Registration Dossier

Administrative data

Description of key information

Skin irritation: irritating
Eye irritation: causes irreversible effects to the eye

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin 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:
see in the endpoint summary for justification of read-across
Reason / purpose:
read-across source
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2.67
Max. score:
4
Reversibility:
fully reversible within: 17 days
Remarks on result:
other: no eschar formation observed
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 6 days
Remarks on result:
other: eschar formation after 72 h, fully reversible within 6 days
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 8 days
Remarks on result:
other: eschar formation after 72 h with detachment within 10 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 6 days
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 6 days
Interpretation of results:
other: CLP/EU GHS criteria are not met, no classification required according to Regulations (EC) No 1272/2008
Conclusions:
The target substance is considered to be not skin irritating based on this study result.
One study is available from the structural analogue N-methyl-3-(trimethoxysilyl)propan-1-amine (CAS 3069-25-8). In this study it was observed that the source substance is not irritating to skin according to Regulation (EC) No 1272/2008. As explained in the justification for type of information, the differences in molecular structure between the target and the source are unlikely to lead to differences in the skin irritation potential that are higher than the typical experimental error of the test method.
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
The chemical was applied in 0.01 mL amounts to clipped, uncovered intact skin of 5 rabbit bellies either undiluted or in progressive dilutions of 10, 1, 0.1, 0.01% in solvent. Additionally, a 4 h contact test (occlusive application) for the testing of corrosivity was performed. One of 10 grades is assigned based on appearence of moderate or marked capillary injection, erythema, oedema, or necrosis within 24 h. No injury from undiluted test material = Grade 1.
GLP compliance:
no
Species:
rabbit
Strain:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
- Fasting period before study: none
- Diet: appropriate diet ad libitum (not further specified)
- Water: ad libitum (not further specified)
Type of coverage:
other: Both open and occlusive was tested.
Preparation of test site:
shaved
Vehicle:
other: Both undiluted and diluted in solvent (not further specified) was tested.
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.01 mL
- Concentration (if solution): 10, 1, 0.1, 0.01% in solvent
Duration of treatment / exposure:
4 h
Observation period:
24 h
Number of animals:
5 animals (not further specified) for open administration, 6 animals (not further specified) for occlusive administration.
Details on study design:
TEST SITE
- Area of exposure: abdomen

SCORING SYSTEM: One of 10 grades is assigned based on appearence of moderate or marked capillary injection, erythema, oedema, or necrosis within 24 h. No injury from undiluted test material = Grade 1.
Irritation parameter:
overall irritation score
Basis:
mean
Remarks:
out of all animals tested
Time point:
24 h
Score:
4
Max. score:
10
Reversibility:
no data
Remarks on result:
other: The undiluted test material was openly applied and caused marked capillary injection on 4 rabbits and moderate erythema in one animal.
Irritation parameter:
other: necrosis
Basis:
mean
Remarks:
out of all 6 animals tested
Time point:
24 h
Score:
0
Max. score:
10
Reversibility:
other: reversibility: not applicable
Remarks on result:
other: The test material was occlusively applied to the rabbits for 4 h and did not cause necrosis. Hence, the test material was found to be "not corrosive".
Other effects:
No further effects were reported.
Interpretation of results:
study cannot be used for classification
Conclusions:
The test item was tested for its skin irritating properties in a non-guideline study and without GLP compliance. The chemical was applied in 0.01 mL amounts to clipped, uncovered intact skin of 5 rabbit abdomen either undiluted or in progressive dilutions of 10, 1, 0.1, 0.01% in solvent. Additionally, a 4 h contact test (occlusive application) for the testing of corrosivity was performed. The undiluted test material was opnely applied and caused marked capillary injection on 4 rabbits and moderate erythema in one animal. Furthermore, the test material was occlusively applied to the rabbits for 4 h and did not cause necrosis. Hence, the test material was found to be "not corrosive". In conclusion, the test material was found to be irritating under the conditions of the test.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
Only the eyes of rabbits not staining with 5% fluorescein in 20 s contact were accepted for the study. Single instillation of 0.005, 0.02, 0.1, or 0.5 ml undiluted or 0.5 ml of 40, 15, 5, or 1% test material dilutions were made into the conjunctival sac of 5 rabbits. The eyes were read immidiately unstained and after fluorescein at 24 h, with 1 of 10 grades assigned. Trace or no injury from undiluted test material = Grade 1.
GLP compliance:
no
Species:
rabbit
Strain:
not specified
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Fasting period before study: none
- Diet: appropriate diet ad libitum (not further specified)
- Water: ad libitum (not further specified)
Vehicle:
other: Both undiluted and diluted in propylene glycol (PG) was tested.
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.005, 0.02, 0.1, or 0.5 ml undiluted or 0.5 ml of dilutions
- Concentration (if solution): 40, 15, 5, or 1%
Duration of treatment / exposure:
24 h
Observation period (in vivo):
24h
Number of animals or in vitro replicates:
5 (not further specified)
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: no

SCORING SYSTEM: 1 of 10 grades assigned. Trace or no injury from undiluted test material = Grade 1.

