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Description of key information

Oral (OECD 423), rat: LD50 cut off = 5000 mg/kg bw (limit test)

Dermal (OECD 402), rat: LD50 > 2000 mg/kg bw (limit test)

Inhalation: The study does not need to be conducted as exposure of humans via inhalation is unlikely taking into account the very low vapour pressure of the substance (< 8.4E-7 Pa at 20°C).

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:
11 - 27 Oct 2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
adopted Feb 2002
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
May 2008
Deviations:
not specified
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
2002
Deviations:
not specified
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries, No 8147
Version / remarks:
Nov 2000
Deviations:
not specified
GLP compliance:
yes (incl. QA statement)
Remarks:
Food and Consumer Product Safety Authority (VWA), Utrecht, The Netherlands
Test type:
acute toxic class method
Limit test:
yes
Specific details on test material used for the study:
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The formulations (w/w) were prepared within 4 hours prior to dosing. Homogeneity was accomplished to a visually acceptable level. Adjustment was made for specific gravity of the vehicle and test substance. In order to obtain homogeneity, the test substance formulations were heated in a water bath with a maximum temperature of 79.1ºC for a maximum of 40 minutes. The test substance formulations were allowed to cool down to a temperature of maximally 40ºC prior to dosing.
Species:
rat
Strain:
Wistar
Remarks:
Crl:WI (Han) (outbred, SPF-Quality)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 11 weeks
- Weight at study initiation: group 1: 171 ± 22 g; group 2: 183 ± 10 g
- Fasting period before study: animals were fasted overnight prior to administration of the test substance
- Housing: group housing of 3 animals per cage in labeled Makrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material and paper as cage enrichment.
- Diet: SM R/M-Z, pelleted, (Ssniff Spezialdiäten GmbH, Soest, Germany),ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 ± 3.0 (actual range: 19.3 – 21.2)
- Humidity (%): 40 - 70 (actual range 44 - 73)
- Air changes (per hr): approximately 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: dehydrated corn oil
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6 females (3 females dosed per step in 2 steps)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animals were observed twice daily for mortaility; individual body weights were determined on days 1 (pre-administration), 8, 15 and prior to sacrifice.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs
Key result
Sex:
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: Hunched posture was observed in 6/6 animals on Day 1-2, and recurred in 6/6 animals on Day 5 or 7, persisting until Day 11 in 5/6 and until Day 14 in 1/6. Piloerection was noted in 3/6 animals on several or all days in the period from Day 7-11. A lean ap
Gross pathology:
No substance-related findings.

Table 1 Clinical signs

Test Days 1 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Hours after dosing 0 2 4                            
Animal 1                                  
Hunched posture - 1 1 - - - - - 1 1 1 1 1 - - - -
Animal 2                                  
Hunched posture - 1 1 - - - - - - - 1 1 1 - - - -
Animal 3                                  
Hunched posture - 1 1 1 - - - - - - 1 1 1 - - - -
Animal 4                                  
Hunched posture 1 1 1 1 - - 1 1 1 1 1 1 1 1 1 1 -
Piloerection - - 1 - - - - - 1 1 1 1 1 - - - -
Lean - - - - - - - - - 1 1 1 1 1 1 1 -
Animal 5                                  
Hunched posture 1 1 1 1 - - - - 1 1 1 1 1 - - - -
Piloerection - - - - - - - - 1 1 - - 1 - - - -
Animal 6                                  
Hunched posture 1 1 1 1 - - 1 1 1 1 1 1 1 - - - -
Piloerection - - - - - - 1 1 1 1 - - - - - - -
Lean - - - - - - - - - 1 1 1 1 - - - -

1 = Max Grade of clinical signs

Table 2 Body weights (gram)

Days 1 8 15
Animal 1 146 146 175
Animal 2 188 200 215
Animal 3 178 197 203
Mean ± SD 171 ± 22 181 ± 30 198 ± 21
Animal 4 181 151 170
Animal 5 194 201 216
Animal 6 174 158 201
Mean ± SD 183 ± 10 170 ± 27 196 ± 23
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008
Conclusions:
CLP: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

