Registration Dossier

Diss Factsheets

Administrative data

Description of key information

The information on acute oral toxicity was assessed in a weight of evidence approach. It was concluded the registered substance does not require classification with respect to acute toxicity via the oral and dermal routes of exposure.

- Acute Oral Toxicity

Auletta (1984)

Under the conditions of this study the acute oral LD50 value to CDR Sprague Dawley rats was determined to be 1700 mg/kg.

Bathe (1973)

Under the conditions of the study the LD50 of the test material was determined to be 5000 mg/kg.

Gunzel & Richter (1969)

Under the conditions of this study, the oral LD50 value in male Wistar rats was established to exceed 4000 mg/kg body weight.

Klimmer (1969)

Under the conditions of the study the acute oral LD50 to male Wistar rats was 2.85 mL/kg (3078 mg/kg).

Prinsen (2012) Read across to Octyltin tris(2-ethylhexylmercaptoacetate) (MOTE) (CAS No 27107-89-7)

Under the conditions of this study, the oral LD50 value in female Sprague-Dawley rats was established to exceed 2000 mg/kg body weight.

- Acute Dermal Toxicity

Prinsen (2010) Read across to Octyltin tris(2-ethylhexylmercaptoacetate) (MOTE) (CAS No 27107-89-7)

Based on the result obtained from the test (LD0 >2000 mg/kg bw) the test material does not meet the criteria for classification as set out in 67/548/EEC.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
6 December 2011 to 24 Juanuary 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose for cross-reference:
other: read-across target
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
- Acclimatisation: at least 5 days
- Caging: a maximum of 6 animals/sex per macrolon cage with sterilized wood shavings (Lignocel) as bedding material, environmental enrichment (Enviro-Dri) and wood black
- Identification: ear tattoo
- Photopeiod: 12 hours light / 12 hours dark cycle
- Room temperature : 20-24 °C.
- Relative humidity during testing : 45-65%. The upper limit was incidentally up to 83% (not exceeding ca 1-2 hours) because of meteorological circumstances and/or wet cleaning of the room.
- Ventilation: ca 10 air changes/hour
- Diet/water : standard laboratory diet ad libitum. Each batch of this diet is analysed by the supplier (SDS Special Diets services, Whitham, England) for the nutrients and contaminants and the results are kept available in the archives. Tap water (N.V. Vitens) ad libitum. Results of routine physical, chemical and microbiological examin­ ation of drinking water as conducted by the supplier are kept available in the archives. The results of diet and water analyses were considered acceptable for this study.
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
VEHICLE
- Justification for choice of vehicle:B ecause the test substance is a liquid and considered non corrosive , the 2000 mg/kg body weight anaimls was recorded.
- Lot/batch no. (if required):ESOC21.341
- Purity: 97.7%

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg for dose-levels of 50 and 300 mg/kg and 1.8 ml/kg body weight for the 2000 mg/kg dose-level.

Doses:
2000 mg/kg, 300 mg/kg, 50 mg/kg.
No. of animals per sex per dose:
6 females at 2000 mg/kg
3 females at 300 mg/kg
3 females at 50 mg/kg.
Control animals:
no
Details on study design:
Duration of observation period following administration: 14 days
- Frequency of observations: observation were made 1 hour and within 4 hour after dosing. and subsequently at least once daily throughout an observation period of 14 days.
- Weighing: the body weight of each animal was recorded just prior to dosing and of surviving animals on day 3, 7 and 14 of the study.
- Necropsy of survivors performed: yes
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 - < 5 000 mg/kg bw
Based on:
test mat.
Mortality:
At 2000 mg/kg/day, one animal was sacrificed prematuraly, this animals shows protrusion of eyes, ataxia, paralysis and an abominal lump on day 1 of the study.
At 50 and 300 mg/kg, No mortality or clinical signs were observed during the 14-day study period.

