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Administrative data

Description of key information

Skin irritation/corrosion (OECD 404): not irritating
Eye irritation (OECD 405, RA from CAS 3069-29-2): corrosive

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
Study period:
02 April 2012 to 29 August 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
(2002)
Deviations:
yes
Remarks:
(no information is given on the analytical purity)
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Version / remarks:
(2008)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Version / remarks:
(1998)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit, München, Germany
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain: Crl: KBL (NZW)
- Source: Charles River Deutschland, 97633 Sulzfeld, Germany
- Age at study initiation: approximately 13-14 weeks old
- Weight at study initiation: > 2 kg
- Housing: semi barrier in an air-conditioned room in ABS - plastic rabbit cages, floor 4200 cm²
- Diet: autoclaved hay and to Altromin 2123 maintenance diet for rabbits (lot no. 1410), rich in crude fibre, ad libitum
- Water: tap water (drinking water, municipal residue control, microbiological controls at regular intervals), ad libitum
- Acclimation period: at least 5 days under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18±3 (recommendations of TVT, GV-SOLAS)
- Humidity (%): 55±10
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
other: the untreated right side of the dorsal area of the trunk served as control
Amount / concentration applied:
A dose of 0.5 ml of the test item was applied to each test site.
Duration of treatment / exposure:
The test item was held in contact with the skin throughout a 4-hour period.
Observation period:
Animal no. 1 was observed for 11 days after the patch removal.
Animals no. 2 and 3 were observed for 9 days after the patch removal.
Number of animals:
3 females
Details on study design:
TEST SITE
- Area of exposure: dorsal area of the trunk, approximately 6 cm²
- Type of wrap if used: gauze patch immobilised with non-irritating tape

REMOVAL OF TEST SUBSTANCE
- Washing: None stated in the study report

SCORING SYSTEM: Draize Scoring System
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 11 days
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 9 days
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 9 days
Irritation parameter:
edema score
Basis:
mean
Remarks:
over all 3 animals
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Irritant / corrosive response data:
Slight irritant effects (erythema grade 1) were observed on the intact skin of the three female rabbits (strain NZW) after a contact time
of 4 hours. These signs of irritation were reversible within 11 days in animal no. 1 and within 9 days in animals no. 2 and 3.
The application area was not rinsed.

Other effects:
Neither mortalities nor significant clinical signs of toxicity were observed.
There were no significant body weight changes during the contact and observation period.

Table 2: Dermal Irritation Evaluation

Animal
No.

Application
Site

Irritation (hours after patch removal)

1 hour

24 hours

48 hours

72 hours

T

C

T

C

T

C

T

C

1

Erythema

0

0

1

0

1

0

1

0

Oedema

0

0

0

0

0

0

0

0

2

Erythema

0

0

1

0

1

0

1

0

Oedema

0

0

0

0

0

0

0

0

3

Erythema

0

0

1

0

1

0

1

0

Oedema

0

0

0

0

0

0

0

0

T = test item;       C = control;        0 – 3 = grade

 

Animal
No.

Application
Site

Irritation (days after patch removal)

4 days

5 days

6 days

7 days

T

C

T

C

T

C

T

C

1

Erythema

1

0

1

0

1

0

1

0

Oedema

0

0

0

0

0

0

0

0

2

Erythema

1

0

1

0

1

0

1

0

Oedema

0

0

0

0

0

0

0

0

3

Erythema

1

0

1

0

1

0

1

0

Oedema

0

0

0

0

0

0

0

0

T = test item;       C = control;        0 – 3 = grade

Animal
No.

Application
Site

Irritation (days after patch removal)

8 days

9 days

10 days

11 days

T

C

T

C

T

C

T

C

1

Erythema

1

0

1

0

1

0

0

0

Oedema

0

0

0

0

0

0

0

0

2

Erythema

1

0

0

0

--

--

--

--

Oedema

0

0

0

0

--

--

--

--

3

Erythema

1

0

0

0

--

--

--

--

Oedema

0

0

0

0

--

--

--

--

T = test item;       C = control;        0 – 3 = grade

Table 3: Individual Data

Individual Systemic and Local Findings - Animal No. 1

Time after
Patch Removal

Systemic Findings

Specific Local Findings (apart from erythema/oedema)

