Registration Dossier

Administrative data

Description of key information

The key study for skin irritation is read across from the structurally analogous substance 1-methyl-N,N',N''-tris(1-methylpropyl)silanetriamine (CAS 37697-65-7). The study, which was conducted according to OECD TG 404 and in compliance with GLP, reports that the test substance is corrosive to skin (Hazleton, 1990).

In accordance with Column 2 of REACH Annex VIII, the in vivo eye irritation study (required in Section 8.2.1) does not need to be conducted as the substance is classified as corrosive to skin.

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:
1988-08-05 to 1990-04-11
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
read-across source
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Principles of method if other than guideline:
6 animals used.
GLP compliance:
yes
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, France
- Age at study initiation: adult
- Weight at study initiation: 2.40 - 2.65 kg
- Housing: individually hosted in polystyrene cages
- Diet: 150 g per rabbit per day of complete pelleted rabbit maintenance diet
- Water: softened and filtered mains drinking water, ad libitum
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 -23
- Humidity (%): 36 - 75 % R.H.
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5ml


Duration of treatment / exposure:
3 minutes (group 1) or 4 hours (group 2)
Observation period:
14 days (at 1h, 24h, 48h and 72h)
Number of animals:
6 males per group (2 groups)
Details on study design:
TEST SITE
- Area of exposure: back and flank
- % coverage: no data
- Type of wrap if used: semi-occlusive dressing (perforated adhesive tape, applied on a band of gauze)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no
- Time after start of exposure: 3 minutes or 4 hours

SCORING SYSTEM: Draize
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks:
whole application area 'burned' by day 7 of observation. Desquamation by day 14.
Remarks on result:
other: corrosion
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
3.3
Max. score:
4
Reversibility:
not reversible
Remarks:
Whole application area 'burned' by day 7 of observation. Desquamation by day 14.
Remarks on result:
other: corrosion
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks:
whole application area 'burned' by day 7 of observation.
Remarks on result:
other: corrosive
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
3.3
Max. score:
4
Reversibility:
not reversible
Remarks:
whole application area 'burned' by day 7 of observation. Desquamation by day 14.
Remarks on result:
other: corrosive
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
24/48/72 h
Score:
3.7
Max. score:
4
Reversibility:
not reversible
Remarks:
whole application area 'burned' by day 7 of observation. Desquamation by day 14.
Remarks on result:
other: corrosive
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
24/48/72 h
Score:
2.7
Max. score:
4
Reversibility:
not reversible
Remarks:
whole application area 'burned' by day 7 of observation. Desquamation by day 14.
Remarks on result:
other: corrosive
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #5
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #6
Time point:
24/48/72 h
Score:
1.67
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritant / corrosive response data:
The erythema observations of group 1 (3 minutes application) showed that less than a quarter or half of the treated area, in all the individuals, was burnt. Dryness of the treated area could be also observed 72 hours post-treatment. Very slight edema was noted in 4 individuals, within the observation period.

The erythema observations of group 2 (4 hours application) showed that the treated area was necrotic and dry throughout the whole observation period. Slight to moderate edema was reported in most of the individuals within 72 hours post-exposure.
Other effects:
The severe lesions in group 1 (3 minutes application) at 72-hour observation, were reported to be noticeably reversible within 14 days post-application. However, when the test substance was applied for 4 hours to the area in group 2, no reversibility could be observed.
Interpretation of results:
Category 1B (corrosive) based on GHS criteria
Conclusions:
The skin irritation study, conducted according to OECD TG 404 and in compliance with GLP, reports that the substance, 1-methyl-N,N',N''-tris(1-methylpropyl)silanetriamine, is corrosive.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (corrosive)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The key study for skin irritation is read across from the structurally analogous substance 1-methyl-N,N',N''-tris(1-methylpropyl)silanetriamine (CAS 37697-65-7; source substance). The study was conducted according to OECD TG 404 and in compliance with GLP. The source substance, N,N',N''-tributyl-1-methylsilanetriamine (CAS 37697-65-7), is corrosive to skin (Hazleton, 1990).

Following a 3 minute application of the test material onto rabbit skin, erythema was evident in all the animals. Dryness of the treated area could be observed 72 hours post-treatment. The severe lesions at 72-hour observation, were reported to be noticeably reversible within 14 days post-application. Very slight oedema was noted in 4 out of the 6 rabbits, until the end of the 14 day observation period.

Following the 4 hour exposure, erythema was evident in all the animals, with necrosis and dry skin until the end of the observation period. Slight to moderate oedema was reported in 5 out of 6 of the animals at 72 hours post-exposure. There was no evidence for reversibility of the lesions, which remained until day 14 days after the application of the test material. In accordance with Column 2 of REACH Annex VIII, the in vitro eye irritation study (required in Section 8.2.1) does not need to be conducted as the substance is classified as corrosive to skin.

READ-ACROSS JUSTIFICATION

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 relevant properties are structural similarity, hydrolysis rate and the physical-chemical parameters in the same range. In the following paragraphs the proposed read-across from 1-methyl-N,N',N''-tris(1-methylpropyl)silanetriamine (CAS 37697-65-7) to 1,1-dimethyl-N,N'-bis(1-methylpropyl)silanediamine (CAS 93777-98-1; target substance) is evaluated point by point.

Read-across hypothesis

The hypothesis is that the predominant corrosive effect is due to the high pH of the substances and to their reactivity with water. The source and target substances produce the amine-functional hydrolysis product, sec-butylamine, which is of high pH and drives their corrosive properties. This is discussed further below.

