <2% aromatic hydrocarbon fluids are not corrosives or dermal irritants for rabbit (OECD TG 404). Many studies were examined that covered these substances of which a majority indicated that these hydrocarbon fluids had irritation scores well-below the threshold for classification. Using qualitative weight of evidence reasoning, the isoparaffinic, normal paraffinic, and mixed C9-C14 aliphatic, <2% aromatic hydrocarbon fluids are not dermal irritants to rabbits. However, cycloparaffinic C9-C14 aliphatic, <2% aromatic hydrocarbon fluids are not corrosives but considered dermal irritants to rabbits (OECD TG 404) and to humans.

 

Skin Irritation

 

Hydrocarbons, C9-C11, cyclics, <2% aromatics

 

In a study (ExxonMobil, 1991a), fifteen panellists entered and completed the study. Each subject received one exposure to the test material (Hydrocarbons, C9-C11, cyclics, <2% aromatics) under semi-occlusive conditions. The exposure was for a 24 hour period and dermal irritation scores were recorded at 60 minutes and 24 hours after test material application. The average irritation score after 24 hours was 2.13. Four of the 15 subjects were noted with dermal irritation scores of 5. Hydrocarbons, C9-C11, cyclics, <2% aromatics would be classified as a Category 2 dermal irritant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

 

A primary dermal irritation study (ExxonMobil, 1990), was conducted to evaluate the dermal irritation potential of a single dose of Hydrocarbons, C9-C11, cyclics, <2% aromatics in the rabbit. All animals survived the study. One animal (JEH743) was noted to vocalize at patch removal. Topical application of Hydrocarbons, C9-C11, cyclics, <2% aromatics elicited dermal responses in all animals. At the 45 minute observation, four animals displayed well defined erythema, one animal displayed very slight erythema, and one animal displayed no erythema. The average erythema score (24,48, and 72 hours) was 2. At study termination, four animals displayed well-defined erythema, one animal displayed moderate/severe erythema, and one animal displayed severe erythema. At the 45 minute observation, three animals displayed very slight edema, two animals displayed slight edema, and one animals displayed moderate edema. The average edema score (24,48, and 72 hours) was 0.94. At study termination, one animal showed no edema, two animals showed very slight edema, and three animals showed slight edema. This finding warrants classification of the test material as a Category 3 mild dermal irritant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

 

A primary dermal irritation study (ExxonMobil, 1989) was conducted to evaluate the dermal irritation potential of a single dose of Hydrocarbons, C9-C11, cyclics, <2% aromatics in the rabbit. All animals survived the study. Dermal application of Hydrocarbons, C9-C11, cyclics, <2% aromatics produced erythema in all test animals. At the 45 minute observation, five animals were noted with well-defined erythema and one animal was noted with very slight erythema. All animals were noted with well-defined erythema at the 24 hour and 48 hour observations. At the day 7 observations, one animal was noted with very slight erythema, four animals were noted with well-defined erythema, and one animal showed an increased erythema score of moderate/severe. Edema was also noted for all animals at the 45 minute observation, with two animals noted with moderate edema, while the remaining four animals exhibited slight edema. At the 24 hour observation, edema generally decreased with four animals noted with slight edema and two animals with very slight edema. At the 48 hour observation, very slight edema remained in two animals. At the 72 hour and day 7 observations, all animals were free of edema scores. These finding warrant classification of the test material as a Category 3 mild dermal irritant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

 

Hydrocarbons, C9-C11, cyclics, <2% aromatics was found to cause a primary irritation score of 4.3 when applied to intact rabbit skin (ExxonMobil, 1988a). Local signs (mean 1 hour to 14 days) consisted of grade 1.8 erythema and grade 1.2 edema. They were reversible by day 14. In the area of application, no staining of the treated skin by pigment or coloring of the test article was observed. If necessary prior to the first reading of the reactions, the skin was flushed with lukewarm water to clean the application site from staining produced by the test article so that the reactions (erythema) were clearly visible at that time. Slight to severe scales were observed in animal nos. 7,8 (males), 10 and 12 (females) within 7 to 14 days of treatment. These findings warrant classification of the test material as a Category 2 dermal irritant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

 

