Registration Dossier

Administrative data

Description of key information

In the key skin irritation study (WIL, 2003), 3-(trimethoxysilyl)propylamine was found to be a skin irritant since effects were not fully reversed at the end of the observation period.

The key study for eye irritation was read across from the structurally analogous 3-aminopropyltriethoxysilane (CAS 919-30-2). The test substance is found highly irritating to the eye, and the result is further supported by weight of evidence from other amine containing alkoxysilanes (PFA, 2015t).

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:
from 20 Jan 2003 to 3 Feb 2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Remarks:
This study was conducted largely according to the appropriate OECD test guideline and in compliance with GLP.
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
observations only to 7 days, when effects still evident
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Covance Research Products Inc., Denver, PA, USA
- Age at study initiation: "young adult"
- Weight at study initiation: 3.018-3.171 kg
- Housing: 1/suspended wire mesh cage
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.5-19
- Humidity (%): 43.6-48.0. (The summary indicates the maximum humidity was 49.3%, the data provided do not appear to support this.)
- Photoperiod (hrs dark / hrs light): 12 h/12 h

IN-LIFE DATES: From: 2003-01-20 To: 2003-02-03 (14 days - although observational data are only given for 7 days)
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.5 ml
- Concentration: neat
Duration of treatment / exposure:
3 min
1 h
4 h
Observation period:
3-min: immediately and 1 (or 24) h
1-h: immediately and 24, 48, 73 h, and days 4 and 7
4-h: 1, 24, 48, 73 h, and days 4 and 7
Number of animals:
1 rabbit: 3-min, 1 h, 4 h
2 further rabbits: 4 h
Details on study design:
TEST SITE
- Area of exposure: 2.5 cm x 2.5 cm
- % coverage: not stated
- Type of wrap if used: 2-ply gauze secured with Micropore tape, overwrapped with gauze binder secured with Dermiform tape.

REMOVAL OF TEST SUBSTANCE
- Washing: yes
- Time after start of exposure: 3 min, 1 h, 4 h

SCORING SYSTEM: Draize, 1965. Mean of 1, 24, 48, 72 h
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Remarks:
of 3 animals
Time point:
other: 1, 24, 48, 72 h mean
Score:
1.8
Max. score:
8
Reversibility:
other: effects evident at 7 days, no data given after 7 days
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 7 days, no data given after 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 7 days, no data given after 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
4-Hour exposure caused erythema and oedema (grade 1 or 2) in up to three animals; erythema persisted to the final observation at 7 days. See tables 1-3.

Table 1: Irritant/corrosive response data for each animal after exposure for 3 minutes, at each observation time up to removal of each animal from the test

Score at time point / Reversibility

Erythema

Edema

Max. score: 4

Max. score: 4

Immediately after exposure

0

0

1 h*

0

0

Reversibility*

n/a

n/a

* the text describes a second observation at 1 h, the tabulated data describes the second observation at 24 h.

** Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

Table 2: Irritant/corrosive response data for each animal after exposure for 1 hour, at each observation time up to removal of each animal from the test

Score at time point / Reversibility

Erythema

Edema

Max. score: 4

Max. score: 4

Immediately after exposure

0

0

24 h

1

0

48 h

1

0

72 h

2a

1

4 days

1

1

7 days

0b

0

Reversibility*

c

n/a

Average time (unit) for reversion

7 days

 

* Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

a erythema spreading outside dosed site to

b = desquamation

Table 3: Irritant/corrosive response data for each animal after exposure for 4 hour, at each observation time up to removal of each animal from the test

Score at time point / Reversibility

Erythema

Edema

Max. score: 4

Max. score: 4

60 min

0/1/0

0/0/0

24 h

1/2/1

0/2/1

48 h

1/2/1

0/1/0

72 h

2a/2/1

1/1/1

4 days

2/1b/1

1/1/1

7 days

0b/1b/1b

0/0/0

Average 24 h, 48 h, 72 h (EU criteria)

1.3/2/1

0.3/1.3/0.7

Average 1 h, 24 h, 48 h, 72 h (as given in report); PII=1.8

1.2

0.6

Reversibility*

unclear

c

Average time (unit) for reversion

No data at 14 days

Day 7

* Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

a erythema spreading outside dosed site to

b = desquamation

Interpretation of results:
Category 2 (irritant) based on GHS criteria
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
A reliable study conducted broadly in accordance with OECD 404 and GLP, found the test material to be slightly irritating to the skin of rabbits. According to EU criteria, classification as a skin irritant is required since the observed effects were not reversed at the end of the study.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

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:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
not specified
Remarks:
SIAR (2003) notes that this laboratory was GLP certified at the date of this study
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: no details given
- Age at study initiation: : no details given
- Weight at study initiation: no details given
- Housing: no details given
- Diet: standard diet ad libitum
- Water : drinking water ad libitum
- Acclimation period: no details