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
Study period:
17 Nov - 01 Dec 2011
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:
adopted Feb 1987
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
May 2008
Deviations:
not specified
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Version / remarks:
Aug 1998
Deviations:
not specified
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries, No 8147
Version / remarks:
Nov 2000
Deviations:
not specified
GLP compliance:
yes (incl. QA statement)
Remarks:
Food and Consumer Product Safety Authority (VWA), Utrecht, The Netherlands
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The formulation (w/w) was prepared within 4 hours prior to dosing. Homogeneity was accomplished to a visually acceptable level. Adjustment was made for specific gravity of the vehicle and test substance. In order to obtain homogeneity, the test substance formulation was heated in a water bath with a maximum temperature of 81.1 °C for a maximum of 1 hour and 37 minutes. The test substance formulation was allowed to cool down to a temperature of maximally 40 °C prior to dosing.
Species:
rat
Strain:
Wistar
Remarks:
Crl:WI (Han) (outbred, SPF-Quality)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approximately 10 weeks
- Weight at study initiation: 290 ± 13 g (males); 197 ± 11 g (females);
- Housing: individually housed in labeled Makrolon cages (MIII type, height 18 cm.) containing sterilized sawdust as bedding material and paper as cage-enrichment.
- Diet: SM R/M-Z, pelleted (Ssniff Spezialdiäten GmbH, Soest, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 ± 3.0 (actual range: 19.6 – 21.9)
- Humidity (%): 40 - 70 (actual range: 40 - 56)
- Air changes (per hr): approximately 15
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Vehicle:
other: hydrogenated corn oil
Details on dermal exposure:
TEST SITE
- Area of exposure: approximately 25 cm² for males; approximately 18 cm² for females
- % coverage: 10
- Type of wrap if used: a surgical gauze patch (Surgy 1D), successively covered with aluminum foil and Coban elastic bandage. A piece of Micropore tape was additionally used for fixation of the bandages in females only.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): residual test material was removed with tap water
- Time after start of exposure: 24 h

TEST MATERIAL
- Concentration: 10 mL/kg bw
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: 14 days
- Frequency of observations and weighing: Animals were observed twice daily for mortality and morbidity; individual body weights were determined on days 1 (pre-administration), 8, 15 and prior to sacrifice; clinical signs were determined at periodic intervals on the day of dosing (Day 1) and once daily thereafter until Day 15
- Necropsy of survivors performed: yes
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
One female was sacrificed for ethical reasons on Day 8 due to an excessive weight loss.
Clinical signs:
other: Lethargy was noted in 1/5 males on Day 2 and in 4/5 males on Day 1, and recurred in 2/5 males on Day 8. In females lethargy was observed in 3/5 females on Day 1, in 2/5 females on Days 7 or 8. Flat posture was observed in 1/5 males on Day 1. Hunched postu
Gross pathology:
The female that was sacrificed for ethical reasons on Day 8 showed a reduced size of the thymus at macroscopic post mortem examination. No abnormalities were observed at macroscopic post mortem examination in the 9 surviving animals.

Table 1 Clinical signs

Test Days   1 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Hours after dosing   0 2 4                            

