N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]ethylenediamine

Endpoint summary

Description of key information

Oral ( EPA OPPTS 870.1100): LD50 rat (male/female) = 2295 mg/kg bw (read across from CAS 1760 -24 -3)

Inhalation ( EPA OPPTS 870.1300): LC50 rat (male/female) = 1.49 - 2.44 mg/L(read across from CAS 1760 -24 -3)

Dermal ( EPA OPPTS 870.1200): LD50 rabbit > 2000 mg/kg bw (read across from CAS 1760 -24 -3)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

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

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 295 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 539 - <= 3 423

Remarks on result:

other:

Remarks:

CAS 1760-24-3, Dow Corning Corporation, 2001

Further supporting studies are available for the source substance CAS 1760-24-3:

Hazleton, 1992: LD50 male/female: 2413 mg/kg bw

Mellon Institute, 1975: LD50 male: 7460 mg/kg bw

Mellon Institute, 1966: LD50 male: 7460 mg/kg bw

Tejin: LD50 male: 2250 mg/kg bw; LD50 female: 1680 mg/kg bw (not used for classification as the documentation was insufficient for assessment)

Interpretation of results:

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

Conclusions:

Several acute oral toxicity studies are available for the source substance CAS 1760-24-3 which all show LD50 > 2000 mg/kg bw. As explained in the analogue justification, it is considered that the target and the source substances are unlikely to lead to differences in acute oral toxicity potential.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 295 mg/kg bw

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 1) from a source substance with similar structure and intrinsic properties. Read-across is justified based on common functional group and similarities in physico-chemical and toxicological properties (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

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

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 1.49 - < 2.44 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: CAS 1760-24-3, Dow Corning Corporation, 2000

Interpretation of results:

other: CLP/EU GHS criteria are met, Category 4 classification is required according to Regulations (EC) No 1272/2008.

Conclusions:

An acute inhalation (aerosol) study conducted to EPA OPPTS 870.1300, which is comparable to OECD 403, and to GLP (reliability score 1) is available with the source substance N-(3-(trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3). A LC50 between 1.49 - 2.44 mg/L was derived. As explained in the analogue justification, it is considered that the target and the source substances are unlikely to lead to differences in acute inhalation toxicity potential.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

1 490 mg/m³ air

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2) from a source substance with similar structure and intrinsic properties. Read-across is justified based on common functional group and similarities in physico-chemical and toxicological properties (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

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

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: CAS 1760-24-3, Dow Corning Corporation, 2000

Further supporting studies are available for the source substance CAS 1760-24-3:

Hazleton France, 1992: LD50 male/female > 2009 mg/kg bw

Mellon Institute, 1975: LD50 male = 16000 mg/kg bw

Mellon Institute, 1966: LD50 male > 16000 mg/kg bw

Interpretation of results:

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

Conclusions:

An acute dermal toxicity study conducted to EPA OPPTS 870.1200 (Acute Dermal Toxicity) and to GLP (reliability score 1) is available with the source substance N-(3-(trimethoxysilyl)propyl)ethylenediamine. The LD50 was at least 2000 mg/kg bw in rabbits as no deaths occurred at the highest dose of 2000 mg/kg bw. There were no clinical signs, macroscopic findings, or significant effects on bodyweight. The only findings were irritation at the application site. Three further supporting studies are available which support the key study. As explained in the analogue justification, it is considered that the target and the source substances are unlikely to lead to differences in acute dermal toxicity potential.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2) from a source substance with similar structure and intrinsic properties. Read-across is justified based on common functional group and similarities in physico-chemical and toxicological properties (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Additional information

Acute oral toxicity

 

Beside a non-guideline study without GLP compliance (Carnegie-Mellon Institute of Research, 1975, reliability score 4) no further reliable data on acute oral toxicity are available with N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]-ethylenediamine (CAS 35141-30-1). Therefore, read across from the similar substance N-(3-trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3) was applied.

Further details are provided in the analogue justification attached to the respective target entry.

