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Administrative data

Description of key information

Oral (OECD 401): Males LD50 > 5170 mg/kg bw (limit test); Females LD50 = 5170 mg/kg bw (estimated)


Inhalation (OECD 403): LC50 > 22200 mg/m³


Dermal: There are no measured acute dermal toxicity data available (data waiving according to Column 2 of REACH Annex VIII, Section 8.5.3).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
25 Feb 1987 to 12 March 1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
Non GLP. No data on purity or stability. The females were tested at 2 doses, whereas at least 3 are recommended to permit an "acceptable determination of the LD50".
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Wistar Bor:WISW (SPFTNO)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Winkelmann Versuchstierzucht GmbH & Co., Borchen, GERMANY
- Age at study initiation: 57 days (males), 71-72 days (females)
- Weight at study initiation: 172-197 g (males), 146-164 g (females)
- Fasting period before study: 16 h
- Housing: Macrolon cages type II
- Diet: standard diet (Ssniff R, special diet for rats), ad libitum
- Water: drinking water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 15
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 25 February 1988 To: 12 March 1988
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 5.62 ml/kg bw

Doses:
5170 mg/kg bw (males)
2401 or 5170 mg/kg bw (females)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observation for mortality twice daily (once daily on weekends and holidays); clinical observations after treatment continuously for 4-6 h then daily; bodyweights on days 0, 7, 14.
- Necropsy of survivors performed: yes, macroscopic examination included external appearance, body orifices, body cavities (thoracic and abdominal), and their contents.
Statistics:
None given. LD50 value for males is derived from a limit test (1 dose). The LD50 value for females (based on 2 doses) is described as an estimate.
Sex:
male
Dose descriptor:
LD50
Effect level:
> 5 170 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD50
Effect level:
ca. 5 170 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Estimate
Mortality:
Two females died at 5170 mg/kg bw (3 - 4 hours after exposure). There were no deaths in males at this dose or in females at 2401 mg/kg bw.
Clinical signs:
other:
Body weight:
other body weight observations
Remarks:
See Table 2 (Any other information on results including tables).
Gross pathology:
The stomach and intestines of the two females that died were filled with liquid and the mucosa of the proventricular was red.

Table 1: Number of animals dead and with evident toxicity, and time range within which mortality occurred











































Dose
(mg/kg bw)



Mortality (# dead/total)



Time range of deaths (hours)



Number with evident toxicity (#/total)



Male



Female



Combined



 



Male



Female



Combined



2401



-



0/5



0/5



n/a



Reduced locomotion


Impaired co-ordination


Loss of muscle tone


Loss of righting reflex - lateral


Loss of righting reflex - supine


Loss of pinna, pain, corneal reflexes


Clonic spasms


Excitation-like twitching


Ptosis (drooping eyelid)


Lacrymation


Mydriasis (dilated pupils)


Hypersialosis (excessive salivation)


Fur, ruffled


Laboured breathing


Reduced body temperature


Abnormal gait


Sunken flanks


Cyanosis



-


-


-


-


-


-


-


-


-


-


-


-


-


-


-


-


-


-



4/5


4/5


2/5


1/5


1/5


0/5


1/5


0/5


0/5


1/5


0/5


0/5


1/5


0/5


1/5


1/5


2/5


0/5



-


-


-


-


-


-


-


-


-


-


-


-


-


-


-


-


-


-



5170



0/5



2/5



2/10



3-4 h



Reduced locomotion


Impaired co-ordination


Loss of muscle tone


Loss of righting reflex - lateral


Loss of righting reflex - supine


Loss of pinna reflex


Loss of pain reflex


Loss of corneal reflex


Clonic spasms


Excitation-like twitching


Ptosis (drooping eyelid)


Lacrymation


Mydriasis (dilated pupils)


Hypersialosis (excessive salivation)


Fur, ruffled


Laboured breathing


Reduced body temperature


Abnormal gait


Sunken flanks


Cyanosis



5/5


5/5


4/5


2/5


2/5


0/5


0/5


0/5


1/5


0/5


0/5


0/5


0/5


0/5


0/5


4/5


0/5


0/5


1/5


0/5



4/5


4/5


3/5


3/5


3/5


2/5


2/5


2/5


0/5


1/5


2/5


0/5


2/5


4/5


1/5


4/5


2/5


1/5


3/5


2/5



9/10


9/10


7/10


5/10


5/10


2/10


2/10


2/10


1/10


1/10


2/10


0/10


2/10


4/10


1/10


8/10


2/10


1/10


4/10


2/10



 


 


Table 2: Body weights (g) – individual values








































Dose


(mg/bw day)



Animal No.