Males

Animal 1                                    
Lethargy (3) - 1 1 - - - - - - - - - - - - - -
Hunched posture (1) - 1 1 - - - - - - - - - - - - - -
Flat posture (1) - - - 1 1 1 1 1 - 1 1 1 - - - - -
Piloerection (1) - - 1 1 - - - - - - - - - - - - -
Chromodacryorrhoea (snout) (3) - - - 2 1 - - - - - - - - - - - -
ptosis (3) - 1 1 - - - - - - - - - - - - - -
Animal 2                                    
Lethargy (3) - 1 1 - - - - - - - - - - - - - -
Hunched posture (1) - - - 1 1 1 1 1 - - - - - - - - -
Piloerection (1) - - 1 1 1 - - - - - - - - - - - -
Chromodacryorrhoea (snout) (3) - 1 1 1 - - - - - - - - - - - - -
ptosis (3) - - 1 - - - - - - - - - - - - - -
Animal 3                                    
Lethargy (3) - - - 2 - - - - - - - - - - - - -
Hunched posture (1) - 1 1 1 1 1 1 1 1 1 1 - - - - - -
Piloerection (1) - 1 1 1 1 1 1 1 - 1 - - - - - - -
Chromodacryorrhoea (snout) (3) - 1 1 1 - - - - - - - - - - - - -
ptosis (3) - - 1 1 - - - - - - - - - - - - -
Animal 4                                    
Lethargy (3) - 1 1 - - - - - - 1 - - - - - - -
Hunched posture (3) - - - 1 1 1 1 1 - 1 1 1 - - - - -
Piloerection (1) - - 1 1 1 - - - - 1 1 - - - - - -
Scales (3) - - - - - - - 1 1 1 - - - - - - -
Chromodacryorrhoea (snout) (3) - 1 1 1 - - - - - 1 - - - - - - -
ptosis (3) - 1 1 - - - - - - - - - - - - - -
Animal 5                                    
Lethargy (3) - 1 1 2 - - - - - 1 - - - - - - -
Hunched posture (1) - - - 1 1 1 1 1 1 1 1 1 1 - - - -
Shallow respiration (3) - - - - - - - - - 1 - - - - - - -
Piloerection (3) - 1 1 1 1 - - - - 1 1 - - - - - -
Chromodacryorrhoea (snout) (3) - 1 1 1 - - - - - - - - - - - - -
lean (1) - - - - - - - - - 1 - - - - - - -
ptosis (3) - 1 1 1 - - - - - - - - - - - - -

Females

Animal 6                                    
Lethargy (3) - 1 1 - - - - - - 1 - - - - - - -
Hunched posture (1) - - - 1 1 1 1 1 - 1 1 1 1 - - - -
Piloerection (3) - 1 1 1 1 - - - - 1 1 - - - - - -
Chromodacryorrhoea (snout) (3) - 1 2 2 - - - - - - - - - - - - -
ptosis (3) - 1 1 - - - - - - - - - - - - - -
Animal 7                                    
Restless (3) - - - - - - - - 1 -              
Lethargy (3) - - 1 - - - - - - 1              
Hunched posture (1) - - - 1 1 1 1 1 1 1              
Shallow respiration (3) - - - 2 - - - - - 1              
Piloerection (1) - 1 1 1 1 1 1 1 1 1              
Chromodacryorrhoea (snout) (3) - - - 2 - - - - 1 1              
lean (1) - - - - - - - - - 1              
ptosis (3) - - - - - - - - - 1              
Animal 8                                    
Lethargy (3) - - 1 - - - - - - - - - - - - - -
Hunched posture (1) - - - 1 1 1 1 1 1 1 1 1 - - - - -
Piloerection (1) - - 1 1 1 1 1 1 - - - - - - - - -
Chromodacryorrhoea (snout) (3) - 1 1 2 - - - - - - - - - - - - -
Animal 9                                    
Hunched posture (1) - - - 1 1 1 1 1 1 1 1 1 1 - - - -
Piloerection (1) - - 1 1 1 1 1 1 - - - - - - - - -
Chromodacryorrhoea (snout) (3) - - - 2 - - - - - - - - - - - - -
Animal 10                                    
Lethargy (3) - - - - - - - - - 1 - - - - - - -
Hunched posture (1) - - - 1 - - 1 1 1 1 1 1 1 - - - -
Piloerection (1) - 1 1 1 1 1 1 1 1 1 1 1 1 - - - -
Chromodacryorrhoea (snout) (3) - - - 2 - - - - - 1 - - - - - - -
lean (1) - - - - - - - - - 1 - - - - - - -

Number in brackets = Max score

Table 2 Body weights (gram)

Days 1 8 15
Males
Animal 1 284 274 313
Animal 2 309 306 347
Animal 3 288 271 309
Animal 4 274 265 298
Animal 5 296 268 311
Mean ± SD 290 ± 13 277 ± 17 316 ± 18
Females
Animal 1 199 187 206
Animal 2 189 142 -
Animal 3 188 197 208
Animal 4 194 191 205
Animal 5 214 196 226
Mean ± SD 197 ± 11 183 ± 23 211 ± 10
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008
Conclusions:
CLP: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

