2-[2-(dimethylamino)ethoxy]ethanol

Endpoint summary

Description of key information

Oral (OECD Guideline 401), Dermal (OECD Guideline 402) and Inhalation (OECD Guideline 403) tests were conducted on DMEE. Toxicity in the oral gavage study was dose dependent for males and females with an LC50 of 2150 - 3830 mg/kg bw. Toxicity in the dermal study was also dose dependent and the observed LD50 was 1.74 mL/kg bw for males and 2.14 mL/kg bw for females. The potential LC50 for male and female rats exposed to the test substance for 4 hours via the inhalation route is > 72 ppm, which was the maximum concentration tested.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Experimental: 10 Apr 1987 - 25 June 1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to OECD guideline study. Acceptable, well documented report which meets basic scientific principles.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

(adopted 1981)

Deviations:

yes

Remarks:

A test group consisting of 5 animals was treated by single gavage application with an aqueous solution of the test substance.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Germany
- Weight at study initiation: male: 187 g (mean); female: 177 g (mean)
- Fasting period before study: 16 h before administration but water was available ad libitum
- Housing: 5 animals per cage
- Diet: KLIBA-Labordiaet 343, Klingentalmuehle AG, CH, ad libitum
- Water: tap water ad libitum
- Acclimation period: at least 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 °C
- Humidity (%): 30 - 70 %
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

0.5 % aqueous CMC

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 50, 38.3, 21.5, and 10.0 % (w/v), respectively, for 5000, 3830, 2150, and 1000 mg/kg bw doses
- Amount of vehicle (if gavage): 10 mL/kg bw

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

Doses:

1000, 2150, 3830 and 5000 mg/kg bw

No. of animals per sex per dose:

5 animals/sex/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: recording of signs and symptoms several times on the day of administration, at least once each workday. Check for moribund and dead animals twice each workday and once on holidays.
- Frequency of weighing: days 0, 5, 7, 13
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 2 150 - <= 3 830 mg/kg bw

Based on:

test mat.

Sex:

male

Dose descriptor:

LD50

Effect level:

>= 2 150 - <= 3 830 mg/kg bw

Based on:

test mat.

Sex:

female

Dose descriptor:

LD50

Effect level:

ca. 2 150 mg/kg bw

Based on:

test mat.

Mortality:

See details in "remarks on results".

Clinical signs:

other: See details in "remarks on results".

Gross pathology:

- Animals that died:
General congestion.
Stomach/small intestines: mucosa reddened, bloody contents.

- Sacrificed animals:
No pathologic findings noted.

Mortality:

Dose (mg/kg bw)	Conc.	Gender	1 h	24 h	48 h	day 7	day 14
5000	50	male	0/5	5/5	5/5	5/5	5/5
5000	50	female	0/5	5/5	5/5	5/5	5/5
3830	38.3	male	0/5	5/5	5/5	5/5	5/5
3830	38.3	female	0/5	5/5	5/5	5/5	5/5
2150	21.5	male	0/5	0/5	0/5	0/5	0/5
2150	21.5	female	0/5	2/5	2/5	2/5	2/5
1000	10	male	0/5	0/5	0/5	0/5	0/5
1000	10	female	0/5	0/5	0/5	0/5	0/5

Weight (g):

Dose (mg/kg bw)	Gender	day 0	day 5	day 7	day 13
5000	male	92	-	-	-
5000	female	179	-	-	-
3830	male	186	-	-	-
3830	female	172	-	-	-
2150	male	179	-	238	272
2150	female	179	-	197	215
1000	male	189	244	-	291
1000	female	180	205	-	217

Clinical signs:

Dose (mg/kg bw)	5000		3830		2150		1000
	male	female	male	female	male	female	male	female
Dyspnea	1 h - 4 h	1 h - 4 h	30 m - 5 h	30 m - 5 h	1 d - 2 d	4 h - 2 d	-	-
Apathy	1 h - 4 h	1 h - 4 h	30 m - 5 h	30 m - 5 h	1 d - 2 d	4 h - 2 d	-	-
Abnormal position	4 h	4 h	-	4 h - 5 h	-	-	-	-
Staggering	4 h	4 h	30 m - 5 h	30 m - 1 h	-	1 d - 2 d	-	-
Atonia	4 h	4 h	-	4 h - 5 h	-	-	-	-
Paresis	4 h	4 h	-	4 h - 5 h	-	-	-	-
Piloerection	1 h - 4 h	1 h - 4 h	30 m - 5 h	30 m - 5 h	1 d - 2 d	4 h - 2 d	-	-
Cyanosis	4 h	4 h	4 h - 5 h	4 h - 5 h	-	-	-	-
Exsiccosis	4 h	4 h	-	4 h- 5 h	-	-	-	-
Salivation	4 h	4 h	-	-	-	-	-	-
Poor general state	1 h - 4 h	1 h - 4 h	30 m - 5 h	30 m - 5 h	1 d - 2 d	4 h - 2 d	-	-

min: minutes

h: hour

d: day

The test substance caused systemic toxicity (including mortality) in a dose dependent manner.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 150 mg/kg bw

Quality of whole database:

One reliable acute oral toxicity study is available for DMEE (CAS# 1704-62-7).

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1987-04-13 to 1989-08-10

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study following internal Laboratory standards and protocols that are equivalent to OECD Guideline 403.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Principles of method if other than guideline:

The study followed a specific protocol (87-15-04-AI-A) and standard protocol amendment.

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Sprague-Dawley, Inc., Indianapolis, IN)
- Age at study initiation: 45 d (Static), 46 d (Dynamic bubbler), 51 d (Dynamic evaporator)
- Weight at study initiation: 174 g (Static mean weight- Male), 150 g (Static mean weight- Female), 186 g (Dynamic bubbler mean weight- Male), 152 g (Dynamic bubbler mean weight- Female), 210 g (Dynamic evaporator Mean weight- Male), 165 g (Dynamic evaporator Mean weight- Female)
- Fasting period before study: None
- Housing: Housed five per sex in 23.5 X 40 X 18 cm stainless steel wire-mesh cages on carriers
- Diet (e.g. ad libitum): Pelletted feed (Pro Lab RMH#3000, Agway, Inc.); ad libitum except during exposure
- Water (e.g. ad libitum): Tap water (Municipal Authority of Westmoreland County, Greenburg, PA); ad libitum except during exposure
- Acclimation period: yes, 2 days for static, 3 days for dyanmic bubbler, and 8 days for dynamic evaporator; the Study Director opinion was that the lower than 5-day acclimation period for the first two tests did not alter the interpretation of results.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 deg C
- Humidity (%): N/A
- Air changes (per hr): N/A
- Photoperiod (hrs dark / hrs light): 12-hr photoperiod throughout the entire study

IN-LIFE DATES: From: April 10 To: April 27 (Static), April 28 (Dynamic bubbler), May 3 (Dynamic evaporator).

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Static and dynamic bubbler exposures were in plexiglass and stainless steel chambers and the dynamic evaporator exposures were in glass and stainless steel chamber
- Exposure chamber volume: approximately 120 liters (static and dynamic bubbler exposures); 900 liters (dynamic evaporator exposures)
- Method of holding animals in test chamber: 5 per sex free to move in 26x18.5x18 cm wire-mesh cages for the static and dynamic bubbler exposure chambers; individually housed in 21x12.5x18 cm wire-mesh cages, free to move in the dynamic evaporator exposure chambers.
- Source and rate of air:
(A) For the static exposure, the test substance (120 grams untreated) was placed in an open tray at the top of the sealed 120-liter chamber and the vapor was allowed to achieve equilibration (17 hours). The animals were then placed into the chamber for a 4 hour exposure period.
(B) For the dynamic bubbler exposure, compressed air was passed through a 250 mL gas washing bottle containing approximately 59 grams of test substance. The air containing the test substance vapor entered directly into the exposure chamber at a rate of 30 L/min.
(C) For the dynamic evaporator exposure, the test substance was metered with a piston pump (Fluid Metering Inc., Oyster Bay, NY) into a heated evaporator. The resulting vapor mixture was carried to the chamber by a countercurrent air stream that entered the bottom of the evaporator at a rate of 200 L/min.
- Method of conditioning air: N/A
- System of generating particulates/aerosols: N/A
- Method of particle size determination: N/A
- Treatment of exhaust air: N/A
- Temperature, humidity, pressure in air chamber:
Static: 25 +/- 1 deg C, 77 +/- 23% % relative humidity
Dynamic bubble: 24 +/- 0 deg C, 37 +/- 2% relative humidity
Dynamic evaporator: 24 +/- 0 deg C, 43 +/- 2% relative humidity