Comments

1 hour

nsf

nsf

-

24 hours

nsf

nsf

-

48 hours

nsf

nsf

-

72 hours

nsf

nsf

-

4 days

nsf

nsf

-

5 days

nsf

nsf

-

6 days

nsf

nsf

-

7 days

nsf

nsf

-

8 days

nsf

nsf

-

9 days

nsf

nsf

-

10 days

nsf

nsf

-

11 days

nsf

nsf

-

Individual Systemic and Local Findings - Animal No. 2

Time after
Patch Removal

Systemic Findings

Specific Local Findings (apart from erythema/oedema)

Comments

1 hour

nsf

nsf

-

24 hours

nsf

nsf

-

48 hours

nsf

nsf

-

72 hours

nsf

nsf

-

4 days

nsf

nsf

-

5 days

nsf

nsf

-

6 days

nsf

nsf

-

7 days

nsf

nsf

-

8 days

nsf

nsf

-

9 days

nsf

nsf

-

Individual Systemic and Local Findings - Animal No. 3

Time after
Patch Removal

Systemic Findings

Specific Local Findings (apart from erythema/oedema)

Comments

1 hour

nsf

nsf

-

24 hours

nsf

nsf

-

48 hours

nsf

nsf

-

72 hours

nsf

nsf

-

4 days

nsf

nsf

-

5 days

nsf

nsf

-

6 days

nsf

nsf

-

7 days

nsf

nsf

-

8 days

nsf

nsf

-

9 days

nsf

nsf

-

nsf = no specific findings

Table 4: Absolute Body Weights in kg

 

Animal No. 1

Animal No. 2

Animal No. 3

Start of Study
(weight in kg)

3.2

3.1

3.4

72 Hours after Application (weight in kg)

3.2

3.1

3.5

End of Study
(weight in kg)

3.3

3.3

3.5

Interpretation of results:
other: CLP/EU GHS criteria are not met, no classification required according to Regulations (EC) No 1272/2008
Conclusions:
In an acute dermal irritation/corrosion study, conducted according to the OECD TG 404, and in compliance with GLP, the single dermal application of the test item N-[3-(dimethoxymethylsilyl)-2-methylpropyl]ethylenediamine to three rabbits at a dose of 0.5 ml showed very slight irritant but no corrosive effects which were resolved within 11 days of patch removal. Based on this result, there are no classification and no obligatory labelling requirements for skin irritation per the Annex VI of Commission Directive 2001/59/EC, Annex I of Regulation (EC) 1272/2008, and GHS (Globally Harmonized Classification System).
Executive summary:

Summary Results

The study was performed in order to assess the potential of the test item to induce acute dermal irritation/corrosion when applied directly to the skin of rabbits. Animals were exposed to 0.5 ml of the test item by application onto clipped skin for four hours using a semi-occlusive dressing. The test sites were assessed one, 24, 48, and 72 hours following patch removal. Three male New Zealand White rabbits (Crl: KBL (NZW)) were selected for testing. An initial test was conducted with one of the animals to determine if the test item produced significant irritation. The test item was applied to the two remaining animals selected for testing when the initial test showed that the test item was neither corrosive nor a severe irritant. During the initial test and confirmatory test, no irritation was observed one hour following patch removal. However, 10 days post application; animal no. 1 (initial test) had a grade 1 erythema score. Animal nos. 2 and 3 (confirmatory test) had a grade 1 erythema score for 8 days post application.  For animal no. 1 (initial test), the erythema was no longer apparent within 11 days after patch removal. For animal nos. 2 and 3 (confirmatory test), the erythema was no longer apparent within 9 days after patch removal.

Table 5: Average Scores – (24, 48, 72 h reading)

Mean Value Irritation Scores

Animal No.

Mean 24 – 72 hours

Erythema

Oedema

1

1

0

2

1

0

3

1

0

Total Mean Value

1

0

No mortalities, significant body weight changes, or significant clinical signs of toxicity were observed during the experimental period. The experimental phase for the initial test was terminated 11 days after patch removal. The experimental phase for the confirmatory test was terminated 9 days after patch removal.

