N,N-dimethylisopropylamine

Endpoint summary

Description of key information

N,N-dimethylisopropylamine is corrosive to skin and eyes and irritating for the respiratory tract.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Centre Lago S. A., 01540 Vonnas, France
- Age at study initiation: ca. 6 months
- Weight range at study initiation: 3.43 kg – 3.52 kg
- Housing: single housing
- Diet: Kliba-Labordiaet (Kaninchen & Meerschweinchenhaltung “GLP”), Provimi Kliba SA, Kaiseraugst, Basel, Switzerland, ad libitum
- Water: Tap water ad libitum
- Acclimation period: at least 5 days before application


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Air changes (per hr): The animals were housed in fully air-conditioned rooms.
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

other: Untreated skin sites of the same animal.

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): The test patch (2.5 cm x 2.5 cm) was moistened with a dose of 0.5 mL of the undiluted liquid test substance.

Duration of treatment / exposure:

3 min

Observation period:

14 days
(A check for dead or moribund animals was made twice each workday and once daily at weekends.)

Number of animals:

2

Details on study design:

TEST SITE
- Area of exposure: 2.5x2.5 cm


REMOVAL OF TEST SUBSTANCE
- Washing (if done): The test substance was removed at the end of the exposure period with Lutrol and Lutrol/water (1:1).
- Time after start of exposure: 3 min

Irritation parameter:

other: corrosion

Basis:

mean

Remarks:

(2 animals)

Remarks on result:

other: Full thickness necrosis occurred after a 3 min exposure period.

Irritation parameter:

erythema score

Basis:

mean

Remarks:

(2 animals)

Time point:

other: 24, 48 and 72 h

Score:

3.3

Max. score:

4

Reversibility:

not fully reversible within: 14 days

Irritation parameter:

edema score

Basis:

mean

Remarks:

(2 animals)

Time point:

other: 24, 48 h and 72 h

Score:

2.2

Max. score:

4

Reversibility:

not fully reversible within: 14 days

Mean erythema score after 24, 48 and 72 h; (animal1/animal2)

	24 h	48 h	72 h	mean
3 min	3/3	3/4	3/4	3/3.7

Mean edema score after 24, 48 and 72 h; (animal1/animal2)

	24 h	48 h	72 h	mean
3 min	2/3	2/2	2/2	2/2.3

Moderate to severe erythema (grade 2-4) and moderate to marked edema (grade 2-3), partly extended beyond the area of exposure, were observed in all animals immediately after removal of the patch up to study termination on day 14.

Additional findings like scaling, severe scaling, petechiae, eczematoid skin change and thickening of the skin at the application area were noted over the observation period. The skin of the application area appeared temporarily whitish-brownish, slightly brownish or dark brown. The cutaneous reactions were not reversible in the animals within 14 days after removal of the patch. The first animal still showed erythema, edema, severe scaling, eczematoid skin change and thickening of the skin at study termination. The skin was soft and relocatable. In the second animal erythema, edema, eczematoid skin change and thickening of the skin were noted and the skin appeared dark brown.

Pathological-anatonomical evaluation:

Animal 02 (right flank): lesion at the application area, incrusted surface.

Histopathological examination:

Animal 02 (right flank): full thickness necrosis of epidermis with severe, diffuse intraepidermal infiltration with lymphocytes, histiocytes, neutrophilic and eosionophilic granulocytes and serocellular crusts.

Major finding: Full thickness necrosis occurred after a 3 min exposure period.

Interpretation of results:

Category 1A (corrosive) based on GHS criteria

Conclusions:

Under the experimental conditions, DMIPA was considered as corrosive when applied topically to rabbits

Executive summary:

The acute dermal irritation of N,N-dimethylisopropylamine (DMIPA) was evaluated in rabbits according to OECD 404 guideline. DMIPA was applied undiluted to the skin of 2 New-Zealand White albino rabbits and held in contact for 3 minutes by means of a semi-occlusive dressing. Mean scores over 24, 48 and 72 hours for each animal were for erythema and for oedema. Animals were then observed daily during 14 days. Moderate to severe erythema (grade 2-4) and moderate to marked oedema (grade 2-3), partly extended beyond the area of exposure, were observed in all animals immediately after removal of the patch up to study termination on day 14. Additional findings like scaling, severe scaling, petechiae, eczematoid skin change and thickening of the skin at the application area were noted over the observation period. The skin of the application area appeared temporarily whitish-brownish, slightly brownish or dark brown. The cutaneous reactions were not reversible in the animals within 14 days after removal of the patch. The first animal still showed erythema, oedema, severe scaling, eczematoid skin change and thickening of the skin at study termination. The skin was soft and relocatable. In the second animal erythema, edema, eczematoid skin change and thickening of the skin were noted and the skin appeared dark brown.

Under the experimental conditions, DMIPA was considered as corrosive when applied topically to rabbits.

