Registration Dossier

Administrative data

Description of key information

N, N, N', N'-tetramethyltrimethylenediamine (TMDAP) is corrosive to the skin and the eyes and irritating to 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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions (occlusive treatment)
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
(limited documentation, occlusive treatment)
Principles of method if other than guideline:
Method: BASF-Test
Three animals were treated for 3 min and 1 h using occlusive conditions. The application site of 2.5 x 2.5 cm (flanks) was covered with the liquid test substance. After exposure the skin was washed with Lutrol (conc.) and Lutrol/water (1:1). The animals were observed for 8 days and skin changes were recorded after patch removal, 24 h, 48 h and 8 days after application. The test is comparable to the initial test descirbed in the OECD guideline 404 to evaluate the corrosive potential of a test substance.
GLP compliance:
no
Species:
rabbit
Strain:
Vienna White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Firma Gaukler; Offenbach Germany
- Weight at study initiation: 3.07 kg (mean)
- Housing: one per cage
- Diet: Ovator Solikanin 4 mm; Muskator-Werke Duesseldorf; ad libitum
- Water: FulIy demineralized water ad libitum each workday; tap water ad libitum on public holidays.
- Acclimation period: ca. 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-26 °C
- Humidity (%): 30-70 %
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:
occlusive
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated skin served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): ca. 0.5 mL
Duration of treatment / exposure:
3 min (right flank) and 1 h (left flank)
Observation period:
8 days
Number of animals:
1 male and 2 females
Details on study design:
TEST SITE
- Area of exposure: 2.5 x 2.5 cm


REMOVAL OF TEST SUBSTANCE
- Washing (if done): with Lutrol (conc.) and Lutrol/water (1:1)
- Time after start of exposure: 3 min or 1 h

EVALUATION: according to the Draize Scoring System
Irritation parameter:
other: corrosion
Basis:
mean
Remarks:
(3 animals, 3 min exposure)
Remarks on result:
other: Non-reversible necroses (superficial) were observed in all animals.
Irritation parameter:
other: corrosion
Basis:
mean
Remarks:
(3 animals, 1 h exposure)
Remarks on result:
other: Non-reversible, full thickness necroses were observed in all animals.
Irritation parameter:
erythema score
Basis:
animal #1
Remarks:
(3 min exposure)
Time point:
other: 24 h - 48 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
erythema score
Basis:
animal #2
Remarks:
(3 min exposure)
Time point:
other: 24 h - 48 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
erythema score
Basis:
animal #3
Remarks:
(3 min exposure)
Time point:
other: 24 h - 48 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
erythema score
Basis:
animal #1
Remarks:
(1 h exposure)
Time point:
other: 24 h - 48 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
erythema score
Basis:
animal #2
Remarks:
(1 h exposure)
Time point:
other: 24 h - 48 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
erythema score
Basis:
animal #3
Remarks:
(1 h exposure)
Time point:
other: 24 h - 48 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
edema score
Basis:
animal #1
Remarks:
(3 min exposure)
Time point:
other: 24 h - 48 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
edema score
Basis:
animal #2
Remarks:
(3 min exposure)
Time point:
other: 24 h - 48 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
edema score
Basis:
animal #3
Remarks:
(3 min exposure)
Time point:
other: 24 h - 48 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
edema score
Basis:
animal #1
Remarks:
(1 h exposure)
Time point:
other: 24 h - 48 h
Score:
3.5
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
edema score
Basis:
animal #2
Remarks:
(1 h exposure)
Time point:
other: 24 h - 48 h
Score:
3.5
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
edema score
Basis:
animal #3
Remarks:
(1 h exposure)
Time point:
other: 24 h - 48 h
Score:
3.5
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Interpretation of results:
Category 1B (corrosive)
Remarks:
Migrated information Criteria used for interpretation of results: EU
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:
other: Comparable to guideline study with acceptable restrictions (limited documentation on test substance and test animals)
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
(application amount, limited documentation, 2 animals)
Principles of method if other than guideline:
50 µL of the test substance were applied to the conjunctival sac of one eye in 2 animals. The animals were observed after 10 min, 1 h and 3 h on the day of treatment and up to 8 days afterwards. Findings were recorded daily. The eyes were not washed out after 24 hours as specified in OECD Guideline 405.
GLP compliance:
no
Species:
rabbit
Strain:
not specified
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 3.03 kg and 3.24 kg (males)
Vehicle:
unchanged (no vehicle)
Controls:
other: The adjacent eye served as saline control.
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 50 µL
Duration of treatment / exposure:
Single application, no rinsing
Observation period (in vivo):
8 days
Number of animals or in vitro replicates:
2
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
other: 24 h - 48 h - 72 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
other: 24 h - 48 h - 72 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
iris score
Basis:
animal #1
Time point:
other: 24 h - 48 h - 72 h
Score:
0.66
Max. score:
2
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
iris score
Basis:
animal #2
Time point:
other: 24 h - 48 h - 72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: 24 h - 48 h - 72 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: 24 h - 48 h - 72 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
(2 animals)
Time point:
other: 24 h - 48 h - 72 h
Score:
0
Max. score:
3
Reversibility:
other: not applicable
Remarks on result:
other: conjunctivae score of 2 in animal#2 on day 8.
Irritant / corrosive response data:
1 h post application: nictitating membrane and mucosae reddish-brown, discharge of blood.
24 h post application: nictitating membrane grey, mucosae reddish-brown, margins of eyelid necrotic.
8 days post application: nictitating membrane grey, mucosae grey, margins of eyelid necrotic, beginning staphyloma.