Conclusion

Under the conditions of the present study, the single dermal application of the test item N-[3-(dimethoxymethylsilyl)-2-methylpropyl]ethylenediamine to three rabbits at a dose of 0.5 ml showed very slight irritant but no corrosive effects which were resolved within 11 days of patch removal.  Based on this conclusion, there are no classification and no obligatory labelling requirements for skin irritation per the Annex VI of Commission Directive 2001/59/EC, Annex I of Regulation (EC) 1272/2008, and GHS (Globally Harmonized Classification System).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye 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:
REPORTING FORMAT FOR THE ANALOGUE APPROACH


1. HYPOTHESIS FOR THE ANALOGUE APPROACH

To reduce animal testing REACH recommends to make use of a read-across approach where appropriate based on the high accordance in properties relevant for the specific endpoint. In the case of irritation/corrosion relevant properties are structural similarity as well as physical-chemical properties in the same range. In the following paragraphs the read-across approach for N-[3-(dimethoxymethylsilyl)-2-methylpropyl]ethylenediamine (CAS 23410-40-4) is evaluated point by point.

Health hazards for both, skin irritation/corrosion and eye irritation, are characterised by local effects exhibited by the test material. Thus, similar toxicokinetics are not considered to be of importance for the development of an appropriate read-across strategy. Therefore, the following read-across justification will solely focus on the similarity of the physical-chemical properties and the structural similarity of the submission substance N-[3-(dimethoxymethylsilyl)-2-methylpropyl]ethylenediamine (CAS 23410-40-4) and the read-across substance N-[3-(dimethoxymethylsilyl)propyl]ethylenediamine (CAS 3069-29-2).
Both substances are close structural analogues, differing only in the alkyl amine moiety bound to the central atom silane, which is branched in te submissin substance and linear in the read-across substance. Both substances hydrolyse rapidly to similar hydrolysis products N-[3-(dihydroxymethylsilyl)-2-methylpropyl]ethylenediamine and N-[3-(dihydroxymethylsilyl)propyl]ethylenediamine (see Section 4.1.1.1). The hydrolysis half-lives are 15 min at 20-25°C and pH 7 (relevant for eyes).


2. SOURCE AND TARGET CHEMICAL(S)
Target: N-[3-(dimethoxymethylsilyl)-2-methylpropyl]ethylenediamine (CAS 23410-40-4) (purity >= 80%)
Source: N-[3-(dimethoxymethylsilyl)propyl]ethylenediamine (CAS 3069-29-2) (purity >= 80%)

3. ANALOGUE APPROACH JUSTIFICATION
The target substance showed no irritating effects on the skin (according to OECD 405). Slight erythema (grade 1) were observed in 3/3 animals, but were fully reversible within 11 days.
The source substance showed skin irritating properties with 24-72 h mean values of 3 for erythema in 2/3 animals. In addition erythema and edema scores were not fully reversible within 14 days in all animals.
The non-silanol hydrolysis product methanol is not expected to contribute to any local adverse effects.
It is therefore considered appropriate to read-across the available eye irritation data from N-[3-(dimethoxymethylsilyl)-2-methylpropyl]ethylenediamine (CAS 23410-40-4) to N-[3-(dimethoxymethylsilyl)propyl]ethylenediamine (CAS 3069-29-2) as a worst case scenario.