0 d



7 d



14 d



Males



5170



1


2


3


4


5



188


172


194


197


186



226


203


236


231


217



258


235


271


265


249



Females



2401



11


12


13


14


15



156


164


150


164


148



171


183


166


186


165



185


190


176


191


171



5170



6


7


8


9


10



150


162


154


146


149



168


182


-


-


170



171


186


-


-


178



 

Interpretation of results:
other: CLP/EU GHS criteria are not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
In an acute oral toxicity study conducted in compliance with the now deleted OECD 401, but not to GLP (reliability score 2), the LD50 values for trimethoxy(propyl)silane were > 5170 mg/kg bw in males and 5170 mg/kg bw (estimated) in females. These values indicate low acute toxicity by the oral route. The most common signs of toxicity were reduced locomotion, impaired co-ordination, loss of muscle tone and loss of righting reflex.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
5 170 mg/kg bw
Quality of whole database:
The available key study is considered adequate and reliable (Klimisch score 2), and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5.1, of Regulation (EC) No 1907/2006.

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:
7 Feb 1990 to 21 Feb 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
adopted 12 May 1981
Deviations:
yes
Remarks:
Deviations unlikely significantly to affect the outcome of the study: excursions from recommended relative humidity and temperature; limited reporting of clinical observations.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Wistar derived Crl:WI(WU)BR
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, Sulzfeld, GERMANY
- Age at study initiation: 7 weeks
- Weight at study initiation: mean - 218 g (males), 166 g (females)
- Fasting period before study: none stated
- Housing: (after exposure) 5 males or 5 females per suspended stainless steel cage
- Diet: standard diet, ad libitum
- Water: drinking water, ad libitum
- Acclimation period: 15 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): during exposure: mean 22.6; after exposure: 22 ± 3 (excursion 18.5 for 1 h)
- Humidity (%): during exposure: mean 79 ± 15 (relative humidity was above 70% for about 2 hours, during the rest of the exposure humidity was between 30 and 70%); after exposure: 30 - 70 (excursions 29, 74, 95 for 1 h on each occasion)
- Air changes (per hr): during exposure: 38; after exposure: 10
- Photoperiod (hrs dark / hrs light): 12 h/12 h

IN-LIFE DATES: From: 1990-02-07 To: 1990-02-21
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: horizontal glass chamber; animals separated by perforated stainless steel plates
- Exposure chamber volume: 16 L (total volume)
- Method of holding animals in test chamber: see above
- Source and rate of air: 0.6 m³/h; flow velocity 34 m/h; ventilation frequency 38/h
- System of generating particulates/aerosols: heated air bubbled through heated test material at 35° C, passed through heated Pall filter (30° C) to remove aerosol as far as possible
- Method of particle size determination: to determine aerosol content: 11-stage cascade impactor
- Treatment of exhaust air: no details
- Temperature, humidity, pressure in air chamber: (mean of hourly measurements) 22.6° C; 79 ± 15%; pressure unstated

TEST ATMOSPHERE
- Brief description of analytical method used: hourly GC analysis
- Samples taken from breathing zone: yes

TEST ATMOSPHERE: 22.2 ± 6.9 g/m³ (4 measurements); nominal 59.8 g/m³; particle size tabulated (about 1% of the total test atmosphere consisted of aerosol).
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
Single exposure concentration:
22.2 ± 6.9 g/m³ (measured)
59.8 g/m³ (nominal)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations daily; body weights prior to exposure and on observation days 7 and 14.
- Necropsy of survivors performed: yes
Statistics:
None relating to LC50.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 22 200 mg/m³ air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
One of each sex died during exposure. One male died on observation Day 4 (see Table 2, Any other information on results incl. tables).
Clinical signs:
other: See field "Any other information on results incl. tables"
Body weight:
Body weights were generally not affected. Body weights were reduced in two females on Days 14, or 7 and 14 (see Attachment for tabulated data).
Gross pathology:
The lungs of the three animal that died during treatment or observation were discoloured red, spotted or swollen. No abnormalities were found in the remaining animals autopsied on Day 14.
Other findings:
None reported.