A primary dermal irritation study was conducted to evaluate the dermal irritation potential of a single dose of Hydrocarbons, C9-C11, cyclics, <2% aromatics in the rabbit (ExxonMobil, 1988b). All animals survived the study. Topical application of the test material elicited well-defined erythema slight to moderate edema in all animals at the 45 minute observation. At 24 hours erythema increased to moderate/severe for one animal, while edema scores decreased for two animals and increased for one animal. The other scores remained the same as the 45 minute scores. Edema scores decreased to very slight to slight for all animals at 48 hours, while well-defined to moderate/severe erythema was noted for all animals at this interval. All animals exhibited well -defined erythema and very slight edema at the 72 hours and the Day 7 observations. A thin line of severe erythema was noted for all animals bordering outside the dose site at the 45 minute observation. An area of eschar outside the dose site was noted for five animals from the 24 hour through the day 7 observations. Two animals also exhibited desquamation on Day 7. Classification as a dermal irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

 

A primary dermal irritation study was conducted to evaluate the dermal irritation potential of a single dose of Hydrocarbons, C9-C11, cyclics, <2% aromatics in the rabbit (ExxonMobil, 1988c). All animals survived the study. Topical application of Hydrocarbons, C9-C11, cyclics, <2% aromatics elicited very slight to well-defined erythema in all animals and very slight to slight edema in all animals at the 45 minute observation. There was little change in the severity of erythema at 24 hours, but at 48 hours erythema scores increased to severe for four animals and was very slight to well defined for two animals. Edema decreased slightly at the 24 hour observation and very slight edema was noted for five animals at 48 hours. The incidence and severity of dermal irritation remained generally unchanged at 72 hours and on Day 7. Eschar was noted for five animals during the test period mainly at 48 and 72 hours and on day 7. Desquamation was noted for one animal on Day 7. These findings warrant classification of the test material as a Category 2 dermal irritant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

 

Hydrocarbons, C9-C11, isoalkanes, cyclics, < 2% aromatics

 

Hydrocarbons, C9-C11, isoalkanes, cyclics, < 2% aromatics was administered  via semi-occlusive patch for four hours to six male rabbits to assess dermal irritation (ExxonMobil, 1990). Dermal responses were evaluated at 1, 24, 48, and 72h post-dosing and on Day 7 according to the Draize method of scoring. Dermal responses were observed in all animals. At the 45 minute, 48 hour and 72 hour observations, three animals displayed well-defined erythema and three displayed very slight erythema. Four animals were noted with well-defined erythema and two were noted with very slight erythema at the 24 hour observations. At study termination (Day 7), four animals showed very slight erythema   No other dermal observations were noted during the study. The mean erythema and edema scores for Hydrocarbons, C9-C11, isoalkanes, cyclics, < 2% aromatics were 1.56 and 0 respectively. Classification as a dermal irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

 

Hydrocarbons, C9-C11, n-alkanes, isoalkanes, cyclics, < 2% aromatics

 

The test material (Hydrocarbons, C9-C11, n-alkanes, isoalkanes, cyclics, < 2% aromatics) was administered via semi-occlusive patch for four hours to 3 male rabbits to assess dermal irritation (TOTAL, 1991). Dermal responses were evaluated at 1, 24, 48, and 72h post-dosing and once daily for 11 days according to the Draize method of scoring. After 24 hours and up until Day 5 post exposure, animals exhibited moderate erythema (grade 4). By day 6, one animal had very light erythema while 2 animals exhibited well-defined erythema. Erythema gradually lessened until all animals were free of adverse clinical signs at Day 8. Edema was not noted at any observation time during the study. The mean erythema and edema scores for the test material were 2.67 and 0 respectively. This finding warrants classification of the test material as a Category 2 dermal irritant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

 

Hydrocarbons, C11-C14, n-alkanes, < 2% aromatics

 

In a key study (Cepsa Quimica, 2000), 3 rabbits were subjected to a 4h dermal (shaved) exposure of 0.5 ml of Hydrocarbons, C11-C14, n-alkanes, < 2% aromatics (50/50) via a semi-occluded patch. Dermal responses were evaluated at 1, 24, 48, and 72h post-dosing and once a day for a total of 14 days according to the Draize method of scoring. Topical application of the test material (50/50) elicited dermal responses in all animals. Well defined erythema and slight oedema followed exposure and was resolved by day 13. The average erythema score (24,48, and 72 hours) was 1.9, with 2 out of 3 animals having a mean (24-72 hour) erythema score of 2.0. The average edema score (24,48, and 72 hours) was 1.1. Based on the individual animal dermal irritation scores, classification as a dermal irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