The key study on acute oral toxicity conducted according to EPA OPPTS 870.1100 (Acute Oral Toxicity) and to GLP (Dow Corning Corporation, 2001) identified an LD50 for N-(3-(trimethoxysilylpropyl)ethylenediamine (CAS 1760 -24 -3) of 2295 mg/kg bw in rats. Five male and female Sprague Dawley rats were treated with 500, 1200, 3000 and 5000 mg/kg bw. Four males and all five females treated with 3000 mg/kg bw and all of those at 5000 mg/kg bw died during the study. Deaths occurred between 2 hours and Day 2 and are all considered to be treatment-related.. Piloerection was present at all doses, hunched posture, waddling/unsteady gait, pallid extremities, eyes dulled, increased salivation, abnormal respiration, ungroomed appearance, fecal disturbances, increased sensitivity and increased lacrimation (among rats at 1200, 3000 and/or 5000 mg/kg bw), walking on toes, blue/cold extremities, lethargy, partially closed eyelids and body tremors (3000 and 5000 mg/kg bw) and prostration (5000 mg/kg bw) were seen in test animals. These clinical signs had resolved by Day 6. All animals that died had congestive changes in the majority of organs and tissues. There were no changes in animals that survived to the end of the observation period.

Several supporting studies are also available for acute oral toxicity, of which the reliable studies are briefly described here. A reliable study with the read-across substance conducted to the now deleted OECD 401 but not in compliance with GLP, identified an LD50 of 7.46 mL/kg bw in male rats (Mellon Institute, 1966). A fairly briefly reported reliable study, conducted according to generally accepted scientific standards but prior to GLP, reported an LD50in rats of 7.46 mL/kg bw (Mellon Institute, 1975). A reliable study conducted in compliance with the now deleted OECD test guideline 401 and GLP, identified an oral LD50 of 2413 mg/kg bw for male and females rats treated with CAS 1760 -24 -3 (Hazleton 1992). The available studies support the key findings for acute oral toxicity. A more limited study cited in the OECD SIDS of 2003, for which it has not been possible to obtain the primary source (reliability 4), gives LD50 values in male and female rats of 2.25 and 1.68 mL/kg bw, respectively (Tejin, undated). Due to the insufficient documentation, this study could not be used for classification and labelling. However, these latter values would not give cause to doubt the validity of a classification based on the key and supporting studies.

 

An acute oral toxicity study with N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]-ethylenediamine (CAS 35141-30-1) was performed in a non-guideline study and was not GLP compliant (Carnegie-Mellon Institute of Research, 1975a). The test material was administered via oral gavage to 5 male Wistar rats each dose group (4080, 8160 and 16320 mg/kg bw), except in the 1020 mg/kg bw group, where only 2 male rats were used. The animals were observed for 14 days after administration. The LD50 was calculated to be 7609 mg/kg bw. The predominant clinical signs detected were sluggishness and deep breathing. 5/5 and 3/5 animals died on day 1 after dosing with 16320 and 8160 mg/kg bw of the test material, respectively. No deaths and no clinical signs throughout the study period were observed at 1020 and 4080 mg/kg bw. The gross pathology findings observed during the study period were lung petechial hemorrhages, mottled livers and spleens; distended transparent and liquid filled stomachs; distended, liquid filled and yellow intestines; and slightly congested kidneys. The results found with the registered substance support the results with the source substance and therefore N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]-ethylenediamine (CAS 35141-30-1) is also considered to be of low acute oral toxicity.

 

Acute inhalation toxicity

 

Besides a non-guideline study without GLP compliance (Carnegie-Mellon Institute of Research, 1975, reliability score 4) no further reliable data on acute inhalation toxicity are available with N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]-ethylenediamine (CAS 35141-30-1). Therefore, read across from the similar substance N-(3-trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3) was applied (Dow Corning Corporation, 2000). Further details are provided in the analogue justification attached to the respective target entry.

 

Five rats of each sex and dose were exposed to the structural analogue N-(3-trimethoxysilyl)propyl)ethylenediamine (CAS 1760 -24 -3) in a whole body exposure chamber for 4 h at concentrations (aerosols) of 0.515, 1.06, 1.49, 2.44 and 5.75 mg/L. The animals were observed for 14 days after administration. The LC50 was found to be > 1.49 - < 2.44 mg/L air. Eight out of ten animals (5 male, 3 female) died at a concentration of 2.44 mg/L during the observation period. Nine out of 10 animals (5 male, 4 female) died during the observation period when exposed to the highest concentration of 5.75 mg/L. No animals died at the lower dose levels. The predominant clinical signs detected during exposure were exaggerated breathing and partially closed eyes in all test groups as well as reduced motor activity in exposure groups 0.515 to 2.44 mg/L. Clinical signs recorded during the observation period were irregular noisy and/or exaggerated breathing in all groups as well as partially closed eyes in all treated groups, except the 0.515 mg/L group. Ataxia was observed in the two female rats from the 2.44 mg/L group that survived. A dose-related reduction in body weight gain over the observation period was observed in animals from 0.515 to 1.49 mg/L. Gross pathology revealed severely congested lungs in all deceased animals, which is considered to be associated with the cause of death. Pale raised lungs were also observed in the lungs of a proportion of surviving rats of both sexes in all other groups exposed to the test aerosol. Food consumption by the test groups was lower compared to the control group during the observation period. With the LC50 between 1.49 and 2.44 mg/L the test substance has to be classified as harmful if inhaled (Acute Cat. 4).

