Carbonic acid, compound with 2-aminoethanol (1:2)

Endpoint summary

Description of key information

No acute toxicity studies have been identified on the registered substance. However, read across to the minor constituent and analogue substance, monoethanolamine is justified (see read across justification attached in IUCLID Section 13). These data indicate that the substance is expected to be acutely toxic if ingested, but not via dermal or inhalation routes of exposure.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to a guideline study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH

The target substance carbonic acid, compound with 2-aminoethanol (1:2) is formed from the reaction of 2-aminoethanol and carbon dioxide, at a 2:1 molar ratio. The hypothesis of the analogue approach is that the systemic toxicity of the target substance will be determined by the fact that in aqueous conditions of a mammalian system, it rapidly degrades to 2-aminoethanol, and therefore reading across to 2-aminoethanol provides a reasonable worst-case scenario.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

Source substance: 2-aminoethanol
Target substance: carbonic acid, compound with 2-aminoethanol (1:2)

For further information on purity and impurities please see the full read across justification attached in Section 13 of IUCLID.

3. ANALOGUE APPROACH JUSTIFICATION

The target substance is expected to break down to form the source substance in mammalian systems; both target and source substances would be expected to have the same mechanism of action and therefore similar systemic toxicity. The target substance is essentially a neutralised form of the source substance. Therefore, the target substance would not be expected to display the topical irritancy and/or corrosive properties of the source substance. However, for systemic effects read across is appropriate as the target substance will degrade rapidly to produce the source substance under physiological conditions.

For a full justification of the read across approach see the read across justification attached in Section 13 IUCLID.

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

substance purity not given

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 200-300g
- Fasting period before study: over night

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

0.25, 0.50, 1.0, 2.0, 4.0 ml/kg bw (based on a density of 1.018 g/ml: 254, 509, 1018, 2036, 4072 mg/kg bw)

No. of animals per sex per dose:

5 males and 5 females (0.25-2.0 ml/kg dosing groups)
2 males (4.0 ml/kg dosing group)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: daily
- Frequency of weighing: on day 0, 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights

Statistics:

LD50 values and the estimated LD50 slopes were calculated by the moving average method (Thompson 1947; Weil 1983).

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 089 mg/kg bw

Remarks on result:

other: based on a density of 1.018 g/ml

Sex:

male

Dose descriptor:

LD50

Effect level:

1.19 mL/kg bw

95% CL:

0.79 - 1.8

Sex:

female

Dose descriptor:

LD50

Effect level:

1.07 mL/kg bw

95% CL:

0.72 - 1.59

Mortality:

Dose (ml/kg) Numbers of Animals Dead Time of Death
(M,F)
0.25 0,0 N/A
0.50 1,0 12 days
1.0 1,2 1 or 2 days
2.0 5,5 4 hrs to 1 day
4.0 2 (M) 3 hrs

All deaths occurred relatively rapidly after dosing (within 2 days), except for one male rat that died after 12 days after a dose of 0.5 ml/kg. Both of the male rats receiving monoethanolamine at the maximum peroral dosage of 4.0 ml/kg died after 3 hours. One female in the 2.00 ml/kg group died after 4 hours.

Clinical signs:

MALES
Dosage (ml/kg) Signs of Toxicity
4.00 sluggishness at 15 min; slight piloerection at 1 hr. death at 3 hr.
2.00 sluggishness at 1.5 hr; slight piloerection at 2 hr.
1.00 slight red crust on perinasal fur, slight red crust on periocular fur (of 2); slight brown stain on periurogenital fur (of 1) at 1 day. Affected survivors recovered at 2 days.
0.50 one animal with slight sluggishness at 30 min, red crust at perinasal fur at 1 day; pallor, slight emaciation at 11 days; kyphosis, u nkempt appearance, red crust on periocular fur at 12 days (death).
0.25 none noted

FEMALES
Dosage (ml/kg) Signs of Toxicity
2.00 marked sluggishness at 15 min; piloerection, slight kyphosis, lacrimation at 3 hr; unsteady gait, marked sluggishness and lacri mation at 4 hr; death of one at 4 hr.
1.00 sluggishness at 1.0 hr; piloerection, slight lacrimation at 4 hr; red crust on perinasal fur, red crust on periocular fur, slight wetne ss of periurogenital fur (in 2)* at 1 day (*the presence of occult blood in discharge was verified by use of Hemastix Reagent Strips [Ames]); emaciation of 2 at 6 days, persisting through 14 days; recovery of 1 survivor at 2 days.
0.50 sluggishness, slight lacrimation at 4.0 hr; red crust on perinasal and periocular fur at 2 days; emaciation in 1 at 6 days, persisting through 14 days; recovery of 4 at 2 days.
0.25 none noted

Body weight:

Nothing abnormal reported.

