N-[3-(trimethoxysilyl)propylcyclohexylamine]

Endpoint summary

Description of key information

Skin irritation (OECD 404, rabbit): not irritating

Eye irritation (OECD 405, rabbit): causes irreversible effects to the eye (RA from N-methylaminopropyltrimethoxysilane, CAS 3069 -25 -8 and N-[3 -(trimethoxysilyl) propyl]butylamine, CAS 31024-56-3)

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:

21 - 28 Apr 1993

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

(1981)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Version / remarks:

(1984)

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Broekman Institute, Someren, The Netherlands
- Age at study initiation: 12 weeks
- Weight at study initiation: 2198 - 2452 g
- Housing: animals were housed individually in labelled cages with perforated floors
- Diet: approximately 100 g/day standard laboratory rabbit diet LKK-20 (Hope Farms, Woerden, The Netherlands), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- Humidity (%): 55
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

other: untreated sites of the same animal served as control

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied: 0.5 mL

Duration of treatment / exposure:

4 h

Observation period:

7 days
Reading time points: 45 min, 24, 48 and 72 h and 7 days

Number of animals:

3 males

Details on study design:

TEST SITE
- Area of exposure: 2 x 3 cm
- Type of wrap if used: A surgical gauze patch mounted on Micropore tape was used, the dressing was wrapped around the abdomen and secured with an elastic bandage.

REMOVAL OF TEST SUBSTANCE
- Washing: 4 h after the application the dressing was removed and residual test material was removed using a tissue moistened with tap water and subsequently a dry tissue.
- Time after start of exposure: 4 h

SCORING SYSTEM: Draize scoring system

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1.67

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.67

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 48 h

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 72 h

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 48 h

Irritant / corrosive response data:

Forty-five minutes after exposure to the test material, very slight (grade 1) or well defined erythema (grade 2) and very slight (grade 1) or slight edema (grade 2) were observed in the treated skin areas in 3/3 animals. The erythema persisted for 72 h and had resolved in 3/3 animals within 7 days after exposure to the test material. The edema had resolved within 48 h in 2/3 animals and within 72 h in 1/3 animal after exposure with the test material. No evidence of a corrosive effect was observed on the skin.

Other effects:

No symptoms of systemic toxicity were observed in the animals during the study period and no mortality occurred.

Table 1: Individual skin irritation scores

Observation time	Rabbit no.
	1		2		3
	Erythema	Edema	Erythema	Edema	Erythema	Edema
45 min	2	1	1	1	2	2
24 h	2	1	1	2	2	1
48 h	2	0	1	1	2	0
72 h	1	0	1	0	1	0
Mean value 24 + 48 + 72 h	1.67	0.33	1	1	1.67	0.33

Interpretation of results:

other: CLP/EU GHS criteria are not met, no classification required according to Regulations (EC) No 1272/2008

Conclusions:

In a primary skin irritation/corrosion study according to OECD guideline 404 and in compliance with GLP, three male New Zealand White rabbits were exposed to the test material for 4 h under semi-occlusive dressing. In conclusion, the test material can be considered as non-irritant under the conditions of the test.

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)

Remarks:

Summary of available data used for the endpoint assessment of the target substance

Adequacy of study:

key study

Justification for type of information:

Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

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: CAS 3069-25-8, Huls AG, 1989

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: CAS 3069-25-8, Huls AG, 1989

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: CAS 3069-25-8, Huls AG, 1989

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 21 days

Remarks on result:

other:

Remarks:

CAS 3069-25-8, Huls AG, 1989

Irritant / corrosive response data:

In a supporting study done with the read across substance CAS 31024-56-3 the following results were observed (Bushy Run Research Center, 1981):
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 iritis 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.

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:

In two in vivo acute eye irritation/corrosion studies in rabbit with the source substances CAS 3069-25-8 and CAS 31024-56-3 showed irreversible damage to the eyes. As explained in the analogue justification, it is considered that the target and the source substances are unlikely to lead to differences in eye irritation potential.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation

In the reliable skin irritation study performed with N-[3-(trimethoxysilyl)propylcyclohexylamine] (CAS 3068-78-8) according to OECD TG 404 and in compliance with GLP three male New Zealand White rabbits were exposed to 0.5 mL of the neat test material (CAS 3068-78-8) for 4 hours applied onto the shaved skin via semi-occlusive dressing (RCC, 1993). Skin reactions were evaluated according to the Draize scoring system 45 min, 24, 48 and 72 hours and 7 days post-application. No symptoms of systemic toxicity were observed in any animal during the test period and no mortality occurred during the course of the study. Forty-five minutes after exposure with the test material, very slight (grade 1) or well defined erythema (grade 2) and very slight (grade 1) or slight edema (grade 2) were observed in the treated skin areas in 3/3 animals. The erythema persisted for 72 h and had resolved in 3/3 animals within 7 days after exposure with the test material. The edema had resolved within 48 h in 2/3 animals and within 72 h in 1/3 animal after exposure with the test material. No evidence of a corrosive effect was observed on the skin. The mean values for erythema and edema were calculated to be 1.67, 1.0, 1.67 and 0.33, 1.0, 0.33, respectively.

 

Eye irritation

No data on the eye irritation of N-[3-(trimethoxysilyl)propylcyclohexylamine] (CAS 3068-78-8) are available. Therefore, the risk assessment was performed based on the available data from the source substances N-methyl-3-(trimethoxysilyl)propan-1-amine (CAS 3069-25-8) and N-[3-(trimethoxysilyl)propyl]butylamine (CAS 31024-56-3). In accordance with Regulation (EC) No. 1907/2006 Annex XI, 1.5 “Grouping of substances and read across” and in accordance with the Read across assessment framework (RAAF, ECHA 2017) read across from analogue substances has been applied to support the human health hazard assessment of N-[3-(trimethoxysilyl)propylcyclohexylamine] (CAS 3068-78-8). Details on read across justifications can be found in the attached justification in the respective target entry and in the overall justification for grouping of substances attached in IUCLID Section 13.

Studies were chosen as key when the available study was of relevance and of sufficient quality for classification and labelling and for risk assessment.

 

In the available key study (Hüls AG, 1989) conducted according to the OECD TG 405, but not in compliance with GLP, one Small White Russian rabbit was instilled with 0.1 mL of the undiluted N-methyl-3-(trimethoxysilyl)propan-1-amine (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-methyl-3-(trimethoxysilyl)propan-1-amine (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 iritis was noted from 0.005 mL undiluted test material per eye. In another dose group moderate to severe corneal injury with iritis 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.

Considering the positive results in tests with structural similar substances, it is concluded that the target substance N-[3-(trimethoxysilyl)propylcyclohexylamine] (CAS 3068-78-8) has eye damaging properties as well.

Justification for classification or non-classification

The available data on skin irritation/corrosion of the registered substance do not meet the criteria for classification according to Regulation (EC) No. 1272/2008, and are therefore conclusive but not sufficient for classification.

Reliable data from a structural analogue on eye irritation indicates that the registered substance meets the criteria for classification according to Regulation (EC) 1272/2008, and is therefore classified as Eye Damaging Category 1 (H318).