2-dimethylaminoethanol

Eye irritation

Administrative data

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.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting 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 other 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 401 (Acute Oral Toxicity)

Deviations:

not specified

Principles of method if other than guideline:

The description of the test method is insufficient to compare in detail with the OECD guideline (because it is a publication).

GLP compliance:

no

Test type:

standard acute method

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

not reported

No. of animals per sex per dose:

not reported

Control animals:

not specified

Sex:

male

Dose descriptor:

LD50

Effect level:

2 083 mg/kg bw

95% CL:

2 011 - 2 154

All deaths occured overnight following dosing. Signs of toxicity (with times to onset) included sluggishness (2 min to 2 h), lacrimation (1.5 h to 1 d), chromodacryorrhea (1 d), diarrhea (30 min), kyphosis (1.5 h to 1 d) and prostration (1 d).

Necropsy of animals that died revealed distended stomachs containing blood and having dark red or purple discoloration of the glandular portion. Intestines contained blood and had variable degrees of congestion. Lungs in general showed dark red mottling. Survivors had no gross pathology at necropsy.

Interpretation of results:

GHS criteria not met

Conclusions:

It is probable that systemic toxicity and local irritation of the gastrointestinal tract were both factors in the acute lethal peroral toxicity of the alkylalkanolamines. Thus, with most of the materials investigated the gross pathological features included marked congestion of the stomach and small intestine with blood in the lumen of the gastrointestinal tract.

Executive summary:

N,N-dimethylethanolamine was studied for its potential in acute toxicity and was considered to be moderately toxic if administered peroral to rats.

Cross-reference 3

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting 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 other 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 402 (Acute Dermal Toxicity)

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

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Duration of exposure:

24h

Doses:

not reported

No. of animals per sex per dose:

not reported

Control animals:

not specified

Sex:

male

Dose descriptor:

LD50

Effect level:

1 219 mg/kg bw

95% CL:

1 077 - 1 380

Remarks on result:

other: time to death ranged 1-12 days

In general, deaths occurred within a few days of the start of epicutaneous dosing, but later deaths were seen more frequently. Signs, which were few, included sluggishness, unsteady gait, emaciation and prostration, all of which developed by the end of the dosing period. Animals lost weight during the first postdosing week, with partial recovery during the second week.

On removal of the occlusive dressing there was moderate to severe erythema and edema with ecchymoses, necrosis and ulceration. These effects, in general, persisted to the end of the observation period. During the second postapplication week local desquamation, alopecia and scarring had developed.

Necropsy of animals that died revealed dark red mottled lungs, dark red livers and mottled kidneys. Most survivors at necrospy did not reveal any gross pathology, but a few showed red mottled lungs and dark red livers.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

By sustained (24-h) skin contact the alkylalkanolamines (among others DMEA) studied showed a potential for percutaneous systemic toxicity.

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 ,-dimethyIisopropanolarnine (DMIPA), N-methyldiethanoIamine (MDEA), and tert-butyldiethanolamine (BDEA).

By 24 h occluded epicutaneous contact in the rabbit, MMEA, DMEA and DMIPA were of moderate acute percutaneous toxicity (LD50 range 1.13-2.0 mL/kg).

The irritation and percutaneous toxicity findings clearly indicate a need for skin protection (including gloves) when handling alkylalkanolamines. Should skin become contaminated, then immediate and sustained washing of the area is required.

Cross-reference 4

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

acute toxicity: inhalation

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 403 (Acute Inhalation Toxicity)

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

Test type:

other: Acute Inhalation Toxicity (OECD 403)

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

1600, 2500 and 3300 ppm

No. of animals per sex per dose:

5

Control animals:

no

Sex:

male/female

Dose descriptor:

LC50

Effect level:

1 641 ppm

95% CL:

862 - 3 125

Exp. duration:

4 h

Remarks on result:

other: times to death ranged from 1 to 12 day

For the DMEA 4-h LC50 study, the mean (±SD) analytically measured chamber vapor concentrations were 1668 ±138, 2408 ± 178 and 3311 ± 156 ppm. The respective nominal concentrations, calculated from a knowledge of the total DMEA used and air flow rates, were 1799, 2657 and 3138 ppm. The corresponding A/N ratios were 0.93, 0.91 and 1.06 which indicated good generation conditions and little loss of material by chamber leak or adsorption on equipment. Signs were seen at all exposure concentrations and included blepharospasm, salivation, decreased activity and peroral/perinasal/peri-ocular encrustation. Animals lost weight during the first postexposure week, with some regain during the second week for surviving males exposed to 1668 ppm but not for females (Table 1).

TABLE 1. Body weights of rats acutely exposed to vapor from DMEA
Sex	Exposure Concentration (ppm)	Body Weight (g) as Mean ±SD^a
		Pre-exposure	7 Days	14 Days
Male	3311	283 ± 5	198	228
	2408	259 ± 11	162	175
	1668	258 ± 12	218 ± 41	281 ± 57
Female	3311	253 ± 5	117 ± 17	192
	2408	241 ± 6	165 ± 1	168 ± 31
	1668	246 ± 8	176 ± 33	189
^aValues without SD are for only one survivor.

Mortalities for the various exposure concentrations are shown in Table 2. These data allowed the calculation of a combined-sex 4-h LC 50 of 1641 ppm (95% confidence limit 862-3125 ppm). Times to death ranged 1 to 12 d postexposure with, in general, the shorter times to death occurring with the higher concentration (Table 2). There were no deaths during exposure. Necropsy of animals that died revealed dark red lungs, liver and kidneys. Sacrificed survivors did not show any gross pathology.

TABLE 2. Mortality data for rats acutely exposed for 4-hr to DMEA vapor.
Exposure Concentration (ppm)	Sex	Mortality^a	Deaths at Postexposure Day
			1	2	3	4-6	7-9	10-12
3311	M	4/5	0	4	0	0	0	0
	F	4/5	1	0	0	1	1	1
2408	M	4/5	2	0	1	1	0	0
	F	3/5	0	1	1	1	0	0
1668	M	2/5	0	1	0	0	0	1
	F	3/5	0	0	0	0	1	2
^aExpressed as (Number Dying)/(Number Exposed).

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The signs seen during this study were principally those of irritation to the eye and respiratory tract. After 4 h exposure to 1668 ppm of DMEA, 2 of 5 male rats and 3 of 5 female rats died within 12 days. Thus, it is appropriate that respiratory protective equipment be worn if it is anticipated that overexposure to the vapor could occur.

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 ,-dimethyIisopropanolarnine (DMIPA), N-methyldiethanoIamine (MDEA), and tert-butyldiethanolamine (BDEA).

Exposure to a saturated vapor from DMEA (vapor pressure 4.0 torr) for 8 h did not produce any mortalities. However, in a 4-h LC50 study it was possible to determine an LC50 of 1641 ppm. The difference between the 2 studies most probably reflects the mode of exposure. In the static study, equilibration of the atmosphere was overnight, and it is possible that losses of vapor may have occurred from adsorption of material onto the chamber walls. In contrast, in the LC50 study vapor was generated dynamically and continually transferred to the exposure chamber, The signs seen during this study were principally those of irritation to the eye and respiratory tract.

Irritant effects may develop from exposure to vapors from DMEA.

Cross-reference 5

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

other information

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 403 (Acute Inhalation Toxicity)

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

Test type:

other: Acute Inhalation Toxicity (OECD 403)

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Route of administration:

inhalation: vapour

Type of inhalation exposure:

not specified

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

8 h

Concentrations:

saturated vapour

No. of animals per sex per dose:

5

Control animals:

not specified

Sex:

male

Dose descriptor:

other: not identified

Exp. duration:

8 h

Remarks on result:

other: no effects

Interpretation of results:

not classified

Remarks:

An additional study was conducted (see 7.2.2.Acute toxicity inhalation: Ballantyne and Leung, 1996 -Key study) Criteria used for interpretation of results: not specified

Conclusions:

A 8-h exposure to a saturated vapor did not produce any mortalities or significant signs of toxicity.