Findings animal1:

 Time

Opacity

 Chemosis

 Erythema

Iris

1h

 3

3

0

0

24h

 3

3

0

48h

 3

 3

0

72h

 3

3

2

 8d

 3

3

0

2

Findings animal2:

 Time

 Opacity

 Chemosis

Erythema

Iris

1h

3

0

24h

3

 0

0

48h

3

0

0

72h

 3

0

 8d

3

 3

2

0

Interpretation of results:
Category 1 (irreversible effects on the eye)
Remarks:
Migrated information Criteria used for interpretation of results: EU
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, N', N'-tetramethyltrimethylenediamine, 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, N', N'-tetramethyltrimethylenediamine

11.2

1.6

12.8

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

In vivo studies

In a BASF study (BASF 1982), three animals were treated for 3 min or 1 h with N, N, N', N'-tetramethyltrimethylenediamine using occlusive conditions. At the end of the observation period after 8 days deep necrosis and spanning edema exiciting the application site (1 h exposure) were found

The acute dermal irritation of N, N, N', N'-tetramethyltrimethylenediamine (TMPDA) was evaluated in one malealbino rabbit according to OECD N°404 Guideline (Clouzeau, 1988). 0,5mL of TMPDA was held in contact with the skin for 4 hours by a semi-occlusive dressing. The cutaneous reactions were observed one hour, 24, 48 and 72 hours after the removal of the dressing. After application of the substance during 4 hours, tissular destruction on the whole depth of the skin was observed in the three animals, which were sacrificed for ethical reasons.

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

Eye irritation-Corrosion

In vitro studies

To evaluate the potential skin corrosivity of N, N, N', N'-tetramethyltrimethylenediamine, 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, N', N'-tetramethyltrimethylenediamine

11.2

1.6

12.8

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, N', N'-tetramethyltrimethylenediamine is considered as potentially severely irritating to the eye.

In vivo studies

In a BASF study (BASF 1974), 50 µl of N, N, N', N'-tetramethyltrimethylenediamine was applied to the conjunctival sac of one eye in 2 animals. The animals were observed after 10 min, 1 and 3 h on the day of treatment and up to 8 days afterwards. A corneal score of 3 (max score 4) and a chemosis score of 2 (max score 4) were calculated. N, N, N', N'-tetramethyltrimethylenediamine was considered as corrosive to the eye.

Respiratory tract

Clinical signs of respiratory tract irritation were observed in an acute inhalation toxicity study in rats (BASF, 1974).


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

Justification for selection of eye irritation endpoint:
Key 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, N', N'-tetramethyltrimethylenediamine induced skin corrosion after a 1 -hour exposure. On this basis and in accordance with Regulation (EC) No 1272/2008, N, N, N', N'-tetramethyltrimethylenediamine was classified as corrosive category 1B (Hazard statment H314: Causes severe skin burnsand eye damage) and in accordance with Annex VI of Commission Directive 2001/59/EC, N, N, N', N'-tetramethyltrimethylenediamine was classified as corrosive with the symbol C and the phrase R34 "Causes burns".

Eye irritation:

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

Respiratory tract irritation:

In acute inhalation exposure studies, N, N, N', N'-tetramethyltrimethylenediamine induced respiratory tract irritation. On this basis and in accordance with Regulation (EC) No 1272/2008, N, N, N', N'-tetramethyltrimethylenediamine was classified as Specific Target Organ Toxicity (STOT) Single Exposure (SE) Category 3 and in accordance with Annex VI of Commission Directive 2001/59/EC, N, N, N', N'-tetramethyltrimethylenediamine was classified as irritant with the symbol Xi and the phrase R37 "irritating to the respiratory tract".