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Description of key information

Skin irritation/corrosion: Primary Dermal Irritation study, Pharmakon Research International, Inc., 1991, GLP and OECD Guideline study, New Zealand Rabbit, 0.5 mL, abraded and non-abraded sites - corrosive
Eye irritation/corrosion: Ballantyne and Leung. Acute Toxicity and Primary Irritancy of Alkylalkanolamines. Vet Human Toxicol 38 (6) December 1996, Comparable to the OECD guideline 405. New Zealand White Rabbit, 5 µ - corrosive

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was performed according to OECD 404 guideline and in compliance with GLP Regulations. There were no significant deviations from the guidelines.
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
GLP compliance:
yes (incl. QA statement)
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: adult
- Weight at study initiation: 1.941-2.365kg
- Housing: individually in cages sized in accordance with the "Guide for the Care and Use of Laboratory Animals" of the Institute of.Laboratory Animal Resources, National Research Council
- Diet (e.g. ad libitum): Purina Rabbit Chow HF, ad libitum
- Water (e.g. ad libitum): Fresh tap water, ad libitum
- Acclimation period: min. 5 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C ± 3°C (63-73°)
- Humidity (%): 30 - 70%
- Photoperiod (hrs dark / hrs light): 12h light, 12h dark

IN-LIFE DATES: From: Oct 15, 1991 To: Oct 29, 1991
Type of coverage:
occlusive
Preparation of test site:
other: shaved and abraded
Vehicle:
unchanged (no vehicle)
Controls:
other: OECD 404: untreated area of the test animal serves as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL/site, 3 sites per animal
Duration of treatment / exposure:
- 4 h (upper dorsal site-intact)
- 24h (lower dorsal site-intact and abraded)
Observation period:
Upper dorsal site (intact): 14 days
Lower dorsal site (intact and abraded): 14 days
Number of animals:
6 (3 male and 3 female)
Details on study design:
TEST SITE
- Area of exposure: trunk (lower and upper), clipped free of fur
- Type of wrap if used: rubber dam and an elastic bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): wiped with water and gauze
- Time after start of exposure: 4 and 24h

SCORING SYSTEM: observation
Draize Evaluation of Dermal Irritation, Primary Irritation Index and Modified Primary Irritation Index


Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Score:
8
Max. score:
8
Remarks on result:
other: severe dermal irritation
Irritation parameter:
erythema score
Basis:
mean
Remarks:
6/6
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks:
14d observation
Remarks on result:
other: intact site: severe erythema , necrosis
Remarks:
Times of observation included also: 30-60min, and daily up to 14d
Irritation parameter:
edema score
Basis:
mean
Remarks:
6/6
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks:
14d observation
Remarks on result:
other: intact site: severe edema
Remarks:
Times of observations included also 30-60min, and daily up to 14d
Irritation parameter:
erythema score
Basis:
mean
Remarks:
6&6
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks:
14d observation
Remarks on result:
other: no difference between intact and abraded site, severe erythema, necrosis
Remarks:
Times of observations included also daily up to 14d
Irritation parameter:
edema score
Basis:
mean
Remarks:
6&6
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks:
14 d observation
Remarks on result:
other: no difference between intact and abraded site :severe edema
Remarks:
Times of observations included also daily up to 14d
Irritant / corrosive response data:
Modified PDII=8 (severe dermal irritation).
Interpretation of results:
corrosive
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The test article was considered to be a severe dermal irritant (PDII and Modified PDII=8).
Executive summary:

New Zealand White rabbits were used to assess the irritating potential of DMAE. The undiluted test material was administered occlusive to the abraded and non-abraded skin of the animals for 4 and 24 hours. There were no differences between intact and abraded sites. The test material caused severe erythema with necrosis which were not reversible within 14 days of observation.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (corrosive)

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:
not reported, published 1996
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication which meets basic scientific principles.
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
not specified
Principles of method if other than guideline:
The description of the test method is insufficient to compare in details with the OECD guideline (because it is a publication).
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.005 mL undiluted material
Duration of treatment / exposure:
single application
Observation period (in vivo):
not reported
Number of animals or in vitro replicates:
6
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 1h
Score:
ca. 3
Max. score:
3
Reversibility:
not fully reversible within: 21d
Remarks on result:
other: severely hyperemic and edematous with an associated profuse discharge (scores are not reported)
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Remarks:
Only the mentioned time point were determined.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 1h
Score:
ca. 2 - ca. 4
Max. score:
4
Reversibility:
not fully reversible within: 21d
Remarks on result:
other: moderately to severely opaque, affecting 3/4 to the whole of the cornea (scores are not reported)
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 7d
Score:
ca. 4
Max. score:
4
Reversibility:
not fully reversible within: 21d
Remarks on result:
other: severely opaque over the whole of the surface (scores are not reported)
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Remarks:
Only the mentioned time point were determined.
Irritation parameter:
iris score
Basis:
mean
Time point:
other: all time points
Reversibility:
not reversible
Remarks on result:
other: could not be inspected because of the marked keratitis (scores are not reported)
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Remarks:
Only the mentioned time point were determined.
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Remarks:
No information on chemosis provided.
Irritation parameter:
other: necrotic areas in the conjunctivae and nictitating membrane
Basis:
mean
Time point:
other: 4h
Reversibility:
not fully reversible within: 21d
Remarks on result:
other: Scores are not reported
Irritation parameter:
other: corneal ulceration
Basis:
mean
Time point:
other: 4h
Reversibility:
not fully reversible within: 21d
Remarks on result:
other: scores are not reported
Irritation parameter:
other: corneal neovascularization
Basis:
mean
Time point:
other: 7d
Reversibility:
not fully reversible within: 21d
Remarks on result:
other: scores are not reported
Irritant / corrosive response data:
Severe eye irritating effects (including conjunctivitis and corneal injury)
Other effects:
no