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,-dime-thylethanolamine (DMEA), N, N ,-dimethylisopropanolamine (DMIPA), N-methyldiethanolamine (MDEA), and tert-butyldiethanolamine (BDEA).

Due to high vapor pressure, the acute vapor exposure toxicity of the DMEA was determined in an additional 4 -h LC50 study (see 7.2.2. Acute toxicity inhalation: Ballantyne and Leung, 1996 -Key study)

Cross-reference 6

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

supporting 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 404 (Acute Dermal 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

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Duration of treatment / exposure:

3 min, 1h and 4h

Observation period:

up to 21d

Number of animals:

no data

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: 1h-14d

Score:

0 - 4

Max. score:

4

Reversibility:

no data

Remarks on result:

other: clear relationship between time of contact and the degree of injury

Irritation parameter:

other: corrosion

Basis:

mean

Time point:

other: 1h

Score:

1.2 - 1.5

Max. score:

1.5

Reversibility:

no data

Remarks on result:

other: full-thickness necrosis, ecchymoses

Other effects:

see Table 1 in "Remarks on results"

TABLE 1. Local effects produced by occluded epicutaneous application of 0,5 mL of DMEA to the shaven dorsal trunk skin of rabbits.
Effect	Material	Contact Time	Average Score at Inspection Time
			1 hr	1 day	2 days	3 days	7 days	14 days	21 days
Erythema	DMEA	4hr	3.5	4.0	3.2	2.7	1.0	0.5	—
		1 hr^a	1.5	2.3	2.0	—	—	—	—
		3 min	0.2	0.2	0.2	0.2	0.0	0.0	—
Edema	DMEA	4 hr	4.0	3.8	2.8	2.0	1.3	0.8	—
		1 hr^a	1.2	2.5	2.0	—	—	—	—
		3 min	0.0	0.0	0.0	0.0	0.0	0.0	—
Other^b	DMEA	4hr	N	NU	NSU	NS	NS	NS	—
		1 hr^a	NE	NUS	NUS	—	—	—	—
		3 min	E	—	—	—	nD	D	—
^aAnimals sacrificed for humane reasons. ^bEffects noted: n = superficial necrosis; N = full-thickness necrosis; E = ecchymoses; S = scab formation; U = ulceration; D = desquamation. ^cScored according to the system given in the text (maximum =4).

DMEA produced moderate to marked erythema and edema which only slowly resolved and, with 4-h contact, was still present at the end of the observation period. DMEA was skin corrosive as shown by the presence of full-thickness necrosis, with all producing necrosis by a 1-h contact. There was no corrosive effects observed by 3-min contact.

Interpretation of results:

Category 1B (corrosive)

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

By skin contact DMEA was irritant and corrosive by 1-h contact.

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 ,-dimethyIisopropanolarnine (DMIPA), N-methyldiethanoIamine (MDEA), and tert-butyldiethanolamine (BDEA).

All alkylalkanolamines studied, except MDEA, were moderately to markedly irritating and caused variable degrees of skin corrosivity.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1996

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

2-dimethylaminoethanol

EC Number:

203-542-8

EC Name:

2-dimethylaminoethanol

Cas Number:

108-01-0

Molecular formula:

C4H11NO

IUPAC Name:

2-(dimethylamino)ethanol

Details on test material:

- Name of test material (as cited in study report): DMEA (N,N,-dimethylethanolamine)

- Substance type: organic
- Physical state: liquid
- Analytical purity: not reported

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Test system

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

Results and discussion

In vivo

Results

Results 1

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)

Results 2

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.

Results 3

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)

Results 4

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)

Results 5

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.

Results 6

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)

Results 7

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.

Results 8

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not measured/tested

Remarks:

No information on chemosis provided.

Results 9

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

Results 10

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

Results 11

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

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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.