ENVIRONMENTAL CONDITIONS
no details given

IN-LIFE DATES: no details given
Vehicle:
unchanged (no vehicle)
Controls:
other: the untreated eye usually serves as the control
Amount / concentration applied:
undiluted
Amount applied: 0.1 ml, 0.005 ml
Duration of treatment / exposure:
Eyes unwashed.
Observation period (in vivo):
Observation to 21 days in some cases
Number of animals or in vitro replicates:
6 (3/sex)
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: unwashed

SCORING SYSTEM: after Draize, 1959


TOOL USED TO ASSESS SCORE: fluorescein (for 1-day reading)
Irritation parameter:
cornea opacity score
Basis:
animal #1
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
2.33
Max. score:
4
Reversibility:
not reversible
Remarks:
Score of 4 at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #2
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks:
Score of 4 at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #3
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
not reversible
Remarks:
Score of 4 at 7.0 days
Remarks on result:
positive indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #4
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks:
Score of 4 at 7.0 days
Remarks on result:
positive indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #5
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
3.33
Max. score:
4
Reversibility:
not reversible
Remarks:
Score of 4 at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #6
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks:
Score of 2 at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #1
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
not reversible
Remarks:
Score of 1 at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #2
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
2.33
Max. score:
3
Reversibility:
not reversible
Remarks:
Score of 2 at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #3
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
not reversible
Remarks:
Score of 1 at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #4
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
2.33
Max. score:
3
Reversibility:
not reversible
Remarks:
Score of 2 at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #5
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
2.66
Max. score:
3
Reversibility:
not reversible
Remarks:
Score of 2 at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #6
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
2.33
Max. score:
3
Reversibility:
not reversible
Remarks:
Score of 1 at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #1
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not reversible
Remarks:
Score of 1 at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #2
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
1.66
Max. score:
4
Reversibility:
not reversible
Remarks:
Score of 1 at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #3
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks:
Score of 1 at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #4
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not reversible
Remarks:
Score of 1 at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #5
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks:
Score of 2 at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #6
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks:
Score of 1 at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
iris score
Basis:
animal #1
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
other: Scoring not possible at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
iris score
Basis:
animal #2
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
other: Scoring not possible at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
iris score
Basis:
animal #3
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
other: Scoring not possible at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
iris score
Basis:
animal #4
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
other: Scoring not possible at 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
iris score
Basis:
animal #5
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
other: Scoring not possible at 72 hours and 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
iris score
Basis:
animal #6
Remarks:
0.1 ml
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Remarks on result:
positive indication of irritation
Irritant / corrosive response data:
0.1 ml: severe corneal injury, iritis, severe conjuctival irritation and necrosis of the conjunctivae within 1 h. Because of the severe, possibly irreversible, irritation at 7 days all animals were sacrificed. See table 1.

0.005 ml: minor to severe corneal injury with necrosis of the conjunctivae within 1 h. Two of six had recovered at 7 days and only 2 showed clear effects at 14 and 21 days. See table 2.

Table 1: Irritant/corrosive response data, mean for 6 animals, dose 0.1 ml

Score at time point / Reversibility

Cornea

Iris

Conjunctivae

Chemosis

Discharge

Opacity

Max. score: 4

Area involved

Max. score 4

Congestion/swelling

Max. score: 2

Redness

Max. score: 3

Chemosis

Max. score: 4

Discharge

Max. score: 3

1 h

2.7

3.3

*1

2.0

1.7

3.0

4 h

2.8

2.7

*1

2.0

2.0

2.0

24 h

2.5

2.2

1.0

2.2

1.7

3.0

48 h

2.8

2.2

1.0

2.3

1.5

2.8

72 h

3.0

2.5

*1

2.3

1.7

2.7

7 days

3.7

3.7

*

1.5

1.2

1.7

Mean for 24, 48, 72 h

2.8

*

2.3

1.6

Reversibility

Considered possibly irreversible

* scoring not possible for 1 or more animals, mean for the remainder is given

Table 2: Irritant/corrosive response data, mean for 6 animals, dose 0.005 ml (data from selected time intervals are presented here)

