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Description of key information

The key study for acute oral toxicity determined an LD50 value of 2295 mg/kg bw in rats, in a reliable study conducted according to an appropriate test protocol and in compliance with GLP (Dow Corning Corporation, 2001).

The key study for acute inhalation toxicity determined an LC50 value of 1.49 -2.44 mg/l in rats, in a reliable study conducted according to an appropriate test protocol and in compliance with GLP (Dow Corning Corporation, 2000a).

The key study for acute dermal toxicity determined an LD50 value of >2000 mg/kg bw in rabbits, in a reliable limit test conducted according to an appropriate test protocol and in compliance with GLP (Dow Corning Corporation, 2000b).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
14.09.1998 to 09.02.2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: No data
- Age at study initiation: 7-12 weeks
- Weight at study initiation: 202-286 g
- Fasting period before study: Yes, overnight
- Housing: Individually, in suspended metal cages with mesh floors
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Seven days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22± 3
- Humidity (%): 30-70
- Air changes (per hr): Minimum of 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 24.09.1998 To: 25.11.1998
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 4.954 ml/kg
Doses:
500, 1200 (initially only two males and two females were treated on humane grounds to ensure the dose level selected did not result in greater than 50% mortality), 1200, 3000 and 5000 mg/kg bw
No. of animals per sex per dose:
Five
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All rats were observed daily for mortality and morbidity. The bodyweight of each rat was recorded on Days 1 (prior to dosing, 8 and 15 (or at death). Clinical signs were observed immediately after dosing and at approximately hourly intervals for the remainder of Day 1. On subsequent days animals were observed twice daily.
- Necropsy of survivors performed: yes
- Other examinations performed: Macroscopic examination
Statistics:
The acute median lethal dose was calculated using the method of Finney.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 295 mg/kg bw
Based on:
test mat.
95% CL:
>= 1 539 - <= 3 423
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
1 897 mg/kg bw
Based on:
test mat.
95% CL:
>= 1 077 - <= 3 343
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
2 574 mg/kg bw
Based on:
test mat.
95% CL:
>= 1 931 - <= 3 431
Mortality:
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. There were no deaths in the other groups.
Clinical signs:
Piloerection (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). These clinical signs had resolved by Day 6.
Body weight:
No significant effect.
Gross pathology:
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.
Interpretation of results:
GHS criteria not met
Conclusions:
In an acute oral toxicity study conducted to EPA OPPTS 870.1100 (Acute Oral Toxicity) and to GLP (reliability score 1) the LD50 for N-(3-(trimethoxysilyl)propyl)ethylenediamine was 2295 mg/kg bw in rats. Piloerection (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). 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.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
2 295 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
05.10.1998 to 22.06.2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River UK Limited
- Age at study initiation: 7-8 wk
- Weight at study initiation: 186-345g
- Fasting period before study: no
- Housing: Stainless steel sheet and wire mesh suspended cages (holding cages)
- Diet (e.g. ad libitum): Ad libitum (except during exposure)
- Water (e.g. ad libitum): Ad libitum (except during exposure)
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21± 2
- Humidity (%): 55± 10
- Air changes (per hr): 12-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 09.11.1998 To: 06.04.1999
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: whole body exposure chamber
- Exposure chamber volume: The whole body exposure chambers were 51 cm x 51 cm x 38 cm. The chambers were fitted with a pyramidal top section with an enclosed volume of approximately 120 litres.
- Method of holding animals in test chamber: Individual compartments
- Source and rate of air: Compressed air line at flow rate of 25 l/min
- Method of conditioning air: filtered, dried and oil-free
- System of generating aerosols: The test substance was metered at a constant rate from a polypropylene syringe mounted on a syringe pump to a stainless steel concentric jet atomiser. The aerosol produced passed through a 2-piece glass elutriator prior to entering the exposure chamber. During the first exposure with animals the test substance was observed to form a solid substance on contact with water. It was considered that the water vapour produced by the animals during exposure resulted in most of the silane in the chamber being converted to an aerosol of this solid.
- Method of particle size determination: Two additional air samples were taken during the exposure, at a sampling rate of 2 l/min, using a Marple cascade impactor. The amount of test substance collected on the stages of the sampler was determined gravimetrically. The particle size distribution of the test substance was assessed using linear regression analysis of the probit of the cumulative percentage of the total particles collected, smaller that the cut-point of each stage, against the logarithm of the cut-point of each stage.
- Treatment of exhaust air: Test atmosphere was extracted through a perforated base into a large extract cabinet exhausting to atmosphere through an absolute filter.
- Temperature, humidity, pressure in air chamber: 21-23 oC, 39-61%, pressure not clear