 

In a second key study (Petrochem Carless, 1997), the test material (Hydrocarbons, C11-C14, n-alkanes, < 2% aromatics) was administered  via semi-occlusive patch for four hours to three rabbits (3 female) to assess dermal irritation  Dermal responses were evaluated at 1, 24, 48, and 72h post-dosing according to the Draize method of scoring. Application of the test material elicited responses in all animals. Erythema scores decreased as the study progressed. Effects continued to subside until all animals were free of adverse clinical signs by study termination (Day 7). Classification as a dermal irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

 

In a supporting study (ExxonMobil, 1968), the test material (Hydrocarbons, C11-C14, n-alkanes, < 2% aromatics) was administered via occlusive dermal patch on the skin of 100 human (female) test subjects for 48 hours. The test material was administered via semi-occlusive dermal patch on the skin of 25 human (female) test subjects for 48 hours. Clinical observations were made immediately after the patch was removed, 15 minutes, and 24 hours after post-application. In general minimal erythema was observed at the test site, with little to no noted edema. This study should be used for supporting purposes only due to the prolonged 48 hour exposure. Based on the minimal erythema displayed by the test subjects Hydrocarbons, C11-C14, n-alkanes, < 2% aromatics was deemed to be a minimal dermal irritant.  

 

Ocular Irritation

 

Hydrocarbons, C9-C11, cyclics, <2% aromatics

 

In a key eye irritation study (ExxonMobil, 1989), C9-C11, cyclic aliphatics was administered to the left eye of three male and three female rabbits to assess for ocular irritation. Ocular examinations occurred at 1h, 24h, 48h, 72h. Ocular damage was assessed and scored according to the Draize eye test. All animals survived the exposure. The mean corneal opacity, iris lesion, conjunctivae redness, and chemosis scores for C9-C11, cyclic aliphatics were 0, 0, 0, and 0 respectively. Classification as an ocular irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

 

Hydrocarbons, C9-C11, isoalkanes, cyclics, < 2% aromatics

 

In a key study (ExxonMobil, 1991), the test material (Hydrocarbons, C9-C11, isoalkanes, cyclics, < 2% aromatics) was administered to the right eye of six male rabbits to assess for ocular irritation. Ocular examinations occurred at 1h, 24h, 48h, 72h, and day 7 post instillation. Ocular damage was assessed and scored according to the Draize eye test. All animals survived the exposure. Ocular instillation of the test material elicited conjunctival irritation limited to redness noted in five of the six test animals at the 1 hour observation. No other signs of ocular irritation were noted during the study. The mean corneal opacity, iris lesion, conjunctivae redness, and chemosis scores for Hydrocarbons, C9-C11, isoalkanes, cyclics, < 2% aromatics were 0, 0, 0, and 0 respectively. Classification as an ocular irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Hydrocarbons, C11-C14, n-alkanes, < 2% aromatics

 

In a key study (Cepsa Quimica, 2000), the test material, Hydrocarbons, C11-C14, n-alkanes, < 2% aromatics (60/40) (0.1 mL, neat) was administered to the right eye of three rabbits to assess ocular irritation . Irritation and toxicity were monitored at 1, 24, 48, and 72 hours post-treatment. Irritation was scored according to the Draize methodology. No corneal damage or iridial inflammation was observed. Hyperaemia of blood vessels of the conjunctivae was seen in all animals. Ocular reactions had resolved in all instances by one day after instillation. The mean conjunctivae, chemosis, iris, and cornea scores for the Hydrocarbons, C11-C14, n-alkanes, < 2% aromatics (60/40) were 0.0, 0.0, 0.0, and 0.0 respectively. Classification as an ocular irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Respiratory Irritation

No studies were located to indicate that Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics is a respiratory irritant.

Justification for classification or non-classification

Skin Irritation:

For isoparaffinic, normal paraffinic, and mixed C9-C14 aliphatic, <2% aromatic hydrocarbon fluids, the weight of evidence indicates that the erythema and edema scores (24, 48, and 72 average) are below the classification threshold requirements: 2.3, the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP). Based on the weight of evidence from available substance specific and read across data, Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics does not meet the criteria for classification for skin Irritation under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Eye Irritation:

Based on available substance specific and read across data, Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics does not meet the criteria for classification as an ocular irritant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Respiratory Irritation:

There are no studies that warrant classification as a respiratory irritant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).