2-[(2-[2-(dimethylamino)ethoxy]ethyl)methylamino]ethanol

Endpoint summary

Description of key information

Skin irritation / corrosion: Based on available data combined in a weight of evidence approach to evaluate skin effects of the test substance, this test substance should be classified as irritant to the skin.

Eye irritation: The substance was severely irritating to eyes in in vivo eye irritation study and conjunctival, corneal and iridial effects were still observed at the end of the study.

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:

weight of evidence

Study period:

1984-04-05 to 1984-04-15

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Remarks:

No major deviations identified

Qualifier:

no guideline followed

Principles of method if other than guideline:

Method was performed to satisfy DOT corrosivity classification requirements. The test substance was applied for four hours under occluded conditions for four hours and observed after four and 48 hours for positive responses

GLP compliance:

yes

Specific details on test material used for the study:

- Name of test material (as cited in study report): 5601-22-20
- Physical state: Clear liquid
- Lot/batch No.: Order # J-175
- Stability under test conditions: There was no apparent change in the physical state of the test material during administration
- Other: The purity of the test material is the responsibility of the sponsor

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, USA
- Weight at study initiation: 2 - 3 kg
- Housing: 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: Wayne Rabbit Ration, ad libitum
- Water: Fresh tap water, fit for human consumption, ad libitum
- Acclimation period: 5 days

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

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

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:

48 hours

Number of animals:

2 per dose group

Details on study design:

TEST SITE
- Type of wrap if used: test area was covered with one inch square patches; trunk of animal wrapped with a rubber dam and an Ace bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the skin was wiped to remove any remaining material
- Time after start of exposure: 4 hours

SCORING SYSTEM: Corrosion will be considered to have resulted if the substance in contact with the rabbit skin has caused destruction or irreversible alteration of the tissue on at least two out of each six rabbits tested. Tissue destruction is considered to have occurred if, at any of the readings, there is ulceration or necrosis. Tissue destruction does not include merely sloughing of the epidermis or erythema, edema or fissuring.

Irritation parameter:

erythema score

Remarks on result:

other: slight to well defined erythema were observed during the study

Irritation parameter:

edema score

Remarks on result:

other: Slight to moderate edema were observed during the study

Irritant / corrosive response data:

No signs of skin necrosis were visible at any observation period.

Slight to well defined erythema and slight to moderate edema were observed during the study. No signs of skin necrosis were visible at any observation period. The test substance was not considered corrosive based on results of the DOT corrosivity study in rabbits.

Interpretation of results:

study cannot be used for classification

Conclusions:

Based upon the results of this study, the test substance was not considered to be corrosive.

Executive summary:

The test substance was applied to an intact skin site on each of six rabbits (three males and three females). The test substance was kept in contact with the skin for four hours. Animals were observed at 4 and 48 hours after treatment. Slight to well defined erythema and slight to moderate edema were observed during the study. No signs of skin necrosis were visible at any observation period. Based on the results of DOT corrosivity study in rabbits, the substance was not considered to be corrosive.

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1983-09-27 to 1983-10-11

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Remarks:

Exposure for 24 hours; no 48 hour reading so mean scores based on 24 and 72 hour readings. Experiment was run under GLP conditions.

Qualifier:

equivalent or similar to guideline

Guideline:

other: Draize skin irritation assay

GLP compliance:

yes

Specific details on test material used for the study:

- Name of test material (as cited in study report): 5601-22-20
- Physical state: Clear liquid
- Lot/batch No.: Order # J-175
- Stability under test conditions: There was no apparent change in the physical state of the test material during administration
- Other: The purity of the test material is the responsibility of the sponsor.

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Perfection Breeders, Douglassville, Pennsylvania, USA
- Weight at study initiation: 2 - 3 kg
- Housing: 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
- Water (e.g. ad libitum): Fresh tap water, fit for human consumption, at libitum
- Acclimation period: 5 days

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

Type of coverage:

occlusive

Preparation of test site:

other: intact and abraded skin

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

0.5 mL per site

Duration of treatment / exposure:

24 h

Observation period:

at 24 and 72 hours and on Days 4 through 14 after application of the test material.

Number of animals:

6 (3 males and 3 females)

Details on study design:

TEST SITE
- White strain were administered the test article at two skin sites, one abraded and one intact site
- Type of wrap if used: test sites covered with gauze patches; trunk of animal wrapped with a rubber dam and an Ace bandage
- All application sites were clipped free of hair. The skin was abraded using a 21 gauge burred needle.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Yes
- Time after start of exposure: 24 hours

SCORING SYSTEM: Draize JH (1959) The Appraisal of Chemicals in Food, Drugs and Cosmetics, pp. 36-45. Association of Food and Drug Officials of the United States, Austin, Texas.