Oral

The acute oral toxicity of the test substance was assessed in a limit test performed according to OECD guideline 423 and in compliance with GLP (Key, 2012). A total dose of 2000 mg/kg bw of the test substance was administered to 3 female (step 1) and 3 female rats (step 2). Animals were observed for clinical signs at periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. Furthermore, individual body weights were determined before administration and weekly thereafter. Macroscopic examination was performed on test Day 15 (14 days after administration) after terminal sacrifice. There were no mortalities during the observation period. In 4/6 animals, the body weight gain was considered to be normal. A bodyweight loss was observed in 2/6 animals between Day 1 and 8. Although the animals gained weight during week 2 of the observation period, 1 of the 2 animals did not completely regain the body weight recorded on Day 1. Hunched posture, piloerection and/or lean appearance were noted among the animals during the observation period. Macroscopic post mortem examination did not reveal any abnormalities. Based on the results of this study, the LD50 value was determined to be > 2000 mg/kg bw in rats. In accordance with the recent OECD Guideline 423, a cut-off value of 5000 mg/kg bw can be derived, since no mortality occurred at 2000 mg/kg bw.

Dermal

The acute dermal toxicity of the test substance was assessed in a limit test performed according to OECD guideline 402 and in compliance with GLP (Key, 2012). A group of ten rats (five/sex) was given a single, occluded dermal application of the test material formulated in hydrogenated corn oil to the intact skin, at a dose level of 2000 mg/kg bw, for 24 hours. Clinical signs and body weight development were monitored during the study. All animals were observed for 14 days and animals were subjected to gross necropsy at the end of the observation period. One female animal was sacrificed for ethical reasons on Day 8 due to excessive body weight loss. Lethargy was noted in 1/5 males on Day 2 and in 4/5 males on Day 1, and recurred in 2/5 males on Day 8. In females lethargy was observed in 3/5 females on Day 1, in 2/5 females on Days 7 or 8. Flat posture was observed in 1/5 males on Day 1. Hunched posture occured on Days 2-11 in 1/5 males, on Days 1-9 in 1/5 males, and on Days 2-6 in 3/5 males and recurred on Day 8 in 2/5, persisting until Day 10. Hunched posture was observed on Day 2 in 5/5 females, in 1/5 females persisting until Day 6 and recurred on Days 8-11, in 3/5 females until Day 8, 10 or 11, and in 1/5 females recurred on Day 5-11. Piloerection was observed on Day 1, on Days 1-3 or on Days 1-6 in 5/5 males and recurred in 3/5 on Day 8, persisting until Day 9 in 2/5. In females, piloerection was observed in 5/5 on Day 1, persisting until Day 6 in 2/5 and until Day 11 in 1/5, or persisting until Day 3 in 1/5 and recurred on Day 8-9. Chromodacryorrhoea was observed in 5/5 males and in 2/5 females on the day of the treatment, persisting until Day 2 in 4/5 males and 2/5 females and until Day 3 in 1/5 males. In 3/5 females chromodacryorrhoea occured on Day 2, and recurred in 2/5 females on Day 7 or 8. Shallow respiration was observed in 1/5 males and 1/5 females on Day 8. Lean appearance was noted in 2/5 males and in 1/5 females on Day 8. Restless behavior occured in 1/5 female on Day 7. Ptosis was

noted in 3/5 males and 1/5 females on Day 1, in 2/5 males on Days 1-2, in 1/5 females on Day 7. Scales on the treated skin-area was noted in 1/5 males on Day 6 - 8. Slight body weight loss was noted between Days 1 and 8 in 5/5 males and 4/5 females. The female, that was sacrificed for ethical reasons on Day 8 showed a reduced size of the thymus at macroscopic post mortem examination. No abnormalities were observed at macroscopic post mortem examination in the surviving animals. Based on the results of this study, the LD50 value was determined to be > 2000 mg/kg bw in rats.

Justification for classification or non-classification

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

Silicic acid (H4SiO4), tetraethyl ester, reaction products with bis(acetyloxy)dioctylstannane would be rapidly hydrolyzed to dioctyltin dichloride (DOTC), ethanol, acetic acid and silicium dioxide.  However, under neutral conditions in the respiratory system, it is highly expected that Silicic acid (H4SiO4), tetraethyl ester, reaction products with bis(acetyloxy)dioctylstannane would be directly hydrolyzed to dioctyltin hydroxide.  Thus, acute inhalation toxicity for DOTC should not be relevant.