4. DATA MATRIX
CAS Number 23410-40-4 3069-29-2
Chemical Name N-[3-(dimethoxymethylsilyl)-2-methylpropyl]ethylenediamine N-[3-(dimethoxymethylsilyl)propyl]ethylenediamine
Si hydrolysis product N-[3-(dihydroxymethylsilyl)-2-methylpropyl]ethylenediamine N-[3-(dihydroxymethylsilyl)propyl]ethylenediamine
Molecular weight 220.38 g/mol 206.36 g/mol
log Kow (parent) 1.4 (QSAR) -2.0 (QSAR)
log Kow (silanol hydrolysis product) -1.0 (QSAR) -4.0 (QSAR)
Water solubility (parent) 4.5E+05 mg/L (QSAR) 8.6E+05 mg/L (QSAR)
Water solubility (silanol hydrolysis product) 1.0E+06 mg/L (QSAR) 1.0E+06 mg/L (QSAR)
Vapour pressure (parent) 0.76 Pa (QSAR) 1.1 Pa (QSAR)
Hydrolysis t 1/2 at pH 7 and 20-25 °C Not available 15 min (measured)
Hydrolysis t 1/2 at pH 4 and 37.5 °C Not available < 3 min (measured)
Hydrolysis t 1/2 at pH 9 and 20-25 °C Not available < 3 min (measured)
Reason / purpose:
read-across source
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
other: 30 min
Score:
3
Max. score:
4
Reversibility:
other: not possible to assess reversibility because animal was sacrificed in humanity after 30 min of observation
Irritation parameter:
iris score
Basis:
animal #1
Time point:
other: 30 min
Score:
1
Max. score:
2
Reversibility:
other: not possible to assess reversibility because animal was sacrificed in humanity after 30 min of observation
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: 30 min
Score:
3
Max. score:
3
Reversibility:
other: not possible to assess reversibility because animal was sacrificed in humanity after 30 min of observation
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: 30 min
Score:
4
Max. score:
4
Reversibility:
other: not possible to assess reversibility because animal was sacrificed in humanity after 30 min of observation
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Remarks:
sacrifice in humanity after 30 min of observation
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Remarks:
sacrifice in humanity after 30 min of observation
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Remarks:
sacrifice in humanity after 30 min of observation
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Remarks:
sacrifice in humanity after 30 min of observation
Irritant / corrosive response data:
Total score (one rabbit @ 30 mins): 85/110. Opalescent cornal opacity, iridial inflamation, severe conjunctival irriation. See table 1.
Other effects:
Conjunctival blood stained discharge and haemorrhage. Haemorrhage from nicating membranes.

Table 1: Irritant/corrosive response data for a single animal (study terminated at 30 mins)

Score at time point / Reversibility

Cornea

Iris

Conjunctivae

Chemosis

Discharge

Max. score: 4

Max. score: 2

Max. score: 3

Max. score: 4

Max. score: 3

30 min

3

1

3

4

3

Area effected

 4

-

-

-

-

Total score 85/110

60/80

5/10

20/20 

Reversibility

Not possible to assess; unlikely to be reversible

 

Interpretation of results:
other: CLP/EU GHS criteria are met, Catetgory 1 (irreversible effects on the eye) classification required according to Regulations (EC) No 1272/2008
Conclusions:
A reliable study, conducted according to OECD 405 and GLP, with the source substance showed eye damaging potential which is thus also estimated for the target substance.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation/corrosion

In the available key study (BSL, 2012), conducted according to the OECD 404, and in compliance with GLP, 0.5 ml of the registered substance was administered to 3 New Zealand White rabbits under semi-occlusive conditions for 4 h. The test sites were examined for skin irritations 1, 24, 48, and 72 h after test patch removal, as well as once daily thereafter. Erythema grade 1 were observed in all animals after 24 h and were reversible within 9 days in two animals and 11 days in the third animal. No oedema were observed in any test animal at any time point. Moreover, no additional systemic or local findings were reported after test material application, and no effects on body weights were observed throughout the study period. In conclusion, the test material can be considered to be not irritating to the rabbit's skin under the conditions of the test.

Eye irritation

There are no data available on eye irritation of N-[3 -(dimethoxymethylsilyl)-2 -methylpropyl]ethylenediamine. In order to fulfil the standard information requirements set out in Annex VII, 8.3., in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was conducted. In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across). Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical and toxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity. Therefore, read across from the structural analogue substance N-[3 -(dimethoxymethylsilyl)propyl]ethylenediamine was applied.

The key study for eye irritation, conducted according to OECD 405 and GLP, found N-[3-(dimethoxymethylsilyl)propyl]ethylenediamine (CAS 3069-29-2) to be a severe irritant to the eye based on a test in one rabbit in which a pain response, corneal opacity, iridial inflammation and severe conjunctival irritation were evident (Safepharm, 1987). Other recorded effects include conjunctival blood stained discharge and haemorrhage and haemorrhage from nicating membranes. The study was terminated without treatment of additional animals, in accordance with the test guideline. In conclusion, the effects were judged to indicate that the test material was a very severe to extremely severe irritant to the eyes of rabbits, and would be considered to cause irreversible eye effects according to EU criteria.

Based on the above result with the structural analogue substance sufficient evidence is given that the registration substance is considered to be damaging to the eyes.


Justification for classification or non-classification

The available data are reliable and suitable for classification. Based on this data, the registered substance meets the criteria to be classified for irreversible effects on the eye (Cat 1, H318) according to EC/1272/2008. Classification for skin irritation according to EC/1272/2008 is not warranted.