Score at time point / Reversibility

Cornea

Iris

Conjunctivae

Chemosis

Discharge

Opacity

Max. score: 4

Area involved

Max. score 4

Congestion/swelling

Max. score: 2

Redness

Max. score: 3

Chemosis

Max. score: 4

Discharge

Max. score: 3

1 h

1.7

2.2

1.0

2.0

1.3

2.7

24 h

1.5

2.0

1.0

2.0

1.0

2.3

48 h

1.5

2.2

1.0

2.0

1.0

2.0

72 h

1.0

1.8

1.0

1.5

0.7

1.2

7 days

1.2

1.7

0.5

0.7

0

0.7

21 days

0.6

0.6

0

0

0

0

Reversibility

Not fully reversible within 21 days

Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Conclusions:
A reliable study, conducted largely according to OECD 405, but not GLP, reported severe eye irritation with necrosis in rabbits. The study was terminated for humane reasons at 7 days, when clear effects were still evident in all six animals.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The key skin irritation study (WIL, 2003) was the only available study for the registered substance for this endpoint that follows an appropriate OECD test guideline and is compliant with GLP and found 3-(trimethoxysilyl)propylamine to be slightly irritant; the effects were not reversed at the end of the observation period.  A second study is available and the minimal information it provided confirmed the result of the key study.

The key study for eye irritation was read across from 3-aminopropyltriethoxysilane (CAS 919-30-2) which found the test substance to be highly irritating to the eye (BRRC, 1989). No in vivo eye irritation data are available for the substance which meet the requirements of current guidelines. However, further testing is considered inappropriate because suitable read-across is available supported by a non-standard study (BRRC 1980) which also indicated that the substance is a severe eye irritant, with the neat material causing severe corneal damage with iritis using a small dose volume (0.005 ml).

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 eye irritation the relevant properties are structural similarity as well as physicochemical properties with similar values. In the following paragraphs the proposed read-across from 3-aminopropyltriethoxysilane to 3-(trimethoxysilyl)propylamine is described.

(a) Structural similarity

The registration and read-across substances are structurally similar and are members of an analogue group of amino silane substances. Both contain a silicon atom which is attached to an aminopropyl side chain. The aminopropyl side chains of the two substances are identical. Both substances also have three alkoxy groups bound to silicon. The only difference is that these three alkoxy groups are ethoxy for the read-across substance and methoxy groups for the registration substance. Both hydrolyse rapidly to produce the same silicon-containing hydrolysis product, 3-aminopropylsilanetriol, and either ethanol (for the read-across substance) or methanol (for the registration substance). Furthermore, the amino silane analogue group clearly shows a trend for skin and eye irritancy (PFA, 2015t).

(b) Similar physicochemical characteristics

A data matrix is attached in Section 13 of the IUCLID dossier, and the key physicochemical parameters are summarised below. The similarity of the hydrolysis rates at pH relevant to oral exposure is important. Both parent substances are very soluble in water, have low log Kow and low vapour pressure; they are of similar molecular weight.

Table 5.6.3:Key physicochemical parameters

 

Target (registration substance)

Source (read-across substance)

CAS Number

13822-56-5

919-30-2

EC number

237-511-5

213-048-4

Chemical Name

3-(Trimethoxysilyl)propylamine

3-Aminopropyltriethoxysilane

Purity

>97%

>98%

Impurities

Siloxane, alkoxysilanes, alcohol and ester

Siloxane, alkoxysilanes, alcohol and ester

Molecular weight (gmol-1)

179.3

221.4

log Kow(parent)

-2.8 at pH 7

-1.3 at pH 7

log Kow(silanol hydrolysis product)

-4 at pH 7

-4 at pH 7

Water solubility (parent)

5.7E+05 mg/l

1.7E+04 mg/l

Water solubility (silanol hydrolysis product)

1E+06 mg/l (predicted, in practice limited to approximately 1000 mg/l by condensation reactions)

1E+06 mg/l (predicted, in practice limited to approximately 1000 mg/l by condensation reactions)

Vapour pressure (parent)

18 Pa at 25°C

4 Pa at 25°C

Vapour pressure (silanol hydrolysis product)

2.5E-04 Pa at 25°C

2.5E-04 Pa at 25°C

Hydrolysis t1/2at pH 7 and 20-25°C

2.6 h

8.5 h at 24.7°C

Hydrolysis t1/2at pH 2 and 37.5°C (relevant for oral exposure)

5 seconds

5 seconds

 

(c) non-silanol hydrolysis products

The non-silanol hydrolysis products, methanol and ethanol, do not contribute to any irritant effects at the relevant concentrations based on publicly available information (OECD, 2004).



Justification for classification or non-classification

On the basis of the in vivo skin irritation study in which effects were not fully reversed by the end of the observation period, 3-(trimethoxysilyl)propylamine requires classification as a skin irritant and labelled Skin Irrit. 2; H315: causes skin irritation, according to Regulation (EC) No 1272/2008.

Based on a read across from 3-aminopropyltriethoxysilane, 3-(trimethoxysilyl)propylamine requires classification as a severe eye irritant and labelled Eye. Dam. 1; H318: causes serious eye damage, according to Regulation (EC) No 1272/2008.