Irritation parameter:

erythema score

Basis:

mean

Time point:

14 d

Score:

3.3

Max. score:

4

Reversibility:

not reversible

Remarks on result:

other: Intact and Abraded Skin.

Irritation parameter:

erythema score

Basis:

mean

Time point:

24 h

Score:

3.5

Max. score:

4

Remarks on result:

other: Intact Skin.

Irritation parameter:

erythema score

Basis:

mean

Time point:

24 h

Score:

4

Max. score:

4

Remarks on result:

other: Abraded Skin.

Irritation parameter:

edema score

Basis:

mean

Time point:

14 d

Score:

0.5

Max. score:

1

Reversibility:

not reversible

Remarks on result:

other: Intact Skin.

Irritation parameter:

edema score

Basis:

mean

Time point:

14 d

Score:

0.7

Max. score:

1

Reversibility:

not reversible

Remarks on result:

other: Abraded Skin.

Irritation parameter:

edema score

Basis:

mean

Time point:

24 h

Score:

1

Max. score:

2

Remarks on result:

other: Intact Skin.

Irritation parameter:

edema score

Basis:

mean

Time point:

24 h

Score:

1.2

Max. score:

2

Remarks on result:

other: Abraded Skin.

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

72 h

Score:

5

Irritant / corrosive response data:

Reversibility of any observed effect: Changes are not fully reversible within 14 days

Other effects:

Although testing involved use of abraded and non-abraded skin, only results for non-abraded skin are reported here. The pH of the test material was 11.35. Slight to severe erythema and slight to moderate edema was observed at all observation times. Skin necrosis was also observed at the application sites throughout the study. The Primary Irritation Index was 5.0.

Interpretation of results:

corrosive

Conclusions:

Based on the results of the study, the substance could be considered to be corrosive.

Reference 3

Endpoint:

skin irritation: in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2004-05-13 to 2004-05-14

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Remarks:

No guideline is available for the type of study performed and the study report did not provide analytical on the test substance. However, study was GLP, materials and methods were well documented, and positive and negative controls were used.

Qualifier:

no guideline available

Principles of method if other than guideline:

The study was designed to assess the skin corrosivity potential of the test substance following application to the epidermal surfaces of skin discs. Corrosive substances produce an irreversible loss of normal stratum corneum integrity and function; this is measured as a reduction in the inherent Transcutaneous Electrical Resistance (TER) below a corrosive threshold level. Irritant substances do not reduce the TER below the threshold level. The TER was measured using a low voltage alternating current electronic data bridge.

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

- Name of test material (as cited in study report): Jeffcat ZF 10
- Physical state: very pale straw colored liquid
- Storage condition of test material: room temperature in the dark

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: B&K Universal Ltd, Hull, UK
- Age at study initiation: 28-30 days

SKIN DISC PREPARATION:
One female rat was used for skin for the the skin disc preparations. Following an acclimatisation period of two days the animal was shaved to remove hair from the dorsal surface. The shaved area was washed using an antibiotic wash. After three days a second antibiotic wash was performed. Four days later the animal was humanely killed by inhalation of a rising concentration of CO2 followed by cervical dislocation. The animal was in the telogen phase of hair growth and little or no hair growth was visible.
When the animal had been humanely killed the dorsal skin was removed from the rat as a single pelt. Care was taken during procedure to avoid unnecessary damage to the pelt. Excess fat was removed and the pelt mounted, epidermal side uppermost, onto a polytetrfluoroethylene (PTFE) tube. The tissue was secured in place using a rubber "O" ring. Excess tissue was trimmed away and the "O" ring/PTFE interface sealed with soft paraffin wax. The tube was supported by a clamp inside a labeled 30 ml glass receptacle containing 10 ml electrolyte solution (154 mM MgSO4).

Skin disc quality control :
Two skin discs of approximately 0.79 cm^2 were taken from the pelt and the transcutaneous electrical resistance (TER) measured as a quality control procedure. Each disc had to give a resistance value of greater than 10kΩ in order for the remainder of the pelt to be used in the assay. If either disc fell below the 10kohm threshold, the pelt was discarded. The quality control disc were then discarded and new discs from the acceptable pelt were mounted in the PTFE tubes.

Type of coverage:

other: in vitro

Preparation of test site:

other: see above in details on test animals

Vehicle:

unchanged (no vehicle)

Controls:

other: control animal usage - not applicable, however, sterile distilled water (negative control) and 36 % hydrochloric acid (positive control) were used.