Erythema and edema were scored according to the following 5-point system, based on Draize (4); 0 = no effect; 1 = slight (barely perceptible) effect; 2 = slight effect; 3 = moderate effect; and 4 = severe effect.

Interpretation of results:
highly irritating
Remarks:
Criteria used for interpretation of results: other: according to the authors
Conclusions:
Severe irreversible eye irritating effects (including conjunctivitis and corneal injury) were produced by small volume (0.005 mL) contamination of the eye with DMEA. This agrees with its known irritating and corrosive effect on the skin.
Executive summary:

The acute handling hazards of several alkylalkanolamines were determined by investigating their potential acute toxicity and primary irritancy. Materials studied were N-methylethanolamine (MMEA), N,N,-dimethylethanolamine (DMEA), N,N,-dimethylisopropanolamine (DMIPA), N-methyldiethanolamine (MDEA), and tert-butyldiethanolamine (BDEA).

In accordance with the skin irritancy results, the eye irritancy from 0.005 mL DMEA was severe and irreversible.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin corrosivity

DMAE was classified as corrosive by several groups (Union Carbide, 1986; Union Carbide, 1990; BASF, 1990; BASF, 1969; Ballantyne and Leung; 1996). DMAE was corrosive after one-hour occlusive dressing. Severe erythema and edema with necrosis, which were not reversible during the observation period, are the common observations.
In the Key GLP dermal irritation study (Pharmakon Research International, Inc., 1991) undiluted test material was administered occlusive to the abraded and non-abraded sites of rabbits skin for 4 and 24 hours. The animals were observed during 14 days. The primary dermal irritation score was 8 from the maximal possible 8. Erythema and edema with necrosis were irreversible within 14 days. The test material is ranked as corrosive to the skin.

A supporting BASF study confirms these findings (BASF AG., 1990). DMAE caused haemorrhages after 1 hour of exposure. 24 h post application necrosis and edema and at the end of the observation period after 72 h full thickness necrosis and edema were found. In another BASF (BASF AG, 1969) supporting study a scale formation was observed after 1, 5 and 15 min of exposure. Erythema turned into necrosis, which was not reversible within 8 days of observation.

By 3 min skin contact to DMAE, erythema was observed which resolved after 7 days (Union Carbide, 1990; Ballantyne and Leung, 1996).

DMAE was moderately irritating by the short-term contact and corrosive after 1 -hour contact with skin.

Eye corrosivity

Ballantyne and Leung (1996; Key study) applied 5 µL of DMAE to the one rabbit eye. Corneal damage occurred within one hour of treatment, becoming moderately to severely opaque and affecting almost all cornea. By the seventh day of observation, all corneas were severely opaque over the whole surface. The effects persisted to the end of the observation period (14 days). Necrotic areas in the conjunctivae and nictating membrane (four hours post application), corneal neovascularization (seven days), and corneal ulceration (14 days) were also observed. The iris could not be inspected due to marked keratitis.

In the supporting BASF study (BASF AG, 1969), 0.05 mL DMAE was applied to the rabbit eyes. Cornea mean 24 -72 h score was the highest score according to the OECD Draize system. Cornea opacity with chemosis was not fully reversible within 8 days of observation. An instillation of only 0.005 mL of DMAE into rabbit eyes resulted in moderate to severe corneal injury, iritis and severe conjunctival irritation (including necrosis) in all animals tested (Union Carbide, 1986). Each rabbit also exhibited pinpoint pupils, which persisted to 24 hours in one. Within 24 to 72 hours, most rabbits developed protrusions of the eyeball (exophthalmos) and bulges on the corneal surface (giving an irregular shape). Corneal vascularisation was apparent at 7 days. After 10 days, there were thick, white opaque coatings covering the cornea of 2 eyes. Significant ocular injury persisted in 4 of 6 eyes through 21 days.

DMAE is corrosive to eyes.

Respiratory irritation 

The respiratory irritation potential of DMAE is high. In acute inhalation toxicity study, the common signs of toxicity were irritation of respiratory tract and eyes (refer to section 7.2.2. of IUCLID file; Key study: Ballantyne and Leung, 1996).

Justification for classification or non-classification

Due to corrosive effects of DMAE observable in treated animals in irritation studies, classification is warranted according to the criteria of EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008:

According to GHS: Skin corr. Cat.1B; Eye damage Cat.1.

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