Gross pathology:

MALES
Dosage (ml/kg) Gross Pathology
4.00 lungs pale red; stomachs, intestines dark red.
2.00 lungs of 1 mottled light and dark red; stomachs, intestines distended, filled with dark red liquid.
1.00 in deceased, stomach, intestines red; stomach filled with clear red liquid; in survivors, kidneys mottled dark red.
0.50 in deceased, stomach severely distended, filled with brown liquid; emaciation; in survivors, nothing remarkable.
0.25 nothing remarkable

FEMALES
Dosage (ml/kg) Gross Pathology
2.00 lungs mottled or bright red; stomachs, intestines dark red, filled with red liquid.
1.00 in deceased, glandular portion of stomachs dark red; in survivors, livers of 2 adhered to glandular portion of stomachs ; stomachs distended with gas; kidneys dark red.
0.50 liver of 1 adhered to glandular portion of stomach; stomach of 1 distended with gas; kidneys of 1 dark red.
0.25 nothing remarkable

The LD50 values (with confidence limits if calculated) in males and females were 1.19 (0.79 - 1.80) ml/kg and 1.07 (0.72 - 1.59) ml/kg, respectively. The slopes of the curves were 3.84 and 4.96 for males and females, respectively.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 089 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given. Substance concentration was not measured.

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH

The target substance carbonic acid, compound with 2-aminoethanol (1:2) is formed from the reaction of 2-aminoethanol and carbon dioxide, at a 2:1 molar ratio. The hypothesis of the analogue approach is that the systemic toxicity of the target substance will be determined by the fact that in aqueous conditions of a mammalian system, it rapidly degrades to 2-aminoethanol, and therefore reading across to 2-aminoethanol provides a reasonable worst-case scenario.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

Source substance: 2-aminoethanol
Target substance: carbonic acid, compound with 2-aminoethanol (1:2)

For further information on purity and impurities please see the full read across justification attached in Section 13 of IUCLID.

3. ANALOGUE APPROACH JUSTIFICATION

The target substance is expected to break down to form the source substance in mammalian systems; both target and source substances would be expected to have the same mechanism of action and therefore similar systemic toxicity. The target substance is essentially a neutralised form of the source substance. Therefore, the target substance would not be expected to display the topical irritancy and/or corrosive properties of the source substance. However, for systemic effects read across is appropriate as the target substance will degrade rapidly to produce the source substance under physiological conditions.

For a full justification of the read across approach see the read across justification attached in Section 13 IUCLID.

Reason / purpose for cross-reference:

read-across source

Qualifier:

no guideline followed

Principles of method if other than guideline:

Five animals per sex were exposed to substantially saturated vapor for 6 hours using a static exposure system.

GLP compliance:

no

Test type:

other: inhalation risk test

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 200 - 300 g
- Fasting period before study: none
- Diet: commercial appropriate diet ad libitum
- Water: municipal water ad libitum

Route of administration:

inhalation: vapour

Type of inhalation exposure:

not specified

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
The vapor was produced by enclosing approximately 100 g of the test material in a sealed 100 to 151 liter animal chamber for approximately 18 hours under static conditions. A mixing fan periodically agitated the chamber atmosphere to aid in distribution of the vapour. Oxygen was added, as needed to maintain a chamber oxygen content of approximately 20%. The temperature was maintained at 25 degrees C.

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

6 h

No. of animals per sex per dose:

5 males, 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of weighing: day 0, 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Sex:

male/female

Dose descriptor:

LC0

Effect level:

ca. 1.3 mg/L air

Exp. duration:

6 h

Remarks on result:

other: Value derived from theoretical saturated vapor concentrations of monoethanolamine at room temperature and was not measured during the experiment.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 1.3 mg/L air

Exp. duration:

6 h

Mortality:

There were no deaths noted for males or females exposed to the highest concentration achievable for 6 hours.

Clinical signs:

other: There were no signs of toxicity noted for males or females exposed to the highest concentration achievable for 6 hours.