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:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

according to guideline

Guideline:

other: JO RF 5 Avril 1971

GLP compliance:

no

Species:

rabbit

Strain:

not specified

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: no data
- Housing:no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum):no data
- Acclimation period:no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr):no data
- Photoperiod (hrs dark / hrs light):no data


IN-LIFE DATES: From: To:no data

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

Amount applied: 0.1 ml

Duration of treatment / exposure:

not rinsed

Observation period (in vivo):

24h, 48h, 72h, 96h, 7days

Number of animals or in vitro replicates:

6

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

other: 24, 48 and 72h

Score:

4

Max. score:

4

Reversibility:

not reversible

Remarks:

after 7 days

Irritation parameter:

iris score

Time point:

other: 24, 48 and 72h

Reversibility:

not reversible

Remarks:

after 7 days

Remarks on result:

other: not scoreable

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

other: 24, 48 and 72h

Score:

3

Max. score:

3

Reversibility:

not reversible

Remarks:

after 7 days

Irritation parameter:

chemosis score

Basis:

mean

Time point:

other: 24, 48 and 72h

Score:

2.8

Max. score:

4

Reversibility:

not reversible

Remarks:

after 7 days

Irritant / corrosive response data:

severe iris opacification

Reading		Rabbit						Mean
		1	2	3	4	5	6
24hours	Cornea	4	4	4	4	4	4	95.3/100
		4	4	4	4	4	4
	Iris	-	-	-	-	-	-
	Conjunctive	3	3	3	3	3	3
		1	1	2	2	2	2
		3	3	3	3	3	3
48hours	Cornea	4	4	4	4	4	4	95.3/100
		4	4	4	4	4	4
	Iris	-	-	-	-	-	-
	Conjunctive	3	3	3	3	3	3
		1	1	2	2	2	2
		3	3	3	3	3	3
72hours	Cornea	4	4	4	4	4	4	93.3/100
		4	4	4	4	4	4
	Iris	-	-	-	-	-	-
	Conjunctive	3	3	3	3	3	3
		1	1	1	1	1	2
		2	2	2	3	3	3
96hours	Cornea	4	4	4	4	4	4	95.3/100
		4	4	4	4	4	4
	Iris	-	-	-	-	-	-
	Conjunctive	3	3	3	3	3	3
		1	2	2	2	2	2
		2	3	3	3	3	3
7days	Cornea	4	4	4	4	4	4	98.3/100
		4	4	4	4	4	4
	Iris	-	-	-	-	-	-
	Conjunctive	3	3	3	3	3	3
		1	4	4	4	4	4
		1	3	3	3	3	3

 

Interpretation of results:

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

Conclusions:

Under these experimental conditions, DMIPA has to be classified as corrosive.

Executive summary:

The acute eye irritation of Dimethylisopropylamine (DMIPA) was evaluated in rabbits according to the “Journal Officiel Français arrêté du 05 avril 1971”. 0,1mL of DMIPA was applied in the right eye of 6rabbits and the reaction was observed 24, 48, 72, 96hours and 7days after administration.

Iris has never been examined because of the total corneal opacity from 24hours. Maximal scores are recorded until the day7.

Under these experimental conditions, DMIPA has to be classified as corrosive.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

Skin Irritation-Corrosion

 

In vitro studies

 

To evaluate the potential skin corrosivity of N,N-dimethylisopropylamine, the pH and acidic/alkaline reserve was measured according to the method described by Regnier and Imbert (ATLA, 1992, 20, 457-465) and Froment (Arkema unpublished data, 1993) (Gancet, 2012). Under the test conditions, the results are as follow:

 

Test item	pH	log R (acidic/alkaline reserve	Physical-chemical index (I) I = pH + log R, for pH =7 I = (14 -pH) + log R, for pH < 7
N,N-dimethylisopropylamine	12.53	1.6	14.13

 

According to the method, a substance is considered as potentially corrosive to the skin if at least 2 of the 3 following criteria are fulfilled:

pH= 2.5 or pH =9.5; log R = 0 and/ot I= 10.

N,N-dimethylisopropylamine is considered as potentially corrosive to the skin.

The corrosive potential of N, N-Dimethylisopropylamine was evaluatedusing the EpiDerm corrosivity-test in vitro (BASF, 2006). This study was conducted in compliance the OECD guideline 431. The acceptance criteria were fulfilled and the study was therefore considered to be valid. The relative mean viabilities of the test item-treated tissues were: 3 minutes exposure: 30%, 1 hour exposure: 7%,. N, N-Dimethylisopropylamine, tested in its original form, is considered to be corrosive to the skin after a 3-min exposure.

