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Diss Factsheets

Administrative data

Description of key information

Acute oral toxicity (OECD TG 401, GLP): 1250 mg/kg bw < LD50 < 1650 mg/kg bw
Acute inhalation toxicity: data waiving according to Column 2 of REACH Annex VII (Section 8.5.2)
Acute dermal toxicity (OECD 402, GLP): LD50 > 2000 mg/kg bw

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:
1993-03-04 to 1993-06-14
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
(1987)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Version / remarks:
(1984)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: BRL Ltd., Basel, Switzerland
- Age at study initiation: approximately 7-12 weeks
- Weight at study initiation: males: 153-283 g, females: 134-233 g
- Fasting period before study: 18-25 hours prior to and 3-4 hours after dosing
- Housing: The animals were housed under stadard laboratory conditions. The animals were housed in groups of 5 per sex to a cage, using labelled polycarbonate cages containing purified sawdust as bedding material (Woody SPF, supplied by B.M.I., Someren, The Netherlands). Certificates of sawdust analysis were examined and then retained in the RCC NOTOX archives. The animals were identified by earmarks.
- Diet (ad libitum): standard pelleted laboratory animal diet (Kliba 343 from Klingentalmühle AG, Kaiseraugst, Switzerland). Certificates of analysis were examined and then retained in the RCC NOTOX archives.
- Water (ad libitum): tap-water. Certificates of analysis (performed quaterly) were examined and then retained in the RCC NOTOX archives.
- Acclimation period: at least 5 days before start of treatment under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 (fluctuations were noted, but were not considered to be relevant)
- Humidity (%): 55 (fluctuations were noted, but were not considered to be relevant)
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
paraffin oil
Details on oral exposure:
VEHICLE
- Specific gravity: 0.8