TEST ATMOSPHERE
- Brief description of analytical method used: At least five samples of air were removed from the test chamber at intervals during each exposure in order to determine the concentration of the test aerosol. Following the first exposure each air sample was withdrawn through a pre-weighed glass fibre filter mounted in an open face filter holder. The filters were re-weighed following sampling for gravimetric analysis of the test aerosol. For the first test group exposure only, in addition to sample collected on glass fibre filters, attempts were made to collect samples using sintered glass bubblers containing toluene as trapping agent to determine the actual silane concentration by chemical analysis. It had previously been determined that the aerosol of the silane formed a solid substance on contact with water vapour in air, which could not be analysed chemically with the method established. Therefore analysis of the test atmosphere produced from the test substance was analysed by gravimetric means only.
- Samples taken from breathing zone: Not clear from information given.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
Target: 0.5, 1.0, 1.5, 2.0 and 5.0 mg/l
Analysed: 0.515, 1.06, 1.49, 2.44 and 5.75 mg/l
No. of animals per sex per dose:
Five
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The rats were observed continuously for signs of reaction during exposure and at least twice daily throughout the observation period. The clinical signs were recorded at the end of the chamber equilibrium period, 0.25, 0.5 and 1.0 hours into exposure then at hourly intervals during the remainder of the exposure. Signs were also recorded immediately after exposure and at 1 and 2 hours after exposure. During the observation period, signs were recorded twice daily. All rats were weighed at least twice during the week prior to exposure, immediately before exposure and weekly during the observation period.
- Necropsy of survivors performed: yes
- Other examinations performed: The amount of food consumed by each cage of rats was measured from weigh day to weigh day throughout the study. The amount of water consumed by each cage of rats was measured daily from Day 2 of the observation period following the gross observation of reduced consumption in the test rats. A complete macroscopic examination of each rat was performed. The lungs, liver and kidneys were weighed.
Statistics:
None
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 1.49 - < 2.44 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
See Table 2.
Clinical signs:
other:
Body weight:
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:
Severely congested lungs were observed in all deceased animals. The observation is considered to be associated with the cause of death. Areas of severe congestion together with pale raised hardened areas were also observed in the surviving female exposed to 5.75 mg/l. 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.
Other findings:
Food consumption by test groups was lower than that of the control group during the observation period.

Surviving female rats exposed to 2.44 or 5.75 mg/l had lung weights greater than control rats. In all other surviving animals from other test groups there were no differences in organ weights that were considered to be a direct effect of exposure to the test aerosol. Lower liver weights observed in test group survivors were considered to be a secondary effect of reduced body weight gains.

Table 2 Summary of mortality data

 Group (mg/l)  Mortality      
   Male  Female  Total
 0  0/5  0/5  0/10
 0.515 0/5   0/5  0/10
 1.06  0/5  0/5  0/10
 1.49  0/5  0/5  0/10
 2.44  5/5  3/5  8/10
 5.75  5/5  4/5  9/10
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
In an acute inhalation (aerosol) study conducted to EPA OPPTS 870.1300, which is comparable to OECD 403, and to GLP (reliability score 1) the LC50 for N-(3-(trimethoxysilyl)propyl)ethylenediamine was 1.49 -2.44 mg/l.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
1 490 mg/m³

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
14.09.1998 to 25.02.2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: No data
- Age at study initiation: At least 12 weeks
- Weight at study initiation: 2494-2828 kg
- Fasting period before study: No
- Housing: Individually in suspended metal cages with perforated floors
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-22
- Humidity (%): 40-65
- Air changes (per hr): 15-19
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 24.09.1998 To: 08.10.1998
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: lumbar region
- % coverage: approximately 10%
- Type of wrap if used: porous (< 8 ply) gauze held in place with a non irritating dressing, and further covered by a waterproof dressing