TEST ATMOSPHERE
- Brief description of analytical method used: The concentration of test substance in the exposure chamber atmosphere was determined for the dynamic and static exposures by sampling with XAD-2 sorbent tubes. The samples were desorbed and then analyzed by flame ionization gas chromatograpy.
- Samples taken from breathing zone: no

VEHICLE
- Composition of vehicle (if applicable): N/A
- Concentration of test material in vehicle (if applicable): N/A
- Justification of choice of vehicle: N/A
- Lot/batch no. (if required): N/A
- Purity: N/A

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: N/A

CLASS METHOD (if applicable)
Rationale for the selection of the starting concentration: The target concentration for both the static and dynamic exposures was the highest attainable vapor concentrations of the test substance without visual observation of an aerosol (saturated vapor).

Analytical verification of test atmosphere concentrations:

yes

Remarks:

The concentration of test substance in the exposure chamber atmosphere was determined for the dynamic and static exposures by sampling with XAD-2 sorbent tubes. The samples were desorbed and then analyzed by flame ionization gas chromatograpy.

Duration of exposure:

4 h

Concentrations:

Static: Mean 15 ppm, standard deviation +/- 8.11 ppm
Dynamic bubbler: Mean 72 ppm, standard deviation +/- 11.6 ppm
Dynamic evaporator: Mean 63 ppm, standard deviation +/- 3.4 ppm

No. of animals per sex per dose:

5 per sex per type of exposure (static, dynamic bubbler, or dynamic evaporator)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for signs of toxic effects on the day of exposure and daily following exposure for 14 days. The animals were weighed prior to exposure and on postexposure Days 7 and 14. The change in body weight was calculated by subtracting the pre-exposure value from each successive weight.
- Necropsy of survivors performed: Yes, a complete necropsy was performed for all animals. The survivors were anesthetized with methoxyflurane and killed by exsanguination via the branchial blood vessels. The lungs and liver for the female rat which died (static exposure) were extracted and fixed in 10% neutral buffered formalin.
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: N/A

Statistics:

The mean and standard deviation of the body weights and body weight changes of the animals and the exposure concentrations, temperature, relative humidity and oxygen were calculated. No statistical comparisons were made.

Preliminary study:

N/A

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 72 ppm

Based on:

test mat.

Remarks:

generated by dynamic bubbler

Exp. duration:

4 h

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 68 ppm

Based on:

test mat.

Remarks:

generated by dynamic evaporator

Mortality:

One delayed mortality was observed for female rats on postexposure Day 1. No other mortalities occurred during the study.

Clinical signs:

other: Static and dynamic bubbler: No clinical signs of toxicity were observed on the day of exposure or during the 14-day postexposure observation period. Dynamic evaporator: Blepharospasm and periocular wetness were the only clinical signs of toxicity observed

Body weight:

Mean body weight gain was observed for both sexes on postexposure Days 7 and 14.

Gross pathology:

Macroscopic lesions were not observed in animals sacrificed at the end of the 2-week postexposure period. The only macroscopic lesions observed was a dark red (mottled) discoloration of the lungs and liver, noted only in the rat which died.