Read-across justification

The measured hydrolysis half-lives of the registered target substance, 1,1-dimethyl-N,N'-bis(1-methylpropyl)silanediamine, at 25°C are <2 minutes at pH 4, 7 and 9. The products of hydrolysis are sec-butylamine (2 moles; CAS 13952-84-6) and dimethylsilanediol (1 mole; CAS 1066-42-8).

The source substance 1-methyl-N,N',N''-tris(1-methylpropyl)silanetriamine (CAS 37697-65-7) has measured hydrolysis half-lives at 25°C of < 2 minutes at pH 4 and pH 7 and 5.0 min at pH 9. As the hydrolysis reaction may be acid or base catalysed, the rate of reaction is expected to be slowest at pH 7 and increase as the pH is raised or lowered. The hydrolysis products are sec-butylamine (3 moles; CAS 13952-84-6) and methylsilanetriol (1 mole; CAS 2445-53-6).

The available half-lives for the source substance were all measured at 25°C. Reaction rate increases with temperature and the half-lives at 37.5°C (relevant for in vivo studies) are expected to be significantly faster.

No pH or pKa values are available for the parent substances; measurement would not be technically feasible as they hydrolyse extremely rapidly in water. Both substances hydrolyse rapidly to produce an amine, sec-butylamine. This substance (as for other amines) is basic, with a pKaof >9.5 (SIDS INITIAL ASSESSMENT PROFILE for C1 -13 Primary Amines; SIAM 32, 19-21 April 2011). Therefore, solutions of sec-butylamine will be of very high pH (for example a 50% solution of the structurally related substance n-butylamine has a pH of 13 according to the ECHA disseminated dossier for n-butylamine, CAS 109-73-9). Therefore, read-across from 1-methyl-N,N',N''-tris(1-methylpropyl)silanetriamine (CAS 37697-65-7) to 1,1-dimethyl-N,N'-bis(1-methylpropyl)silanediamine (CAS 93777-98-1) for skin irritation is valid.

Analogue approach justification

(a) Structural similarity

The target and source substances are structurally similar silylamines. They each have one or two methyl groups and two or three 1-methylpropylamine groups bound to a central silicon atom. The difference between the target and source substance is that the target substance has two methyl groups and two 1-methylpropylamine groups bound to silicon, whereas the source substance has one methyl group and three 1-methylpropylamine groups.  Both substances hydrolyse extremely rapidly (half-life for full hydrolysis <2 mins at pH 4 and 7) to produce the silicon-containing hydrolysis products, dimethylsilanediol or methylsilanetriol (1 mole) and the common non-silicon hydrolysis productsec-butylamine (2 moles for the target substance, 3 moles for the source substance).

(b) Similar physicochemical characheristics

The similarity of the physicochemical properties and hydrolysis rates at pH relevant to skin exposure is important. Both parent substances hydrolyse very rapidly to give a common product, sec-butylamine, and silanols that are structurally similar and have similar physicochemical properties. The key physicochemical parameters are summarised below.

 

Source

Target

Name

1-Methyl-N,N',N''-tris(1- methylpropyl)silanetriamine

1,1-Dimethyl-N,N'-bis(1- methylpropyl)silanediamine

CAS

37697-65-7

93777-98-1

EC

253-634-7

298-130-8

Amine leaving group

sec-butylamine (CAS 13952-84-6)

3 moles

sec-butylamine (CAS 13952-84-6)

2 moles

Si hydrolysis product

methylsilanetriol (CAS 2445-53-6)

1 mole

dimethylsilanediol (CAS 1066-42-8).

1 mole

Molecular weight

259.51

202.42

Hydrolysis

t1/2 at pH 7 and 25°C

< 2 min

< 2 min

Hydrolysis

t1/2 at pH 4 and 25°C

< 2 min

< 2 min

Hydrolysis

t1/2 at pH 5.5 and 25°C*

< 2 min (estimated)

< 2 min (estimated)

Vapour pressure amine leaving group

24000 Pa at 25°C

24000 Pa at 25°C

Water solubility amine leaving group

1.1E+05 mg/l

1.1E+05 mg/l

Log Kow amine leaving group

0.74

0.74

pKa amine leaving group

>9.5

>9.5

Vapour pressure silanol hydrolysis product

0.05 Pa at 25°C (QSAR)

7 Pa at 25°C (QSAR)

Water solubility silanol hydrolysis product

1E+06 mg/l (limited to around 1000 mg/l by condensation reactions)

1E+06 mg/l (QSAR) (limited to around 1000 mg/l by condensation reactions)

Log Kow silanol hydrolysis product

-2.4 (QSAR)

-0.4

*The half-life at pH 5.5 is expected to be between the half-lives at pH 4 and pH 7.

(C) Corrosive effects of the hydrolysis product, sec-butylamine

Both the target and source substances hydrolyse extremely rapidly to generate sec-butylamine. This substance is Classified in Annex VI of Regulation (EC) No 1272/2008 (CLP Regulation) as Skin Corr. 1A. The source substance produces 3 moles of sec-butylamine per mole of parent substance (85% by weight). The target substance produces 2 moles of sec-butylamine per mole of parent substance (72% by weight). Therefore, the read-across from the source to the target substance can be considered conservative.

Justification for classification or non-classification

Based on the available data on the read across substance, 1-methyl-N,N',N''-tris(1-methylpropyl)silanetriamine (CAS 37697-65-7), 1,1-dimethyl-N,N'-bis(1-methylpropyl)silanediamine is classified as Corrosive to Skin Category 1B, 'H314; Causes severe skin burns and eye damage' according to Regulation (EC) No 1272/2008.