 

The acute inhalation study with N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]-ethylenediamine (CAS 35141-30-1) was not conducted following standard guidelines and without GLP compliance (Carnegie-Mellon Institute of Research, 1975). Six Wistar rats were exposed to a substantially saturated vapour of the test item in a whole body exposure chamber for 8 h. The exposure concentration is not given. The animals were observed for 15 days after administration. One out of six animals died at day 1 which could be due to hypoxia as a consequence of a decrease in the concentration of oxygen in the atmosphere. The predominant clinical signs detected were anesthesia and poor locomotor coordination during exposure and one day post-exposure. Gross pathology revealed no remarkable findings; mean body weight change of 32 to 74 g was recorded.

 

In the guideline study with the read across substance N-(3-trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3) marked toxicity was evident, whereas in the older study with the submission substance only mild toxicity was observed. However, the limited information and the non-standard procedure presented in the older submission substance report are not sufficient for assessment. Thus, data from the read-across substance are used for classification.

 

Acute dermal toxicity

 

Beside a non-guideline study without GLP compliance (Carnegie-Mellon Institute of Research, 1975, reliability score 4) no further reliable data on acute dermal toxicity are available with N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]-ethylenediamine (CAS 35141-30-1). Therefore, read across from the similar substance N-(3-trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3) was applied. Further details are provided in the analogue justification attached to the respective target entry.

 

The key study in acute dermal toxicity study was conducted to EPA OPPTS 870.1200 (Acute Dermal Toxicity) and to GLP (Dow Corning Corporation, 2000). An LD50 of >2000 mg/kg bw in rabbits was identified. No deaths occurred at this dose. There were no treatment-related clinical signs, macroscopic findings, or significant effects on bodyweight. The only findings were irritation at the application site. Persistent slight to moderate irritation (erythema with or without oedema up to Grade 3) was evident in all rabbits following removal of the dressings and over the following days. These reactions had notably ameliorated by the second week of the study with resolution in all but three animals complete by Day 15. In the remaining rabbits slight erythema (Grade 1) was still evident at study termination. Also notable in all rabbits during the first days following treatment was a very dry texture to the skin over the treatment site, desquamation of the skin on the treatment site (all rabbits and present in six rabbits at study termination) and in one rabbit localised necrosis/blanching evident throughout the observation period.

Two reliable supporting studies were also available for acute dermal toxicity. An acute dermal toxicity study conducted with the source substance N-(3-trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3) to OECD 402 and to GLP in rats identified an LD50 value of >2009 mg/kg bw (Hazleton, 1992). There were no deaths, clinical effects or abnormal macroscopic findings at this dose. A fairly briefly reported study, conducted with the source substance according to generally accepted scientific standards but prior to GLP, reported a LD50 in rabbits greater than 16 mL/kg bw (Mellon Institute, 1966 and 1975).

 

The acute dermal toxicity study with N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]-ethylenediamine (CAS 35141-30-1) was conducted according to a non-guideline study and was not GLP compliant (Carnegie-Mellon Institute of Research, 1975). The test material was administered via occlusive dressing to the intact skin of the trunk of 7 male Albino rabbits at a single dose of 16320 mg/kg bw for 24 h. The animals were observed for 14 days after administration. The LD50 was calculated to be greater than 16320 mg/kg bw. No clinical signs of toxicity were observed up to the end of the 14-day observation period. Two out of seven animals died at days 9 and 10, respectively. In these animals, congested kidneys were observed. The results found with registered substance support the results with the source substance and therefore N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]-ethylenediamine (CAS 35141-30-1) is also considered to be of low acute dermal toxicity.

Justification for classification or non-classification

Based on the available data of the read across substance N-(3-(trimethoxysilyl)propyl)ethylenediamine the registered substance

N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]-ethylenediamine (CAS 35141-30-1) is classified 'Acute Toxic 4 (mist) ' with the hazard statement 'H332: Harmful if inhaled' according to Regulation (EC) No 1272/2008. The registered substance is not classified for acute toxicity following oral or dermal exposure.