Diethylammonium chloride

Endpoint summary

Description of key information

Skin corrosion, rabbit: corrosive

Eye damage, rabbit: serious damage to the eye

Respiratory irritation, rat causes respiratory tract irritation (data from acute and repeated dose inhalation studies)

RA from diethylamine (CAS 109 -89 -7)

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented report which meets basic scientific principles.

Principles of method if other than guideline:

according to Draize et al.

GLP compliance:

not specified

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Mohican Valley Rabbitry, Loudonville, Ohio
- Age at study initiation: young adult
- Weight at study initiation: 1.9- .2 kg
- Housing: individually housed in suspended stainless steel cages
- Diet: Agway Prolab Rabbit Ration, ad libitum
- Water: water ad libitum
- Acclimation period: minimum of five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.3 - 26.5 °C
- Humidity (%): 35-70 %
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Preparation of test site:

other: clipped

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL

Duration of treatment / exposure:

3 min

Observation period:

7 days

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: one and one-half inch square gauze patch
- Type of wrap if used: double layer of plastic wrap


REMOVAL OF TEST SUBSTANCE
- Washing (if done): residual test article wiped from the site with gauze soaked in distilled water
- Time after start of exposure: 3 min


SCORING SYSTEM: Draize system

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

4

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

2.2

Max. score:

3

Reversibility:

fully reversible

Remarks:

7 days

Erythema score (animal1/animal2/animal3):

Exposure time	3 min	1 h	24 h	48 h	72 h	7 days
3 min	4/4/4	4/4/4	4/4/4	4/4/4	4/4/4	4/4/4

Edema score (animal1/animal2/animal3):

Exposure time	3 min	1 h	24 h	48 h	72 h	7 days
3 min	1/1/1	2/2/2	2/3/3	2/2/2	2/2/1	0/0/0

Diethylamine produced dermal corrosion at all sites exposed to the test article. The dermal response was initially characterized by necrosis at the three minute scoring interval and progressed to eschar at one hour (2/3 rabbits) and 24 hours (3/3 rabbits). The eschar persisted throughout the remainder of the seven day study. A very slight edema was noted during the test period and diminished by test termination.

Interpretation of results:

Category 1A (corrosive) based on GHS criteria

Conclusions:

CLP: Skin Corr. 1A, H314

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

4

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

2.2

Max. score:

3

Reversibility:

fully reversible

Remarks:

7 days

Erythema score (animal1/animal2/animal3):

Exposure time	3 min	1 h	24 h	48 h	72 h	7 days
3 min	4/4/4	4/4/4	4/4/4	4/4/4	4/4/4	4/4/4

Edema score (animal1/animal2/animal3):

Exposure time	3 min	1 h	24 h	48 h	72 h	7 days
3 min	1/1/1	2/2/2	2/3/3	2/2/2	2/2/1	0/0/0

Diethylamine produced dermal corrosion at all sites exposed to the test article. The dermal response was initially characterized by necrosis at the three minute scoring interval and progressed to eschar at one hour (2/3 rabbits) and 24 hours (3/3 rabbits). The eschar persisted throughout the remainder of the seven day study. A very slight edema was noted during the test period and diminished by test termination.

Interpretation of results:

Category 1A (corrosive) based on GHS criteria

Conclusions:

CLP: Skin Corr. Cat. 1A, H314
Applying the RA approach, similar results are expected for the target substance.

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:

supporting study

Study period:

1989

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

no iris lesions were evaluated; testing material was a 2% solution of diethylamine

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

no iris lesions were evaluated; testing material was a 2% solution of diethylamine

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

GLP compliance:

not specified

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

no data

Vehicle:

not specified

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 µL
- Concentration (if solution): 2 %

Duration of treatment / exposure:

7 days

Observation period (in vivo):

7 days

Number of animals or in vitro replicates:

3

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

of three animals

Time point:

other: 24 h - 48 h - 72 h

Score:

2.44

Max. score:

4

Reversibility:

not specified

Irritation parameter:

conjunctivae score

Basis:

mean

Remarks:

of three animals

Time point:

other: 24 h - 48 h - 72 h

Score:

2.96

Max. score:

3

Reversibility:

not specified

Irritation parameter:

chemosis score

Basis:

mean

Remarks:

of three animals

Time point:

other: 24 h - 48 h - 72 h

Score:

1.44

Max. score:

4

Reversibility:

not specified

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

CLP: Eye Dam. 1, H318
In this assay diethylamine (CAS: 109-89-7) was corrosive to the eyes.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

Justification for read-across

There are no data available regarding skin and eye irritation/corrosion for diethylammonium chloride (CAS 660-68-4). Thus, read-across from an appropriate structural analogue substance (diethylamine, CAS 109-89-7) is conducted in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5. in order to fulfil the standard information requirements defined in Regulation (EC) No 1907/2006, Annex VII and VIII, 8.1. Common functional groups and structural similarities combined with similar toxicokinetic properties of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

Skin irritation

The skin irritancy potential of diethylamine (CAS 109-89-7)was determined in a skin irritation study according to Draize in white rabbits (NZW) (reference 7.3.1-1). The test substance (0.5 mL, undiluted) was topically applied to the skin of three rabbits for 3 min using occlusive conditions. Local reactions were scored at 3 min, 1, 24, 48 and 72 h and 7 days. All three animals showed necrosis at the 3 min scoring interval and progressed to eschar at 1 hr (2/3 rabbits) and 24 h (3/3 rabbits). The eschar persisted throughout the remainder of the seven day study. Based on the results of the conducted study,diethylamineis considered to be corrosive to the skin.