Clinical Signs

During the first 15 minutes of exposure animals were restless. Their eyes were half-closed and breathing was irregular. From 30 minutes and onward, rats seemed to be in narcosis, their breathing became deep and irregular. Directly after exposure, rats were still in narcosis. They showed dyspnoea and moist rales.

The first day of the 14-day observation period revealed wet nose and a dirty fur in several of the surviving rats. Thereafter, no abnormalities were observed. Just before death on Day 4 of the observation period, the male animal demonstrated lethargy, showed flabby muscles, incoordination, piloerection and a visually increased breathing frequency.

Exposure concentration and aerodynamic particle size

The mean actual concentration turned out to be 22.2 ± 6.9 g/m³. The standard deviation resulted from four measurements. The corresponding nominal concentration was 59.8 g/m³.

Particle size analysis is given in Table 1. The 50 percent accumulation point for the distribution was between 2.4 and 2.8 µm. However, the concentration of aerosol measured in this way turned out to be 0.2g/m³, indicating that a negligible amount of about one percent of the total test atmosphere consisted of aerosol.

Table 1: Aerodynamic particle size distribution

Aerodymamic diameter (µm)

Distribution % of total mass (22.2 g/m³)

<1

1.0

1

4.5

1.4

2.5

1.8

15.1

2.4

12.2

2.8

10.8

3.1

18.3

3.4

26.5

3.8

4.4

4.2

0.7

>4.2

3.9

Table 2: Concentrations, exposure conditions and mortality per animals treated

Nominal

Conc. (g/m³)

Analytical Conc. (g/m³ ± SD )

Mortality (dead/total)

Males

Females

Combined

59.8

22.2 +/- 6.9

2/5

1/5

3/10

 

Interpretation of results:
other: CLP/EU GHS criteria are not met, no classification required according to Regulations (EC) No 1272/2008
Conclusions:
In an acute inhalation study according to OECD 403 and in accordance with GLP (reliability score 1) the LD50 for trimethoxy(propyl)silane was in excess of 22200 mg/m³ in the rat.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
> 22 200 mg/m³ air
Physical form:
inhalation: vapour
Quality of whole database:
The available key study is considered adequate and reliable (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5.1, of Regulation (EC) No 1907/2006.

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Studies were chosen as key when the available study was of relevance and of sufficient quality for classification, labelling and for risk assessment. Other available data are included as supporting studies.


 


Acute toxicity: oral


The key acute oral toxicity study on trimethoxy(propyl)silane (CAS 1067-25-0) was conducted in accordance to the now deleted OECD 401, but not according to GLP (ASTA Pharma, 1988). Five male and five female Wistar Bor:WISW (SPFTNO) rats per dose were administered the test item by single oral gavage application. Males were dosed at 5170 mg/kg bw and females were dosed at 2401 or 5170 mg/kg bw.


Clinical signs were characterized by reduced locomotion, reduced muscle tone, loss of righting reflexes, sunken flanks and laboured respiration. Further, ptosis, mydriasis, cyanosis, reduced body surface temperature and general lack of reflexes were observed prior to death in female animals. There were also isolated cases of clonic spasms, excitation-like twitching, lacrimation, hypersialosis, stalking gait and ruffled fur.


Initial symptoms of intoxication were observed 7 minutes after administration of the substance and lasted up to 2 days. Deaths occurred 3 and 4 hours, respectively, among the females after administration of 5170 mg/kg bw.


Necropsy of the two female animals that died revealed that the stomach and intestines were filled with liquid and the mucosa of the proventriculus was red.