Other findings:

N/A

The potential LC50 for male and female rats exposed to the test substance for 4 hours is > 72 ppm, which was the highest exposure concentration, obtained in the dynamic bubbler chamber.

For the static exposure, a decrease in concentration was observed with exposure time as the relative humidity rose during the exposure period. The decrease in concentration may be attributed to interaction of the test material with water (relative humidity), as the test substance is highly soluble in water. Similar interaction with water may have occurred during the dynamic exposures, as indicated by the low actual/nominal ratios of 0.42 and 0.66 for the test substance for the dynamic bubbler and dynamic evaporator exposures, respectively.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: not specified

Conclusions:

LC50 for male and female rats during the 4 hour exposure was > 72 ppm.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

392.2 mg/m³ air

Quality of whole database:

One reliable acute oral toxicity study is available for DMEE (CAS# 1704-62-7).

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Unspecified to 1986-08-25

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study report without statement of guideline used for study or certification of following GLP; however, the methodology provided was equivalent to OECD 402.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

Clinical observations were made before dose (0 days) and at 7 and 14 days instead of daily.

Principles of method if other than guideline:

N/A

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: between 2.0 and 3.0 kg

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: Trunk
- % coverage: N/A
- Type of wrap if used: Vetrap Bandaging Tape wrapped over the impervious sheeting of the intact, clipped skin

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Excess fluid removed to diminish ingestion
- Time after start of exposure: 24 hrs

Duration of exposure:

24 hrs

Doses:

Males: 0.50, 1.00, 1.41, and 2.00 mL/kg (the last dose was inferred by reviewer from lower doses and LD50; first number is erased in study's table).
Females: 0.50, 1.00, 2.00 (this dose inferred by reviewer from other doses and LD50; first number is erased in study's table), and 4.00 mL/kg.

No. of animals per sex per dose:

5 males and 5 females were included on each level for the LD50 calculation.

Control animals:

yes, concurrent no treatment

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: weighing at 0 days (before dose), 7 days and 14 days (just prior to sacrifice).
- Necropsy of survivors performed: yes

Statistics:

Moving average method (Thompson, 1947 (reference in OECD 402); Weil, 1983).

Preliminary study:

N/A

Sex:

male

Dose descriptor:

LD50

Effect level:

1.74 mL/kg bw

Based on:

test mat.

95% CL:

1.5 - 2.01

Remarks on result:

other: Using the density for DMEE of 0.95 g/mL to convert to mg/kg bw resulted in a LD50 value of 1663 mg/kg bw.

Sex:

female

Dose descriptor:

LD50

Effect level:

2.14 mL/kg bw

Based on:

test mat.

95% CL:

1.45 - 3.17

Remarks on result:

other: Using the density for DMEE of 0.95 g/mL to convert to mg/kg bw resulted in a LD50 value of 2033 mg/kg bw.

Mortality:

Time of death ranged from 1 to 4 days.
- Males: 4/5 of the 2.00 mL/kg group died, 0/5 of the 1.41 mL/kg group, 0/5 of the 1.00 mL/kg group, 0/5 of the 0.50 group.
- Females: 5/5 of the 4.00 mL/kg group, 2/5 of the 2.00 mL/kg group.

Clinical signs:

other: Local dermal effects included: erythema, edema, necrosis, ecchymosis, fissuring, ulceration, desquamation and scabs. Dermal reactions persisted through 14 days. Salvation, sluggishness, unsteady gait, red discharge (from nose and mouth), tremors (in 2) an

Gross pathology:

Gross pathology findings included red and mottled lungs, red tracheas, a few discolored livers and kidneys, and subcutaneous edema.

Other findings:

N/A

The author of the study concluded that DMEE was moderately toxic following its administration by single dermal application. The criteria used for interpretation of results is listed above under "Any other information on materials and methods incl. tables".