In vivo studies

 

In a key study, the acute dermal irritation of N,N-dimethylisopropylamine (DMIPA) was evaluated in rabbits according to OECD 404 guideline (BASF, 2006). DMIPA was applied undiluted to the skin of 2 New-Zealand White albino rabbits and held in contact for 3 minutes by means of a semi-occlusive dressing. Mean scores over 24, 48 and 72 hours for each animal were for erythema and for oedema. Animals were then observed daily during 14 days. Moderate to severe erythema (grade 2-4) and moderate to marked oedema (grade 2-3), partly extended beyond the area of exposure, were observed in all animals immediately after removal of the patch up to study termination on day 14. Additional findings like scaling, severe scaling, petechiae, eczematoid skin change and thickening of the skin at the application area were noted over the observation period. The skin of the application area appeared temporarily whitish-brownish, slightly brownish or dark brown. The cutaneous reactions were not reversible in the animals within 14 days after removal of the patch. The first animal still showed erythema, oedema, severe scaling, eczematoid skin change and thickening of the skin at study termination. The skin was soft and relocatable. In the second animal erythema, edema, eczematoid skin change and thickening of the skin were noted and the skin appeared dark brown. Accordingly, N,N-dimethylisopropylamine is considered as corrosive for the skin.

In a rabbit acute dermal irritation study performed according to OECD guideline 404 (Guillot, 1986), N,N-dimethylisopropylamine induced a skin necrosis in 5 out of 6 rabbits after a 4-hour application. Accordingly, N,N-dimethylisopropylamine is considered as corrosive for the skin.

 

The acute dermal irritation of Dimethylisopropylamine (DMIPA) was evaluated in rabbits according to the “Journal Officiel de la République Française, arrêté du 05 avril 1971 ”.0,5mL of DMIPA was applied during 4 hours in 6 rabbits on intact or scarified skin. The cutaneous reaction was observed 24 or 72 hours after removal of the dressing (Truhaut, 1979). After application of the substance during 24 hours, the primary irritation score was 7.6 at 24 and 72 hours (maximum score=8). Under these experimental conditions, DMIPA is considered as corrosive.

Using a BASF AG internal procedure, two Vienna White rabbits were treated with the undiluted N,N-dimethylisopropylamine for 1, 5, 15 or 20 minutes under occlusive conditions; the application site was washed off with Lutrol/water following the contact periods (BASF, 1975). All exposure times caused irreversible necrosis; the substance was considered corrosive.

 

Eye irritation-Corrosion

 

In vitro studies

 

To evaluate the potential corrosivity for the eye of N,N-dimethylisopropylamine, the pH and acidic/alkaline reserve was measured according to the method described by Regnier and Imbert (ATLA, 1992, 20, 457-465) and Froment (Arkema unpublished data, 1993). Under the test conditions, the results are as follow:

 

Test item	pH	log R (acidic/alkaline reserve	Physical-chemical index (I) I = pH + log R, for pH =7 I = (14 -pH) + log R, for pH < 7
N,N-dimethylisopropylamine	12.53	1.6	14.13

 

According to the method, a substance is considered as potentially corrosive to the eye if at least 2 of the 3 following criteria are fulfilled:

pH= 2.5 or pH =9.5; log R = 0 and /or I= 9.

 

N,N-dimethylisopropylamine is considered as potentially severely irritanting to the eye.

 

In vivo studies

 

In a rabbit acute eye irritation study performed according a guideline equivalent to OECD 405 (Truhaut 1979), N,N-dimethylisopropylamine induced a complete corneal opacity and severe conjunctival reactions in the 6 rabbits. The reversibility of these effects was not assessed. Accordingly, N,N-dimethylisopropylamine was considered as severely irritating to eye.

 

An older study (BASF 1975) showed that 50 µl of the test substance instillated in the rabbit eye caused severe irritation, corneal opacity and focal tissue defects (necroses) to the conjunctivae. At the end of the observation period after 8 days beginning staphyloma, partially necrotic lid margins and suppuration was noted. N,N-dimethylisopropylamine

was therefore considered as corrosive to the eye.

Respiratory tract irritation

In a 4 -h acute inhalation toxicity study in rats performed with a structural analogue, dimethyl-n-propylamine, clinical and pathological signs of respiratory tract irritation were observed during exposure and in animals died during exposure (BASF, 2012).

N,N-dimethylisopropylamine is therefore considered as a respiratory tract irritant.

Justification for selection of skin irritation / corrosion endpoint:
Key in vivo study

Justification for selection of eye irritation endpoint:
Key in vivo study

Effects on skin irritation/corrosion: corrosive

Effects on eye irritation: corrosive

Effects on respiratory irritation: irritating

Justification for classification or non-classification

Skin irritation: N,N-dimethylisopropylamine induced skin corrosion after a 3 -min exposure. On this basis and in accordance with Regulation (EC) No 1272/2008, DMIPA was classified as corrosive category 1A (Hazard statment H314: Causes severe skin burns

and eye damage) .

Eye irritation: DMIPA is classified as corrosive to the skin. On this basis and in accordance with Regulation (EC) No 1272/2008 DMIPA was classified as irritating to eyes caregory 1 ( H318: Causes serious eye damage).

Respiratory tract irritation: In acute inhalation exposure studies, dimethyl-n-propylamine, a structural analogue to DMIPA, induced respiratory tract irritation. On this basis and in accordance with Regulation (EC) No 1272/2008 DMIPA was classified as Specific Target Organ Toxicity (STOT) Single Exposure (SE) Category 3.