2,2'-oxydi(ethylamine)

Endpoint summary

Description of key information

Skin irritation:
Mallory VT (1985) determined in a K2, key DOT corrosivity study the skin irritation potential of the test substance in New Zealand White rabbits according to a method equivalent to OECD Guideline 404. The test substance was observed to be corrosive to the skin. This study was selected as key study.
Eye irritation:
Based on the data of a study performed similar to OECD Guideline 405 study, the test substance was shown to cause irreversible effects (necrosis) on the eye (Mallory VT, 1983).

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:

experimental study

Adequacy of study:

key study

Study period:

1985-01-09 - 1985-01-11

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

Two animals are used, and only an exposure time of 4 hours is used. An occlusive dressing is used instead of a semi-occlusive dressing.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

The study is performed similar to the initial test as described in OECD 404. However, two animals are used, and only an exposure time of 4 hours is used. An occlusive dressing is used instead of a semi-occlusive dressing.

GLP compliance:

not specified

Remarks:

Assumed to be GLP compliant as raw data is present and other studies of this lab are performed according to GLP principles.

Specific details on test material used for the study:

- Name of test material (as cited in study report): 5601-22-1, Order #J-170
- Appearance: clear liquid
- Purity: responsibility of the sponsor
- Stability under test conditions: There was no apparent change in the physical state of the test article during administration

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Sgarlat's Rabbitry, Harvey's Lake, Pennsylvania
- Weight at study initiation: 2 - 3 kilograms
- Housing: rabbits were housed individually in cages sized in accordance with the "Guide for the Care and Use of Laboratory Animals" of the institute of Laboratory Resources, National Research Council.
- Diet (e.g. ad libitum): Wayne Rabbit Ration, ad libitum, checked daily and added or replaced as needed. Feeders are designed to reduce soiling, bridging and scattering.
- Water (e.g. ad libitum): ad libitum
- Acclimation period: five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3°C
- Humidity (%): 30 - 70%
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL/site

Duration of treatment / exposure:

4 hours

Observation period:

Animals were observed at 4 and 48 hours after application of the test material.

Number of animals:

2 animals

Details on study design:

TEST SITE
- Area of exposure: trunk
- Type of wrap if used: Following the application of the test material, one-inch square patches were applied to the test site. The trunk of the animal was then wrapped with a rubber dam and an Ace bandage to retard evaporation.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): At the end of the 4 hour exposure period, the wrappings were removed and the skin wiped to remove any remaining material.

SCORING SYSTEM: Initially, two rabbits will be administered the test article. The test will be considered positive if both animals exhibit a positive response and the study will be terminated. If only one animal or no animals exhibit a positive response, the test will be repeated with a different group of two rabbits. If one animal exhibits a positive response in the second group, the test article will be considered corrosive and the study will be terminated provided there was one positive response in Group I. If no positive reactions are observed in Group II, an additional group of two rabbits will be added and conclusions will be based on a total of six rabbits.

Irritation parameter:

other: Skin necrosis

Basis:

animal #1

Time point:

other: 4h

Reversibility:

not specified

Remarks on result:

other: See 'Remarks'

Remarks:

Skin necrosis was visible in both rabbits at 4 hours and 48 hours after application of the test article.

Irritation parameter:

other: Skin necrosis

Basis:

animal #2

Time point:

other: 4h

Reversibility:

not specified

Remarks on result:

other: See 'Remarks'

Remarks:

Skin necrosis was visible in both rabbits at 4 hours and 48 hours after application of the test article.

Irritation parameter:

other: Skin necrosis

Basis:

animal #1

Time point:

48 h

Reversibility:

not specified

Remarks on result:

other: See 'Remarks'

Remarks:

Skin necrosis was visible in both rabbits at 4 hours and 48 hours after application of the test article.

Irritation parameter:

other: Skin necrosis

Basis:

animal #2

Time point:

48 h

Reversibility:

not specified

Remarks on result:

other: See 'Remarks'

Remarks:

Skin necrosis was visible in both rabbits at 4 hours and 48 hours after application of the test article.

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Remarks on result:

other: See 'Remark'

Remarks:

Only skin necrosis is reported

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Remarks on result:

other: See 'Remark'

Remarks:

Only skin necrosis is reported

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Remarks on result:

other: See 'Remarks'

Remarks:

Only skin necrosis is reported

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Remarks on result:

other: See 'Remarks'

Remarks:

Only skin necrosis is reported

Irritant / corrosive response data:

Skin necrosis was visible in both rabbits at 4 hours and 48 hours after application of the test article.