Conclusions:

The LD50 for percutaneous exposure to male rabbits was 1.74 mL/kg (1663 mg/kg bw) and to female rabbits was 2.14 mL/kg (2033 mg/kg bw). Severe skin irritation was apparent on each rabbit through death or sacrifice at 14 days.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 663 mg/kg bw

Quality of whole database:

One reliable acute oral toxicity study is available for DMEE (CAS# 1704-62-7).

Additional information

Justification for selection of acute toxicity – oral endpoint
An oral LD50 study in Wistar rats was conducted equivalent to OECD 401 without deviations and thus was chosen as the key study. Five male and five female rats per dose group (1000, 2150, 3830 and 5000 mg/kg bw) were dosed via oral gavage. The rats were observed over a 14-day period. LD50 results were reported to be 2150 - 3830 mg/kg bw in males; ca. 2150 mg/kg bw in females; and 2150 - 3830 mg/kg bw in males/females. Clinical findings were noted in all dose groups except the low dose (1000 mg/kg bw). Dyspnea, apathy, staggering and piloerection were reported in the 5000, 3830 and 2150 mg/kg bw dose groups. Abnormal position, atonia, paresis, cyanosis, exsiccosis and salivation were reported in the two high-dose groups (5000 and 3830 mg/kg bw). In the animals that died, gross pathology revealed general congestion and maddened mucosa and bloody contents in the stomach/small intestine. No pathologic findings were noted in the animals sacrificed following the 14-day observation period.

Justification for selection of acute toxicity – inhalation endpoint
The key study was chosen due to it being a recent, Klimisch 1-rated study conducted equivalent to OECD 403 and following GLP. In this study, Sprague Dawley rats (5/sex/dose) were exposed whole body to either a 72 ppm (Dynamic bubbler) or a 63 ppm (Dynamic evaporator) vapour concentration of DMEE for four hours. The rats were observed for 14 days post-exposure. No clinical signs of toxicity were observed on the day of exposure or during the 14-day post-exposure observation period for the dynamic bubbler group. Blepharospasm and periocular wetness were the only clinical signs of toxicity observed during the 4-hour exposure period in the dynamic evaporator group. No clinical signs of toxicity were observed for both sexes following exposure or during the 14-day post-exposure observation period. Macroscopic lesions were not observed in animals sacrificed at the end of the 14-day post-exposure period. The only macroscopic lesions observed was a dark red (mottled) discoloration of the lungs and liver, noted only in the one rat which died during the study. The four hour vapour inhalation LC50 for DMEE in male and female rats was >72 ppm (0.39 mg/L) under the conditions of this study.

Justification for selection of acute toxicity – dermal endpoint
The key study is a well-documented study following methods equivalent to OECD Guideline 402 (Acute Dermal Toxicity). New Zealand White rabbits (5/sex/dose) were exposed dermally under occluded conditions for 24-hours to varying doses of undiluted DMEE (0.50, 1.00, 1.41, and 200 mL/kg in males and 0.500, 1.00, 2.00, and 4.00 ml/kg in females). Local dermal effects included: erythema, edema, necrosis, ecchymosis, fissuring, ulceration, desquamation and scabs. Dermal reactions persisted through 14 days. Salvation, sluggishness, unsteady gait, red discharge (from nose and mouth), tremors (in 2) and prostration were among the signs of toxicity observed. No signs of toxicity were observed in the groups exposed to 1.00 mL/kg (males) and 0.50 mL/kg (males and females). Gross pathology findings included red and mottled lungs, red tracheas, a few discolored livers and kidneys, and subcutaneous edema. The LD50 in males was reported to be 1.74 mL/kg bw and in females was 2.14 mL/kg bw. Using the density for DMEE of 0.95 g/mL (OECD guideline 109) to convert to mg/kg bw resulted in LD50 values of 1663 mg/kg bw and 2033 mg/kg bw in males and females, respectively.

Justification for classification or non-classification

Based on acute toxicity results, the suggested classification for 2-[2-(dimethylamino)ethoxy]ethanol according to EU Regulation 1272/2008 is acute dermal category 4.