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 150 µl

Duration of treatment / exposure:

24 hours

Number of animals:

3 skin discs

Details on study design:

TEST SITE
- Area of exposure: The test substance was applied to the inner epidermal surface of the skin discs using an automatic pipettor.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): At the end of the exposure period, the test substance was removed by washing the skin disc with a jet of warm tap water until no further test substance could be removed.
- Time after start of exposure: 24 hours

SCORING SYSTEM:
the transcutaneous electrical resistance (TER) was measured using a Wheatstone Bridge with a low voltage alternating current. Prior to measurement of the resistance, the surface tension of the skin disc was reduced by adding a sufficient volume of 70 % ethanol to cover the epidermis. The ethanol was removed by inverting the tube after approximately 3 seconds. The PTFE tube was then placed in the labeled receptor chamber and the tissue was hydrated by the addition of 3 ml MGSO4 solution (154 mM) to the inside of the PTFE tube. Any air bubbles present were dislodged by tapping the tube.
The stainless steel electrodes of the databridge were placed on either side of the skin disc. The measurement was taken and a value in ohms/kohms per skin disc was displayed on the data bridge display. The mean TER for the skin discs was calculated.

INTERPRETATION OF RESULTS:
Results were accepted on the condition of adherence to the ranges given. If the positive and negative control results for the assay did not fall within the accepted ranges, the data on the test substance could not be interpreted as being reliable, and the experiment had to be repeated.
Hydrochloric acid, positive control range: 0.5 to 1.0kohms
Sterile distilled water, negative control range: 10 to 25kohms
The test substance was classified as "Non-Corrosive" if the mean TER value recorded for the 24 hour contact period was greater than 5kohms.
the test substance was classified as "Corrosive" if the mean TER value recorded for the 24 hour contact period was 5kohms or lower.
A "Non-Corrosive" classification may require further investigation using an in vivo skin corrosivity test.

Irritation / corrosion parameter:

transcutaneous electrical resistance (in kΩ)

Remarks:

Mean of 3

Run / experiment:

1

Value:

8.3

Vehicle controls validity:

not applicable

Negative controls validity:

valid

Positive controls validity:

valid

Other effects / acceptance of results:

Test Substance- 8.3 kohms (mean) - (individuals: 10.7, 11.5 and 2.6 kohms)
Positive Control- 638ohms (mean)
Negative Control-26.0kohms (mean)

The negative control was slightly out of the range stated in the Standard Test Method (10-25kohms). This was considered not to affect the purpose or integrity of the study.

Interpretation of results:

GHS criteria not met

Conclusions:

The test substance was evaluated in the transcutaneous electrical resistance assay for the skin corrosivity potential to skin in vivo. Based on the results, the test substance was considered not to have the potential to be corrosive to skin in vivo under the conditions of the test.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1983-09-26 to 1983-10-12

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

Study GLP compliant. No major deviations were identified compared to OECD and EU guidelines followed.

Qualifier:

according to guideline

Guideline:

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

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

- Name of test material (as cited in study report): 5601-22-20
- Lot/batch No.: Order No J-175
- Physical state: Clear liquid
- Stability under test conditions: There were no apparent changes in the physical state of the test material during administration
- Other: The purity of the test material is the responsibility of the sponsor

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Sgarlat's Rabbitry, Harvey's Lake, PA and Perfection Breeders, Douglassville, PA, USA
- Weight at study initiation: 2 - 3 kg
- Housing: Animals 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
- Water (e.g. ad libitum): Fresh tap water, suitable for human consumption, ad libitum
- Acclimation period: 5 days

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

Vehicle:

unchanged (no vehicle)

Controls:

other: Untreated eye of treated animals served as the control

Amount / concentration applied:

0.1 mL

Duration of treatment / exposure:

Once

Observation period (in vivo):

13 days; eyes examined at 1, 24, 48, and 72 hours and 7, 10, and 13 days after treatment

Number of animals or in vitro replicates:

6 (3 males and 3 females)

Details on study design:

SCORING SYSTEM: Grading of irritation is according to the method of Draize, JH et al, J. Pharm, Exp. Ther. 82:377-390 (1944).