TOOL USED TO ASSESS SCORE: with and without fluorescein
Irritation parameter:
overall irritation score
Basis:
mean
Remarks:
over all animals tested
Time point:
other: 24 h
Score:
9
Max. score:
10
Reversibility:
not specified
Remarks on result:
other: Severe corneal injury with irritis from 0.05 ml undiluted test material per eye; moderate to severe corneal injury with irritis one animal treated with 0.5 ml of 5% test material diluted in PG; no injury o 5 eyes from 1% test material in PG
Other effects:
No further effects were reported.
Interpretation of results:
study cannot be used for classification
Conclusions:
The test item was tested for its eye irritating properties in a non-guideline study and without GLP compliance. Single instillation of 0.005, 0.02, 0.1, or 0.5 ml undiluted or 0.5 ml of 40, 15, 5, or 1% test material dilutions in propylene glycol were made into the conjunctival sac of 5 rabbits. Severe corneal injury with irritis from 0.05 ml undiluted test material per eye and moderate to severe corneal injury with irritis one one animal treated with 0.5 ml of 5% test material diluted in propylene glycol were oserved. No injury was observed in 5 eyes treated with 1% test material in propylene glycol. Hence, the test item was concluded to cause severe damage to the eyes.
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:
see endpoint summary for justification of read-across
Reason / purpose:
read-across source
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks:
within 21 days
Remarks on result:
other: Opacity was observed for an area greater than three quarters up to the whole area.
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
not reversible
Remarks:
within 21 days
Remarks on result:
other: The iris was observed to be strongly reddened with haemorrhage. Delayed iris reaction was noted until day 6 post-treatment, and circumcorneal injection occurred on day 6 and persisted until study termination.
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not reversible
Remarks:
within 21 days
Remarks on result:
other: Necrosis and haemorrhage of the nictitating membrane and the conjunctiva was noted after 24 h until day 6 post-treatment.
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 21 days
Interpretation of results:
other: CLP/EU GHS criteria are met, Categroy 1 (irreversible effects on the eye) classification required according to Regulations (EC) No 1272/2008
Conclusions:
The target substance is considered to be eye damaging.
One study is available from the structural analogue N-methyl-3-(trimethoxysilyl)propan-1-amine (CAS 3069-25-8). In this study it was observed that the source substance is damaging to eyes according to Regulation (EC) No 1272/2008. As explained in the justification for type of information, the differences in molecular structure between the target and the source are unlikely to lead to differences in the eye irritation potential that are higher than the typical experimental error of the test method.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No reliable information about skin irritation/corrosion and eye irritation is available for the registered substance, however, reliable data are available for the closely related substance N-Methylaminopropyltrimethoxysilane (CAS 3069-25-8). The read-across is justified as follows:

 

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/corrosion relevant properties are structural similarity as well as physical-chemical properties in the same range. In the following paragraphs the read-across approach N-[3-(trimethoxysilyl) propyl]butylamine (CAS 31024-56-3) is evaluated point by point.

 

Read-across hypothesis

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 physico-chemical properties and the structural similarity of the submission substance N-[3-(trimethoxysilyl) propyl]butylamine (CAS 31024-56-3) and the read-across substance N-Methylaminopropyltrimethoxysilane (CAS 3069-25-8).

Both substances are close structural analogues, differing only in the length of the alkyl amine moiety bound to the central silicium. Both substances hydrolyse to similar hydrolysis products N-[3-(trihydroxysilyl) propyl]butylamine and N-Methylaminopropyltrihydroxysilane (see Section 4.1.1.1).

Available data indicate that both substances seem to be irritating to skin and may cause damage to the eyes. It is therefore considered appropriate to read-across the available data from N-Methylaminopropyltrimethoxysilane (CAS 3069-25-8) to N-[3-(trimethoxysilyl) propyl]butylamine (CAS 31024-56-3) in a weight of evidence approach.

The non-silanol hydrolysis product methanol is not expected to contribute to any local adverse effects.

Additional information is given in a supporting report (PFA, 2013a) attached in Section 13 of the IUCLID 5 dossier.

 

Discussion of results:

Skin irritation/corrosion:

There are two skin irritation/corrosion studies available (Hüls AG, 1989a and Bushy Run Research Center, 1981), which are suitable for a weight of evidence approach.