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg bw

DOSAGE PREPARATION
The prepared test substance was used within 80 minutes or 18 hours after preparation and the formulation was dosed within one hour after mixing. The prepared test substance was weighed into a dry glass flask on an analytical balance and the vehicle (w/w) was added. Adjustment was made for specific gravity of the vehicle. Homogeneity of the test substance was obtained by shaking and using a magnetic stirrer. Concentration of the test substance in vehicle was varied to allow constant dosage volume in terms of ml/kg body weight.
Doses:
Group 1: 750 mg/kg bw
Group 2: 1250 mg/kg bw
Group 3: 1650 mg/kg bw
Group 4: 2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations (mortality/viability): twice daily. The time of death was recorded as precisely as possible.
- Frequency of weighing: days 1 (pre-administration), 8, 15, and at death (if found dead after day 1)
- Frequency of observations (clinical signs): at periodic intervals on the day of dosing (day 1) and once daily thereafter. The time of onset, degree, and duration were recorded.
- Necropsy of survivors performed: yes (sacrifice by oxygen/carbon dioxide asphyxiation)
Statistics:
No LD50 could be calculated due to mortality distribution.
Preliminary study:
Initially a "Limit study" with the test material in paraffin oil at a dose level of 2000 mg/kg bw was performed. Due to the fact that all animals died, a "Pilot Study" was conducted in which three groups, each comprising of 1 male and 1 female rat were orally dosed with the test substance in paraffin oil at 50, 100, or 650 mg/kg bw. None of these animals died, only rough coat was observed in some animals. Therefore, two lower dose levels were selected for the full study and animals dosed at 1250 or 750 mg/kg bw. Due to the fact that no animals died, a fourth group was added and animals dosed at 1650 mg/kg bw. All animals receiving 1650 mg/kg bw died. No further groups were selected as a clear dose level at which animals died and at which animals survived (all within one classification group) was obtained.
Sex:
male/female
Dose descriptor:
LD0
Effect level:
1 250 mg/kg bw
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LD100
Effect level:
1 650 mg/kg bw
Based on:
test mat.
Mortality:
In groups 1 and 2 (750 and 1250 mg/kg bw) none of the animals (neither male nor female) died. In groups 3 and 4 (1650 and 2000 mg/kg bw) all animals (both males and females) died within 24 hours of dosing.
Clinical signs:
other: Group 1 (750 mg/kg bw): rough coat (1 male on day 10 only) Group 2 (1250 mg/kg bw): salivation (1 female on day 1 only) Group 3 (1650 mg/kg bw): no clinical signs observed Group 4 (2000 mg/kg bw): lethargy, clonic spasms, hunched posture, rough coat, wate
Gross pathology:
Group 1 (750 mg/kg bw): no abnormalities that were not commonly noted among rats of this strain and age
Group 2 (1250 mg/kg bw): no abnormalities that were not commonly noted among rats of this strain and age
Group 3 (1650 mg/kg bw): dark red focus/foci in the glandular stomach, haemorrhages in the wall of the duodenum, jejenum, and ileum, haemorrhages in the thymus
Group 4 (2000 mg/kg bw): dark red focus/foci in the glandular stomach, haemorrhages in the thymus, alopecia in the cervical region
Interpretation of results:
other: CLP/EU GHS Category 4 (H302) according to Regulation (EC) No 1272/2008
Conclusions:
The test item was tested for acute oral toxicity according to the OECD TG 401 (1987) and in compliance with GLP. The test item was found to be harmful as the experiment resulted in 1250 mg/kg bw < LD50 < 1650 mg/kg bw for both male and female rats. Hence, the substance has to be classified as acute oral toxicity Cat 4 according to EC/1272/2008.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating dose
Value:
1 250 mg/kg bw
Quality of whole database:
The study was conducted according to OECD TG 401, and in compliance with GLP.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
(1987)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
(1984)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: BRL Ltd., Basel, Switzerland
- Age at study initiation: approximately 12 weeks
- Weight at study initiation: males: 303-345 g, females: 213-239 g
- Housing: The animals were housed under standard laboratory conditions. The animals were individually housed in labelled poly carbonate cages containing purified sawdust as bedding material (Woody SPF, supplied by B.M.I., Helmond, The Netherlands). Certificates of sawdust analysis were examined and then retained in the RCC NOTOX archives. The animals were identified by earmarks.
- Diet (ad libitum): standard pelleted laboratory animal diet (Kliba 343 from Klingentalmühle AG, Kaiseraugst, Switzerland). Certificates of analysis were examined and then retained in the RCC NOTOX archives.
- Water (ad libitum): tap-water. Certificates of analysis (performed quaterly) were examined and then retained in the RCC NOTOX archives.
- Acclimation period: at least 5 days before start of treatment under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 (fluctuations were observed, but were not considered to be relevant)
- Humidity (%): 55 (fluctuations were observed, but were not considered to be relevant)
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Vehicle:
paraffin oil
Details on dermal exposure:
TEST SITE
- Area of exposure: on the back of the animal, males approximately 25 cm² (5 x 5 cm) and females approximately 18 cm² (3.5 x 5 cm)
- Type of wrap if used: gauze patch fixed successively to aluminium foil and flexible bandage (Coban, 3M, St. Paul ,USA), with drops of petrolatum

REMOVAL OF TEST SUBSTANCE
- Washing: with a tissue moitured with tap-water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount applied: 10 ml/kg bw
- Constant volume or concentration used: yes

VEHICLE
- Specific gravity: approximately 0.8
- Pretreatment: flushing with nitrogen and dehydration by the use of activated grains of molecular sieve (0.3 nm)

DOSAGE PREPARATION
The prepared test substance was used within 24 hours after preparation and the formulation was prepared within 1 hour prior to dosing. The test substance was weighed into a dry glass flask on an analytical balance and the vehicle (w/w) was added. Adjustment was made for specific gravity of the vehicle. No flushing of the glass flask occured before and after preparation of the formulation. Homogeneity of the test substance was obtained by shaking.
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations (mortality/viability): twice daily
- Frequency of weighing: days 1 (pre-administration), 8, and 15
- Frequency of observations (clinical signs): at periodic intervals on the day of dosing (day 1) and once daily thereafter. The time of onset, degree, and duration were recorded.
- Frequency of observations (skin irritation): daily, following bandage removal. The time of onset, degree, and duration were recorded.
- Necropsy of survivors performed: yes (sacrifice by oxygen/carbon dioxide asphyxiation)
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occured during the study period.
Clinical signs:
other: - Lethargy was noted in one animal on day 1. - Erythema was noted in 4 females during the observation period.
Gross pathology:
Macroscopic post mortem examination of the animals at termination did not reveal any abnormalities.
Interpretation of results:
other: CLP/EU GHS criteria are not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
The test item was tested for acute dermal toxicity according to the OECD TG 402 (1987) and in compliance with GLP. No mortality occured and the LD50 was determined to be > 2000 mg/kg bw for both male and female rats. Hence, classification according to EC/1272/2008 is not warranted.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
The study was conducted according to OECD TG 402, and in compliance with GLP.