Irritation parameter:

conjunctivae score

Remarks:

(redness)

Basis:

mean

Time point:

other: Day 13

Score:

2.6

Max. score:

3

Reversibility:

not reversible

Irritation parameter:

conjunctivae score

Remarks:

(redness)

Basis:

mean

Time point:

7 d

Score:

3

Max. score:

3

Irritation parameter:

conjunctivae score

Remarks:

(redness)

Basis:

mean

Time point:

24 h

Score:

3

Max. score:

3

Irritation parameter:

chemosis score

Basis:

mean

Time point:

other: Day 13

Score:

3.8

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

chemosis score

Basis:

mean

Time point:

7 d

Score:

3.8

Max. score:

4

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24 h

Score:

3.3

Max. score:

4

Irritation parameter:

cornea opacity score

Remarks:

(opacity and area)

Basis:

mean

Time point:

other: Day 13

Score:

3.9

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

cornea opacity score

Remarks:

(opacity and area)

Basis:

mean

Time point:

7 d

Score:

3.9

Max. score:

4

Irritation parameter:

cornea opacity score

Remarks:

(opacity and area)

Basis:

mean

Time point:

24 h

Score:

3.6

Max. score:

4

Irritant / corrosive response data:

Reversibility of any observed effect: Changes not fully reversible within 13 days

Other effects:

Partial rupture of the globe was observed in 4/6 animals 7-13 days after exposure. Corneal opacity was too severe to allow scoring of iris damage in four animals at one or more times.

Note: in many cases, severe opacity prevented scoring of the iris. Max. duration: 13 h; Max. value for iris score at end of observation period: 2

Interpretation of results:

Category 1 (irreversible effects on the eye)

Conclusions:

Conjunctival, corneal and iridial effects were still observed at the end of the study. The substance is severely irritating to eyes. The average Draize Score at Day 13 was reported as 105.7.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation/corrosion

One in vitro and two in vivo dermal corrosivity studies were performed to substance.

The in vivo dermal irritation study according to the Draize skin irritation assay was conducted (Mallory et al., 1983c). The test substance was applied at a dose of 0.5 mL per site to unabraded and abraded skin sites in a clipped area of each of six rabbits. The test sites were occluded and the test material remained on the skin for a 24 hour contact period. Application sites were graded using the Draize scoring system at 24, 72 hours after application. The pH of the test material was 11.35. Slight to severe erythema and slight to moderate edema was observed at all observation times. Skin necrosis was also observed at the application sites throughout the study. The Primary Irritation Index was 5.0.

Test substance was applied to an intact skin site on each of six rabbits (three males and three females) in a DOT corrosivity test (Mallory et al.,1984). The test substance was kept in contact with the skin for four hours. Animals were observed at 4 and 48 hours after treatment. Slight to well defined erythema and slight to moderate edema were observed during the study. No signs of skin necrosis were visible at any observation period. Based on the results of DOT corrosivity study in rabbits, the substance was not considered to be corrosive.

The test substance was also evaluated in the transcutaneous electrical resistance (TER) assay for the skin corrosivity potential to skin in vivo (Culling, 2004). The study was designed to assess the skin corrosivity potential of the test substance following application to the epidermal surfaces of skin discs. Corrosive substances produce an irreversible loss of normal stratum corneum integrity and function; this is measured as a reduction in the inherent TER below a corrosive threshold level. Irritant substances do not reduce the TER below the threshold level. The TER was measured using a low voltage alternating current electronic data bridge. Based on the results, the test substance was considered not to have the potential to be corrosive to skin in vivo under the conditions of the test.

Based on available data, a weight of evidence approach was used to evaluate skin effects of test substance. The first study was conducted for a prolonged time (24h) compared to the 4h required by the default guideline OECD 404 (at current date) which tends to overpredict the irritation. The performance of the test on abraded skin and the use of occlusive conditions have an influence towards overprediction. Given the fact that the DOT study and the in vitro TER study predict skin irritation, the substance should be classified as skin irritant. The substance should not consider as a corrosive substance, it should be classified as a skin irritant (category 2).

Eye irritation

One in vivo eye irritation study was conducted in accordance with OECD guideline and EU Method B.5 (Mallory et al.,1983d). Test substance was applied at a dose of 0.1 mL undiluted to one eye in each of six rabbits. Eyes were graded at 1, 24, 48, and 72 hours and 7, 10, and 13 days after treatment. Partial rupture of the globe was observed in 4/6 animals 7-13 days after exposure. Corneal opacity was too severe to allow scoring of iris damage in four animals at one or more times. Conjunctival, corneal and iridial effects were still observed at the end of the study (not reversible within 13 days). The average Draize Score at Day 13 was reported as 105.7. The substance was severely irritating to eyes and the effects were not reversible. The substance is classified as corrosive.

Justification for classification or non-classification

Based on the available data and the criteria of the CLP Regulation, the substance should be classified for skin irritant category 2 and eye damage category 1.