In the first study (Hüls AG, 1989a), N-Methylaminopropyltrimethoxysilane (CAS 3069-25-8) was investigated for skin irritation/corrosion according to the OECD TG 404, but not in compliance with GLP. 3 male Small White Russian rabbits were administered 0.5 mL of the undiluted test substance for 4 h under semiocclusive conditions. 1, 24, 48, and 72 h, as well as 6, 8, 10, 13, 17, and 21 days after removal of the test item the skin reactions were recorded. The mean erythema scores over 24, 48, and 72 h noted were 2.67, 1, and 2, respectively, and the mean oedema scores were 2, 0.3, and 2, respectively. In one animal showing the strongest erythema reaction, the effect was reversible within 17 days.

In the second study, N-[3-(trimethoxysilyl)propyl]butylamine (CAS 31024-56-3) was tested for its skin irritating properties in a non-guideline study and without GLP compliance. 0.01 mL of the registered substance was applied to clipped, uncovered intact skin of 5 rabbits abdomen either undiluted or in progressive dilutions of 10, 1, 0.1, and 0.01% in solvent. Additionally, a 4 h contact test (occlusive application) for the testing of corrosivity was performed. The undiluted test material was openly applied and caused marked capillary injection on 4 rabbits and moderate erythema in one animal. No individual scores were given in the study report. Furthermore, the test material was occlusively applied to the rabbits for 4 h and did not cause necrosis. Hence, N-[3-(trimethoxysilyl)propyl]butylamine was found to be "not corrosive".

Classification for skin irritation Cat 2 according to EC/1272/2008 is warranted, if two or more animals show mean erythema or oedema scores of 2.3 or more. According to this criteria CAS 3069 -25 -8 does not need to be classified since only one animal showed erythema scores above the score of 2.3 and reversibiliy within the observation period of 21 days (Hüls AG , 1989). Nevertheless, mild irritation potential can be concluded for CAS 3069 -25 -8 since mean values between 1.5 and 2.3 for erythema and/or oedema from gradings in 2 of 3 tested animals from grades at 24, 48, and 72 hours are observed. The acute dermal toxicity study (Bushy Run Research Center, 1981) further supports the irritation potential of the registered substance, as erythema, oedema and necrosis were the predominant clinical signs seen in the animals treated with N-[3-(trimethoxysilyl)propyl]butylamine (CAS 31024 -56-3).

In conclusion, as worst case N-[3-(trimethoxysilyl)propyl]butylamine (CAS 31024 -56-3) was considered to be irritating to the skin.

 

Eye irritation:

In the available key study (Hüls AG, 1989) conducted according to the OECD TG 405, but not in compliance with GLP, 1 Small White Russian rabbit was instilled with 0.1 ml of the undiluted N-Methylaminopropyltrimethoxysilane (CAS 3069-25-8) into the eye. It is not stated in the study report, whether the test item was administered into both eyes or one eye remained untreated and served as control. After 1 h severe redness and chemosis of the conjunctiva, corneal opacity grade 3 and iridic irritation grade 1 were observed. Moreover, iris reaction was delayed. Similar reactions persisted after 24 h and necrosis of the nictitating membrane and the conjunctiva was observed, in addition to strongly reddened iris in combination with haemorrhage. Treatment of the eyes with fluorescein revealed opacity of an area greater than three quarters up to the whole area. The mean scores over 24, 48, and 72 h were 2, 1, 3, and 1 for cornea, iris, redness, and chemosis, respectively. Only the noted chemosis was reversible within 21 days; all other damages were still persistent at study termination. Since the measured pH value of the test item was 12.3, only one animal was tested for acute eye irritation in this study. It can be concluded that the severe eye effects could be due to the strong alkalinity of the test substance. Based on this result, N-Methylaminopropyltrimethoxysilane (CAS 3069-25-8) is considered to cause irreversible effects on the eye.

In the supporting study (Bushy Run Research Center, 1981) N-[3-(trimethoxysilyl)propyl]butylamine (CAS 31024-56-3) was tested for its eye irritating properties in a non-guideline study and without GLP compliance. Single instillation of 0.005, 0.02, 0.1, or 0.5 ml undiluted or 0.5 ml of 40, 15, 5, or 1% test material dilutions in propylene glycol were made into the conjunctival sac of 5 rabbits. Severe corneal injury with irritis was noted from 0.005 ml undiluted test material per eye. In another dose group moderate to severe corneal injury with irritis was observed in one animal treated with 0.5 ml of 5% test material diluted in propylene glycol. No injury was observed in 5 eyes treated with 1% test material in propylene glycol. No individual scores were given in the study report. Hence, N-[3-(trimethoxysilyl)propyl]butylamine (CAS 31024-56-3) was concluded to cause severe damage to the eyes.

Justification for classification or non-classification

The available data is 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) and skin irritancy (Cat 2) according to EC/1272/2008.