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit):1.982 mL/kg bw
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
Five
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All rabbits were observed twice daily for mortality and morbidity. The bodyweight of each animal was recorded on Days 1 (prior to dosing), 8 and 15. Animals were observed immediately after dosing and at approximately hourly intervals for the remainder of Day 1. On subsequent days animals were observed twice.
- Necropsy of survivors performed: yes
- Other examinations performed: Dermal responses were examined on Day 2 to 15. Skin reactions were scored according to the Draize scoring system. A gross macroscopic examination of each animal was conducted.
Statistics:
Mean body weights were calculated. No other statistical analyses were conducted.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No deaths.
Mortality:
No deaths occurred.
Clinical signs:
There were no treatment-related clinical signs of toxicity, except fecal disturbance in one female rabbit.
Body weight:
Slight weight loss was recorded for two females on Day 8, with more notable weight loss in a further female on Day 15, but these findings were not considered to be of any toxicological significance.
Gross pathology:
No abnormal findings.
Other findings:
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.
Interpretation of results:
GHS criteria not met
Conclusions:
In an acute dermal toxicity study conducted to EPA OPPTS 870.1200 (Acute Dermal Toxicity) and to GLP (reliability score 1) the LD50 for N-(3-(trimethoxysilyl)propyl)ethylenediamine was at least 2000 mg/kg bw in rabbits. No deaths occurred at this dose. There were no clinical signs, macroscopic findings, or significant effects on bodyweight. The only findings were irritation at the application site.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

An LD50 value of 2295 mg/kg bw in rats is reported in the key acute oral study conducted to EPA OPPTS 870.1100 (Acute Oral Toxicity) and to GLP (Dow Corning Corporation, 2001). Deaths occurred at 3000 and 5000 mg/kg bw but in no other groups (500 and 1200 mg/kg bw). Overt toxicity including hunched posture, waddling or unsteady gait, pallid extremities, abnormal respiration or lethargy occurred at 1200 mg/kg bw and above. All animals that died had congestive changes in the majority of organs and tissues.

 

Three other rat gavage studies conducted according to an appropriate test protocol, with or without GLP (reliability 1 or 2), provide LC50 values in excess of that of the key study (Mellon Institute 1966 and 1975; Wacker, 1992). A more limited study cited in the SIAR of 2003, for which it has not been possible to obtain the primary source (reliability 4), gives LC50 values in male and female rats of 2.3 and 1.7 ml/kg bw, respectively (Tejin, undated). These latter values would not give cause to doubt the validity of a classification based on the key and supporting studies.

 

 

The key acute inhalation study identified an LC50 value in rats in the range 1.49 -2.44 mg aerosol/l, in a reliable study conducted according to EPA OPPTS 870.1300 (comparable to OECD 403), and to GLP (Dow Corning Corporation, 2000a). Deaths occurred at 2.44 mg/l, and above, but not at or below 1.49 mg/l. Overt toxicity (exaggerated breathing, partially closed eyes) was seen in all groups during exposure with reduced motor activity at 1.06 to 2.44 mg/l. Ataxia occurred in the two female survivors from the 2.44 mg/l group. Severely congested lungs were observed in all animals that succumbed.

 

No other studies were suitable for consideration.

 

 

An LD50 in rabbits greater that 2000 mg/kg bw was identified in the key acute dermal toxicity study, conducted to EPA OPPTS 870.1200 (Acute Dermal Toxicity) and to GLP (Dow Corning Corporation, 2000b). At this limit dose there were no deaths, clinical signs of concern, macroscopic findings or significant effects on bodyweight. The only findings were irritation at the application site.

 

A further limit study conducted in the rat to a standard guideline and GLP, reliability 1, reported the LD50 as >2009 mg/kg bw (Hazelton France, 1992). Two studies in the rabbit, one sufficiently documented but without GLP, reliability 2, (Mellon Institute, 1975), and one identified only as a brief report, reliability 4, (Mellon Institute, 1966), record LD50 values in excess of that of the key study.


Justification for classification or non-classification

Based on the available data N-(3-(trimethoxysilyl)propyl)ethylenediamine is classified 'Acute Toxic 4 (mist)' with the hazard statement 'H332: Harmful if inhaled' under Regulation (EC) No 1272/2008. This substance is not classified for acute toxicity following oral or dermal exposure.