Skin necrosis was visible in both rabbits at 4 hours and 48 hours after application of the test article.

Interpretation of results:

Category 1B (corrosive) based on GHS criteria

Conclusions:

Based on the results of the DOT Corrosivity study in rabbits, the substance was considered to be corrosive to the skin. The test substance is classified as skin corrosive category 1B according to the criteria laid down in the CLP Regulation.

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1983-09-16 - 1983-09-30

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

The test substance is applied to intact skin, but also to abraded skin. An occlusive dressing is used, instead of a semi-occlusive dressing. No scoring of skin reactions at 1 h and 48 h after patch removal.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

The test substance is applied to intact skin, but also to abraded skin. An occlusive dressing is used, instead of a semi-occlusive dressing. No scoring of skin reactions at 1 h and 48 h after patch removal.

GLP compliance:

yes

Specific details on test material used for the study:

- Name of test material (as cited in study report): 5601-22-1, Order #J-170
- Substance type: clear liquid
- Physical state: liquid
- Purity: responsibility of the sponsor
- Stability under test conditions: There was no apparent change in the physical state of the test article during administration.
- Other: The pH of the test article was 14.9.

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Sgarlat's Rabbitry, Harvey's Lake, Pennsylvania
- Weight at study initiation: 2 - 3 kilograms
- Housing: rabbits were housed individually in cages sized in accordance with the "Guide for the Care and Use of Laboratory Animals" of the institute of Laboratory Resources, National Research Council.
- Diet (e.g. ad libitum): Wayne Rabbit Ration, ad libitum, checked daily and added or replaced as needed. Feeders are designed to reduce soiling, bridging and scattering.
- Water (e.g. ad libitum): Availability - fresh tap water, fit for human consumption, ad libitum, using 16 ounce glass bottles with rubber stopper and stainless steel sipper tube or automatic watering system supplied by Edstrom Industries, inc. Waterford, Wisconsin.
- Acclimation period: five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3°C
- Humidity (%): 30 - 70%
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark

Type of coverage:

occlusive

Preparation of test site:

other: 1 abraded and 1 intact (shaved) site

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL/site

Duration of treatment / exposure:

24 hours

Observation period:

14 days

Number of animals:

6 animals (3 males and 3 females)

Details on study design:

TEST SITE
Each of six adult albino rabbits of the New Zealand White Strain were administered the test article at two skin sites, one abraded and one intact site. All application sites were clipped free of hair. The skin was abraded using a 21 gauge burred needle; the abrasion penetrated the stratum corneum but not the derma. Following the application of the test material, one-inch square gauze patches were applied to each of the two sites. The trunk of the animal was then wrapped with a rubber dam and an Ace bandage to retard evaporation. The test substance was kept in contact with the skin site for twenty-four hours.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): At the twenty-four hour exposure period, the wrappings were removed and the remaining material was removed in a suitable manner.

SCORING SYSTEM: Animals were observed and signs of erythema and edema were scored according to the Draize scale at 24 and 72 hours and on Day 4 through 14 after application of the test material.

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

other: 24 and 72 hours

Score:

7.5

Max. score:

8

Reversibility:

not fully reversible within: 14 days

Irritant / corrosive response data:

Necrsosis was observed at 24 and 72 hours after treatment and on Days 4 through 14. Very slight to severe edema was also observed at 24 and 72 hours and on Days 4 through 14. The study was terminated on Day 14.

Interpretation of results:

Category 1B (corrosive) based on GHS criteria

Conclusions:

The substance caused necrosis at 24 and 72 hours and on Days 4 through 14. Very slight to severe edema was also observed at 24 and 72 hours and on Days 4 through 14. The study was terminated on Day 14. The primary irritation index was 7.5. Based on the test results and according to the criteria of the CLP Regulation, the substance should be classified as a category 1 (cat 1B) skin corrosive substance.