The mean LD50 values were:


Male > 5170 mg/kg bw (limit test)


Females ca.5170 mg/kg bw (estimate)


 


An additional acute oral toxicity study on trimethoxy(propyl)silane (CAS 1067-25-0) was conducted similar to the now deleted OECD 401 and not to GLP (INBIFO, 1979). 10 male Sprague-Dawley rats per dose were administered 4.22, 5.62, 7.50, 10.0 or 13.3 g/kg bw via a single oral gavage application. Overt toxicity was evident in all dose groups. Effects included reduced to absent spontaneous activity, reaction to external stimuli, backtwist reflex, muscle tone, reaction to pain or corneal reflex. Five rats had blood in the urine. One rat that died had dark red lungs. General condition and behaviour of most rats had returned to normal after 2 days. Deaths within 14 days in the groups treated with 4.22, 5.62, 7.50, 10.0 or 13.3 g/kg bw were 0, 2, 3, 10 and 10, respectively. The LD50 value in male rats was calculated to be 7420 mg/kg bw. 


 


Acute toxicity: inhalation


The key acute inhalation toxicity study on trimethoxy(propyl)silane (CAS 1067-25-0) was conducted in compliance with GLP and according to OECD 403 (TNO, 1990). Groups of five male and five female Crl:WI(WU)BR rats were exposed to vapours of the test item via whole body exposure at a concentration of 22.2 g/m3 for one single period of 4 hours.


Shortly after the beginning of exposure, restlessness started and irregular breathing was observed, followed by signs of narcosis, and deep and irregular breathing. Three rats died during or after exposure (two males and one female). Wet noses and dirty fur were common findings on the first day of the 14-day observation period.


Except for two females, body weight gain was not affected by exposure.


No abnormalities were observed at necropsy in the animals that survived to scheduled sacrifice at the end of the observation period. In the animals which died during or after exposure, dark-red discoloured, occasionally spotted and swollen, lungs were found.


It was concluded that the 4-hour LC50 value of trimethoxy(propyl)silane (vapour) in rats was > 22.2 g/m3.


 


An additional acute inhalation toxicity study on trimethoxy(propyl)silane (CAS 1067-25-0) was conducted similar to OECD 403, but not according to GLP (INBIFO, 1979). Groups of 10 male and 10 female Sprague Dawley rats were exposed to an aerosol of the test item via head-only exposure at measured concentrations of 6.6, 15.4, 19.9 ml/m³ for 6 hours.


Dose dependent narcotic effects were seen, characterized as follows: Apathy, slight trembling and spasms over the whole body, slight to severe ataxia, absent backtwist reflex. Reduction in respiration rate with partial intermittent respiration. Reduced to absent reaction to pain, reduced ability to grip as well as reduced ear muscle and corneal reflex. Mortality in the groups exposed to 0, 6.6, 15.4, or 19.9 ml/m³ of the test item was as follows: Males 1, 1, 0 and 8. Females 0, 3, 3 and 7.


It was concluded that the 6-hour LC50 value for trimethoxy(propyl)silane (aerosol) in rats was 15.2 g/m³ (dose given in ml/m3, converted using a relative density of 0.94).


 


Acute toxicity: dermal


No data available. In accordance with Column 2 of REACH Annex VIII, the acute toxicity study via the dermal route (required in Section 8.5.3 of REACH Annex VIII) does not need to be conducted because inhalation of the substance is likely.

Justification for classification or non-classification

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


Classification as STOT-SE Cat 3, with the hazard statement 'H336: May cause drowsiness and dizziness' according to Regulation (EC) No. 1272/2008 is not warranted for the test substance. Although signs of narcosis were observed in the acute inhalation study, this was rather linked to the systemic effects provoked by the test substance after exposure at a concentration exceeding the limit dose stated in the corresponding OECD guideline. In addition the reported concentration could have been higher due to the whole-body inhalation and possible additional oral uptake of the test substance. Mortality and clinical signs as laboured breathing and lethargy were observed. At necropsy dark red discoloured lungs were reported, thus leading to the conclusion that the narcotic effects were rather a consequence of anoxia provoked by systemic effects.