Body weight:

Nothing abnormal reported.

Gross pathology:

The necropsy findings noted nothing remarkable in males or females.

The theoretical saturated vapor concentration of monoethanolamine at room temperature is 520 ppm (1.3 mg/l). The LC50 is greater than 520 ppm (Reviews of Environmental Contamination and Toxicology, Vol. 149, 1997.)

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

1 300 mg/m³

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to a guideline study Restriction: purity of the test material was not noted.

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH

The target substance carbonic acid, compound with 2-aminoethanol (1:2) is formed from the reaction of 2-aminoethanol and carbon dioxide, at a 2:1 molar ratio. The hypothesis of the analogue approach is that the systemic toxicity of the target substance will be determined by the fact that in aqueous conditions of a mammalian system, it rapidly degrades to 2-aminoethanol, and therefore reading across to 2-aminoethanol provides a reasonable worst-case scenario.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

Source substance: 2-aminoethanol
Target substance: carbonic acid, compound with 2-aminoethanol (1:2)

For further information on purity and impurities please see the full read across justification attached in Section 13 of IUCLID.

3. ANALOGUE APPROACH JUSTIFICATION

The target substance is expected to break down to form the source substance in mammalian systems; both target and source substances would be expected to have the same mechanism of action and therefore similar systemic toxicity. The target substance is essentially a neutralised form of the source substance. Therefore, the target substance would not be expected to display the topical irritancy and/or corrosive properties of the source substance. However, for systemic effects read across is appropriate as the target substance will degrade rapidly to produce the source substance under physiological conditions.

For a full justification of the read across approach see the read across justification attached in Section 13 IUCLID.

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Duration of exposure:

24 hours

Doses:

1.0, 2.0 or 4.0 ml/kg

No. of animals per sex per dose:

5 animals

Control animals:

no

Details on study design:

Groups of five animals per sex (2-3 kg) were subjected to 24 hours of contact with monoethanolamine (1.0, 2.0, or 4.0 ml/kg) which was retained under impervious sheeting on the clipped, intact skin of the trunk. As necessary for larger doses, gauze was wrapped around the trunk over the sample to prevent leakage. Vetrap Bandaging Tape was wrapped over the impervious sheeting and the animal was returned to its cage for the contact period. Doses were varied by adjusting the volume of the test material. After the contact period, excess fluid was removed to diminish ingestion. Observations for toxicity and skin reactions were made at one hour, 7 days, and 14 days after the contact period. Animal weights were recorded at 0 days (before dose), 7 days and 14 days (just prior to termination). LD50 values and the estimated LD50 slopes were calculated by the moving average method (Thompson, 1947; Weil, 1983) and are based on a 14-day observation period. At death or termination, each animal was subjected to a gross pathologic evaluation.

Preliminary study:

The LD50 value for males was 2.46 ml/kg (2504 mg/kg) with a 95% confidence level of 1.79 - 3.39 ml/kg (1822 - 3451 mg/kg) and a slope of 5.60. The LD50 value for females was 2.83 ml/kg (2881 mg/kg) with a 95% confidence level of 1.61 - 4.98 ml/kg (1639 - 5070 mg/kg) and a slope of 3.89.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 2.46 - <= 2.83 mL/kg bw

Sex:

male

Dose descriptor:

LD50

Effect level:

2 504 mg/kg bw

95% CL:

1 822 - 3 451

Sex:

female

Dose descriptor:

LD50

Effect level:

2 881 mg/kg bw

95% CL:

1 639 - 5 070

Mortality:

The numbers of deaths at each dose were as follows:

Dose (ml/kg) Numbers of Animals Dead Time of Death
(M/F)
4.0 5,4 1-2 days
2.0 1,1 2, 13 days
2.0 0,0 N/A

Deaths occurred within two days, except for one female that died at 13 days.

Clinical signs:

MALES
4.00 ml/kg dosing group:
erythema, edema, necrosis, ecchymosis at 1day; prostration in 1 animal at 1 day.
2.00 ml/kg dosing group:
erythema, edema at 1 to 7 days or death; necrosis at 1 to 14 days or death; ecchymosis at 1 day, persisting on 1 to ulceration at 7 or 14 days; desquamation, alopecia on 1 at 14 days; scabs at 14 days; sluggishness at 1 day or at 7 days; emaciation of 1 at 7 days; recovery of 2 survivors after 2 days.

