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Acute Toxicity: inhalation

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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
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
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.

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.

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)

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 hra

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 hra

1.2

2.5

2.0

3 min

0.0

0.0

0.0

0.0

0.0

0.0

Otherb

DMEA

4hr

N

NU

NSU

NS

NS

NS

1 hra

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.

Reason / purpose for cross-reference:
reference to same study
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.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1996

Materials and methods

Test guideline
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

Test material

Constituent 1
Chemical structure
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

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

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

Results and discussion

Effect levels
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

Any other information on results incl. tables

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 ±SDa

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

Mortalitya

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).

Applicant's summary and conclusion

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.

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