Additional information

One acute oral toxicity study and one acute dermal toxicity study are available for assessment of the acute toxicity of the reaction mass containing six benzylated amine silanes.

Acute oral toxicity:

In the key study for acute oral toxicity male and female Wistar rats (5 per sex) were dosed with 750, 1250, 1650, and 2000 mg/kg bw of the test substance by oral gavage (NOTOX, 1993c). The study was performed according OECD TG 401 and in compliance with GLP regulations. Within 24 hours all animals of the 1650 and 2000 mg/kg bw dose group were found dead, whereas no mortality was observed in the 750 and 1250 mg/kg bw dose group. Relevant clinical signs were only observed in the high dose group including lethargy, clonic spasms, hunched posture, rough coat, watery discharge from both eyes and moribund state. Pathology findings for the 1650 and 2000 mg/kg bw dose groups have been dark red focus/foci in the glandular stomach, haemorrhages in the wall of the duodenum, jejunum, and ileum, haemorrhages in the thymus, and alopecia in the cervical region. The LD50 was given as 1250 mg/kg bw < LD50 < 1650 mg/kg bw, as no calculation was possible due to mortality rates distribution.

Acute inhalation toxicity:

In accordance with Column 2 of REACH Annex VIII, the acute toxicity study via the inhalation route (required in Section 8.5.2 of REACH Annex VIII) does not need to be conducted as reliable data via the oral and dermal routes are available.

Acute dermal toxicity:

In the key study for acute dermal toxicity male and female Wistar rats (5 per sex) were treated dermally for 24 h with 2000 mg/kg bw of the test substance under occlusive conditions (NOTOX, 1993d). The study was performed according OECD TG 402 and in compliance with GLP regulations. No mortality was observed. Lethargy was noted in one animal on day 1, and erythema was noted in 4 females during the observation period. Nine animals lost body weight over the first week of observation. Over the second week body weight loss was again noted in one female and low body weight gain was noted in two females. Normal body weight gain was noted in all males and two females over the second week of observation. Macroscopic post mortem examination of the animals at termination did not reveal any abnormalities. In conclusion, a LD50 of >2000 mg/kg bw was deduced.


Justification for classification or non-classification

The submission substance has a harmonised classification in Annex VI of the Regulation (EC) 1272/2008. The substance is classified for the following acute toxicity endpoints:

·        Acute oral toxicity Cat 4 * (H302: harmful if swallowed)

·        Acute dermal toxicity Cat 4 * (H312: harmful in contact with skin)

·        Acute dermal toxicity Cat 4 * (H332: harmful if inhaled)

·        Specific Target Organ Toxicity Single Exposure Cat 2 (H371: May cause damage to organs)

The available data on acute oral toxicity of the test substance meets the criteria for classification as a category 4, acute oral toxicity (H302: harmful if swallowed) according to Regulation (EC) 1272/2008.

However, the acute dermal toxicity data available do not meet the criteria for classification according to Regulation (EC) 1272/2008 and EU Directive 67/548/EEC on the grounds that no mortality occurred up to the limit dose of 2000 mg/kg bw in a guideline compliant study.

Moreover, the data available to the registrant do not support STOT SE Cat 2 classification on the grounds that the effects observed in the acute oral toxicity study are based on corrosive effects rather than systemic toxicity. The submission substance is known to be corrosive to mucosa and is therefore classified as “Eye irritant: Cat 1” (H318: Causes serious eye irritation) according to Regulation 1272/2008/EC. Labelling for corrosion is sufficient and labelling with STOT SE Cat 2 is superfluous according to Section 3.8.5.2 of the Guidance on the Application of Regulation 1272/2008/EC. Moreover, the effects observed are not of significant toxicity, as they do not clearly indicate functional disturbance or morphological changes of toxicological relevance. Additionally, these effects were only observed for the oral route, for which the substance meets the criteria for classification for acute toxicity. Hence, classification for STOT SE Cat 2 is superfluous.

However, the harmonised classification is applied for the purposes of this registration.