1.00 ml/kg dosing group:
erythema at 1 day; persisting on 1 through 7 days; edema at 1 to 7 days; ecchymosis on 1 at 1 day; necrosis at 1 to 14 days; scabs, ulceration at 7 to 14 days. No signs of systemic toxicity.

FEMALES
4.00 ml/kg dosing group:
erythema, edema, ecchymosis at 1 day to death; necrosis at 1 day to death, persisting on 1 through 14 days; scabs, ulcerations on 1 at 7 to 14 days; sluggishness at 1 day; recovery of 1 at 2 days.

2.00 ml/kg dosing group:
erythema, edema at 1 to 7 days; necrosis at 1 to 14 days; ecchymosis at 1 day; scabs at death or termination; ulceration at 7 to 14 days; sluggishness in 2 at 1 day; abdominal distension in 1 at death; recovery of affected survivor at 2 days.

1.00 ml/kg dosing group:
erythema at 1 day; edema at 1 to 7 days; necrosis at 1 to 14 days; ecchymosis on 1 at 1 day; scabs, ulceration at 7 to 14 days; desquamation on 1 at 14 days; abdominal distension and emaciation (in 1), audible breathing in 1 at 14 days.

Body weight:

Nothing abnormal reported.

Gross pathology:

MALES
4.00 ml/kg dosing group:
lungs salmon-colored; trachea of 1 animal dark red; thymus of 1 animal mottled dark red; large intestines of 1 animal hemorrhaged.

2.00 ml/kg dosing group:
in deceased animal, lungs mottled salmon-colored and bright red; in survivors, lungs bright pink, salmon-colored or mottled bright pink to dark red.

1.00 ml/kg dosing group: lungs of 1 animal dark red.

FEMALES
4.00 ml/kg dosing group:
in deceased animals, lungs salmon-colored to dark red, with dark red foci; thymus of 1 dark red; intestines hemorrhaged; in survivor, nothing remarkable.

2.00 ml/kg dosing group:
in deceased animal, stomach, intestines liquid and gas-filled; small intestines hemorrhaged; in survivors, lungs salmon-colored to red; kidneys of 1 with a pitted surface; intestines of 1 gas-filled.

1.00 ml/kg dosing group:
lungs salmon-colored to dark red, 1animal with dark red foci; stomachs and intestines of 2 animals liquid and/or gasfilled; small intestines of 1 animal hemorrhaged; abdominal cavity of 1 animal liquid-filled.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 504 mg/kg bw

Additional information

Justification for selection of acute toxicity – oral endpoint
No data are available from acute oral toxicity studies of the registered substance.
A study is available on the acute oral toxicity of the analogue substance, monoethanolamine. Based on the read across justification provided in IUCLID Section 13, it is expected that the registered substance will exert its acute oral toxicity via degradation to the analogue substance and therefore, the effect level used for chemical safety assessment is the value from this key study.

Justification for selection of acute toxicity – inhalation endpoint
No data are available from acute inhalation toxicity studies of the registered substance.
A reliable study on acute inhalation toxicity is available on the analogue substance, monoethanolamine. This study indicates that exposure of rats to maximal vapour concentration of 1.3 mg/L over 6 hours did not result in any mortlaities. In addition, the vapour pressure of the target substance is significantly lower than the analogue ubstance (i.e. 0.8 Pa vs. 49 Pa, at 25 degrees C), and therefore at maximally attainable vapour concentrations of the registered substance, no acute toxicity is expected.

Justification for selection of acute toxicity – dermal endpoint
No data are available from acute dermal toxicity studies of the registered substance.
Data are available from an acute dermal toxicity study in rabbits of the analogue substance, monoethanolamine. As discussed in the read across justification (attached in IUCLID Section 13), it is known that the topical effects of the registered substance are not as pronounced as with the analogue substance. It is assumed that the registered substance will degrade to the analogue substance in aqueous fluids and that, therefore, read across to acute dermal toxicity data on the analogue substance represents a reasonable worst case.

Justification for classification or non-classification

As detailed in the read across justification document, it is expected that data on the analogue substance (monoethanolamine) represent a reasonable worst-case for the registered (target) substance. As such, the available data support classification of the registered substance as acutely toxic via ingestion, but not via dermal or inhalation, according to the criteria laid down in Regulation (EC) No 1272/2008 (i.e. CLP).