A supporting skin irritation study was conducted with diethylamine (CAS 109-89-7). In this study (reference 7.3.1.-2), two animals were treated for 1, 5 and 15 minutes using occlusive conditions. An application site of 2.5 x 2.5 cm was covered with the liquid test substance (1 animal received the concentrated test substance, the other animal received a 20% solution and a 20% solution at pH 7.5). After the application time, the skin was washed with Lutrol (25%) which contained acetic acid (5%). Immediately after application of the concentrated test substance severe leathery necrosis and erythema were noted. After 4 weeks deep crusts were detected. The 1 min exposure caused red-brown necrosis. After 4 weeks scurfy sites were detected. The observed effects are considered as full thickness necrosis. Diluted test substance (20%) caused grey-brown necrosis after 15 min, redness after 5 min and no symptoms after 1 min application. Based on the results of this study,diethylamineis considered to be corrosive to the skin.

In both studies full thickness necrosis occurred after exposure times of 3 minutes and one minute, respectively. Necrosis was observed immediately after removal of the patch. Thus, based on GHS and CLP criteria, classification as Skin Corr 1A is compulsory.

 

Eye irritation

The read-across substance diethylamine is corrosive to the skin and therefore no studies on the eye irritation potential are required. However, there is an eye irritation study available that supports the evaluation of diethylamine.

To evaluate the irritation potential towards the eyes, 0.1 mL of a 2% diethylamine solutionwas instilled into the eyes of three white rabbits (NZW) (reference 7.3.2-1). In the study, that was conducted equivalent or similar to OECD 405, reactions were observed 24, 48 and 72 h after treatment. Mean scores for corneal opacity, conjunctival redness and swelling were 2.44, 2.96 and 1.44, respectively. No data on the duration towards onset of findings and on reversibility are given. Based on the results of the skin irritation/corrosion study and supported by the eye irritation study, diethylamine is classified ascausing serious eye damage. Thus based on CLP criteria, classification as Eye Dam. 1 is compulsory.

 

Respiratory irritation

No dedicated study on respiratory irritation is available with diethylamine. However clinical signs and necropsy findings from the acute inhalation study (reference 7.2.2-1) indicate that diethylamine causes respiratory irritation. At 8000 ppm, a dose that caused mortality in all six exposed animals, clinical signs were gasping, nasal irritation, poor coordination, bloody nasal discharge and tonic convulsions. Necropsy examination of deceased animals revealed red lungs.

The respiratory irritating properties of diethylamine are further confirmed in the 90-day repeated dose inhalation toxicity studies in rats and mice (references 7.5.2-1 and 7.5.2-2). In the rat study exposure-related histopathology findings were limited to the nose and were seen primarily in animals exposed to 62 or 125 ppm (corresponding to 188 and 379 mg/m³). These lesions included turbinate necrosis, suppurative inflammation, respiratory epithelial hyperplasia, squamous metaplasia of the respiratory epithelium, and olfactory epithelial atrophy. Also in the mouse study, histopathologic changes were noted in the nasal cavity and involved both the respiratory and olfactory epithelium principally in the 62 or 125 ppm groups. These lesions included suppurative inflammation, squamous metaplasia of the respiratory epithelium, olfactory epithelial atrophy, and necrosis of the turbinates.

Based on the observed effects the substance diethylamine is classified as specific target organ toxicant after single exposure Cat. 3 (resp. irritation).

A harmonized classification is available for the source substance diethylamine (CAS 109-89-7, index No. 621-003-00-X) according to Annex VI of regulation EC No. 1272/2008 (CLP regulation) as skin corr. 1A (H314). In addition, harmonized specific concentration limits for STOT SE 3 (H335) are available: C ≥ 1%. Applying the RA approach the same classification and specification limits are applied to the target substance.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the analogue concept is applied to diethylammonium chloride, data will be generated from information on reference source substance(s) to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.

A harmonized classification is available for the source substance diethylamine (CAS 109-89-7, index No. 621-003-00-X) according to Annex VI of regulation EC No. 1272/2008 (CLP regulation) as skin corr. 1A (H314). In addition, harmonized specific concentration limits for STOT SE 3 (H335) are available: C ≥ 1%. Applying the RA approach the same classification and specification limits are applied to the target substance.

Based on the RA-Ae approach, the available data on irritation/corrosion meet the criteria for classification as Skin Corr. 1A, Eye Dam. 1 and STOT SE 3 (respiratory irritation), according to Regulation (EC) 1272/2008.