Reference 3

Endpoint:

skin corrosion: 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:

adverse effect observed (corrosive)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1983-09-02 - 1983-10-05

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Specific details on test material used for the study:

- Name of test material (as cited in study report): 5601-22-1, Order #J-170
- Substance type: clear liquid
- Physical state: liquid
- Purity: responsibility of the sponsor
- Stability under test conditions: There was no apparent change in the physical state of the test article during administration

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Sgarlat's Rabbitry, Harvey's Lake, Pennsylvania
- Weight at study initiation: 2 - 3 kilograms
- Housing: Rabbits were housed individually in cages sized in accordance with the "Guide for the Care and Use of Laboratory Animals" of the Institute of Laboratory Resources, National Research Council.
- Diet (e.g. ad libitum): Wayne Rabbit Ration, ad libitum, checked daily and added or replaced as needed. Feeders are designed to reduce soiling, bridging and scattering.
- Water (e.g. ad libitum): Availability - fresh tap water, fit for human consumption, ad libitum, using 16 ounce glass bottles with rubber stopper and stainless steel sipper tube or an automatic watering system supplied by Edstrom Industries, Inc., Waterford, Wisconsin.
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3 °C
- Humidity (%): 30 to 70%
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark

Vehicle:

unchanged (no vehicle)

Controls:

other: the contralateral eye remained untreated and served as control.

Amount / concentration applied:

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

Duration of treatment / exposure:

frequency and duration of administration: once
The upper and lower lids were then gently held together for one second to prevent loss of material.

Observation period (in vivo):

The eyes were examined at 1, 24, 48 and 72 hours and 7, 10 and 13 days after treatment. The grades of ocular reaction were recorded at each examination.

Number of animals or in vitro replicates:

six animals (three males and three females)

Details on study design:

REMOVAL OF TEST SUBSTANCE: No data

SCORING SYSTEM: An animal exhibited a positive reaction when the test substance produced one or more of the following signs: ulceration of the cornea (other than a fine stippling), opacity of the cornea (other than a slight dulling of the normal luster), inflammation of the iris (other than a slight deepening of the rugae or a light hyperemia of the circumcorneal blood vessels), or an obvious swelling in the conjunctivae (excluding the cornea and iris) with partial eversion of the eyelids and a diffuse crimson color with individual vessels not easily discernible. Grading of irritation is according to the method of Draize, J.H., et al., J. Pharm, Exp. Ther. 82: 377-390, (1944).

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: Day 13

Score:

98.4

Max. score:

110

Reversibility:

not fully reversible within: 13 days

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

7

Max. score:

12

Reversibility:

not fully reversible within: 13 days

Remarks on result:

positive indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

11

Max. score:

12

Reversibility:

not fully reversible within: 13 days

Remarks on result:

positive indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

11

Max. score:

12

Reversibility:

not fully reversible within: 13 days

Remarks on result:

positive indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #4

Time point:

24/48/72 h

Score:

12

Max. score:

12

Reversibility:

not fully reversible within: 13 days

Remarks on result:

positive indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #5

Time point:

24/48/72 h

Score:

8

Max. score:

12

Reversibility:

fully reversible within: 13 days

Remarks on result:

positive indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #6

Time point:

24/48/72 h

Score:

12

Max. score:

12

Reversibility:

not fully reversible within: 13 days

Remarks on result:

positive indication of irritation

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24 h

Score:

5

Max. score:

10

Reversibility:

not fully reversible within: 13 days

Remarks on result:

other: see "Remarks"

Remarks:

beyond this time point, high degree of opacity prevented scoring of iris

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24 h

Score:

10

Max. score:

10

Reversibility:

not fully reversible within: 13 days

Remarks on result:

other: see 'Remarks'

Remarks:

beyond this time point, high degree of opacity prevented scoring of iris

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24 h

Score:

10

Max. score:

10

Reversibility:

not fully reversible within: 13 days

Remarks on result:

other: see 'Remarks'

Remarks:

beyond this time point, high degree of opacity prevented scoring of iris

Irritation parameter:

iris score

Basis:

animal #4

Time point:

24 h

Score:

10

Max. score:

10

Reversibility:

not fully reversible within: 13 days

Remarks on result:

other: see 'Remarks'

Remarks:

beyond this time point, high degree of opacity prevented scoring of iris

Irritation parameter:

iris score

Basis:

animal #5

Time point:

24 h

Score:

10

Max. score:

10

Reversibility:

not fully reversible within: 13 days

Remarks on result:

other: see 'Remarks'

Remarks:

beyond this time point, high degree of opacity prevented scoring of iris

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

46

Max. score:

60

Reversibility:

not fully reversible within: 13 days

Remarks on result:

positive indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

50

Max. score:

60

Reversibility:

not fully reversible within: 13 days

Remarks on result:

positive indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

54

Max. score:

60

Reversibility:

not fully reversible within: 13 days

Remarks on result:

positive indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #4

Time point:

24/48/72 h

Score:

50

Max. score:

60

Reversibility:

not fully reversible within: 13 days

Remarks on result:

positive indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #5

Time point:

24/48/72 h

Score:

50

Max. score:

60

Reversibility:

not fully reversible within: 13 days

Remarks on result:

positive indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #6

Time point:

24/48/72 h

Score:

42

Max. score:

60

Reversibility:

not fully reversible within: 13 days

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

7

Max. score:

12

Reversibility:

not fully reversible within: 13 days

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

8

Max. score:

12

Reversibility:

not fully reversible within: 13 days

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

10

Max. score:

12

Reversibility:

not fully reversible within: 13 days

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #4

Time point:

24/48/72 h

Score:

8

Max. score:

12

Reversibility:

not fully reversible within: 13 days

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #5

Time point:

24/48/72 h

Score:

9

Max. score:

12

Reversibility:

not fully reversible within: 13 days

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #6

Time point:

24/48/72 h

Score:

6

Max. score:

12

Reversibility:

not fully reversible within: 13 days

Remarks on result:

positive indication of irritation

Irritation parameter:

iris score

Basis:

animal #6

Time point:

24/48/72 h

Reversibility:

not fully reversible within: 13 days

Remarks on result:

other: see 'Remarks'

Remarks:

high degree of opacity prevented scoring of iris

Irritant / corrosive response data:

Positive ocular responses were observed at 1, 24, 48 and 72 hours and on Days 7, 10 and 13. Rupture of the globe, conjunctival necrosis and decreased body tone were observed during the course of the study.

Other effects:

One rabbit was found dead on Day 6 of the study. Necropsy revealed distended intestines filled with mucous and gelatinous material. The death was determined to be non-compound related (mucoid enteritis).

Interpretation of results:

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

Conclusions:

The substance was instilled in the right eye of six rabbits. Ocular readings were observed at 1, 24, 48 and 72 hours and 7, 10 and 13 days following administration of the test article. Positive ocular responses were recorded at 1, 24, 48 and 72 hours and on Days 7, 10 and 13. Rupture of the globe, conjunctival necrosis and decreased body tone were observed during the course of the study. The Draize score was observed to be 98.4. Based on the test results and the criteria of the CLP Regulation, the substance should be classified in category 1 (irreversible effects on the eye).

Reference 2

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:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation / corrosion

In a DOT corrosivity study by Mallory VT (1985; Klimisch 2, similar to OECD 404), 2 groups New Zealand White rabbits were exposed to 0.5 ml of undiluted test substance on shaved skin. Exposure time was 4h under an occlusive dressing. The skin was observed after 4h and 48h. Skin necrosis was visible in both rabbits at 4 hours and 48 hours after application of the test article. This study was selected as key study.

In a primary dermal irritation study by Mallory VT (1983), 6 rabbits were exposed to 0.5 ml of undiluted test substance on both intact and abraded skin. Exposure time was 24h under an occlusive dressing. Scoring according to Draize occurred after 24h and 72h, and after days 4 through 14. Necrsosis was observed at 24 and 72 hours after treatment and on Days 4 through 14. Very slight to severe edema was also observed at 24 and 72 hours and on Days 4 through 14. The study was terminated on Day 14.

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

Eye irritation

In the key study by Pharmakon Research (1983), 6 rabbits were instilled 0.1 ml of undiluted test substance in one eye, while the other eye served as control. The eyes were examined at 1, 24, 48 and 72 hours and 7, 10 and 13 days after treatment. Positive ocular responses were observed at 1, 24, 48 and 72 hours and on Days 7, 10 and 13. Rupture of the globe, conjunctival necrosis and decreased body tone were observed during the course of the study. One rabbit was found dead on Day 6 of the study. Necropsy revealed distended intestines filled with mucous and gelatinous material. The death was determined to be non-compound related (mucoid enteritis).

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

Justification for classification or non-classification

Based on the available data and the criteria of the CLP Regulation, the test substance is classified as skin corrosive category 1 (H314), covering both skin and eye corrosive effects.

According to the results of the eye irritation study and the criteria of the CLP Regulation, the test substance would be classified as Eye Effects Cat. 1 (H318). These classifications are however covered already within the classification for skin corrosion.