Clinical signs:
At 2000 mg/kg/day (first and second group) clinical signs generally observed consisted of hunching in 4/6 animals within the first two days after dosing. Occasionnaly, ataxia, blephorasm, piloerection and an abdominal lump were observed in one or two animals within the first day after dosing.
At 50 and 300 mg/kg, no clinical sings were observed during the 14- day study period.
Body weight:
All surviving animals at all dose-levels gained weight at all dose-levels.
Gross pathology:
At 2000 mg/kg dose -level: first and second group: examination at necropsy did not reveal treateent-related gross alterations, other than the animal killed in extremis which schowed a stomach filled with sawdust.
At 300 mg/kg dose-level, examination at necropsy of the animals did not reveal treatment related gross alterations.
At 50 mg/kg dose-level, examination at necropsy of the animals did not reveal treatment-related gross alterations.
Other findings:
none
Interpretation of results:
other: Not classified in accordance with EU criteria
Conclusions:
Under the conditions of this study, the oral LD50 value in female Sprague-Dawley rats was established to exceed 2000 mg/kg body weight.
Executive summary:

A sample of the test material was examined for acute oral toxicity in an experiment with female rats (limit testing), according to EC Directive 96/54/EEC, method B.1 tris and OECD Guideline no.423, under GLP conditions.

Dose levels of 2000, 300 and 50 mg per kg bodyweight were examined and animals were observed for a maximum of 14 days after dosing.

No mortality or clinical signs were observed after treatment with a 50 and 300 mg/kg/ bw dose-levels. The 2000 mg/kg bw dose-level caused mortality in one out of the 6 animals dosed. Clinical signs observed consisted of Hunching, ataxia, blepharospasm, protrusion of eyes, piloerection and an abdominal lump. Macroscopic examination of the surviving animals at the end of the observation period did not reveal any treatment related gross changes.

Since five out of six animals survived the 2000 mg/kg dose-level, the oral LD50 of the test material is considered to be between 2000 and 5000 mg/kg/day.

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted on read-across material
Justification for type of information:
Read Across to Octyltin tris(2-ethylhexylmercaptoacetate) (MOTE) (EC Number 248-227-6 and CAS No 27107-89-7) based on structural similarity and hydrolytical behaviour, see attached justification.
Reason / purpose for cross-reference:
read-across source
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 - < 5 000 mg/kg bw
Based on:
test mat.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
24 January 1984 to 28 February 1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPP 81-1 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: CDR (Sprague-Dawley derived)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: young adults
- Weight at study initiation: males: 253 to 315 g, females: 213 to 259 g
- Fasting period before study: animals were fasted overnight (for approximately 18 hours) prior to dosing.
- Housing: animals were individually housed during the study in suspended, stainless steel cages with wire mesh bottoms.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 14 days, housed in 6 animals/ cage

ENVIRONMENTAL CONDITIONS
- Temperature: 67 to 76 °F
- Humidity: 30 to 70 %
- Photoperiod: 12 hours light, 12 hours dark (controlled by an automatic timer)
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
- The test material was administered as received; no preparation was necessary.
Doses:
600, 800, 1200, 1700 and 2500 mg/kg
No. of animals per sex per dose:
5 animals per sex per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 21 days. Viability checks were performed twice daily.
- Frequency of observations of pharmacologic and toxicological signs: Approximately 1, 2, and 4 hours after dosing and daily thereafter for twenty-one days.
- Frequency of weighing: Pre-test (just prior to dosing; weights used for calculation of doses) and on day 7, 14 and 21. Any animals which did not survive for 21 days were weighed at the time of death or at the time they were found dead.
- Necropsy of survivors performed: yes
Gross post-mortem examinations were performed on all animals which died or were found dead during the study. All animals surviving at termination of the observation period (Day 21) were killed by carbon dioxide inhalation and examined grossly. All abnormalities were recorded but no tissues were saved.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 700 mg/kg bw
Based on:
test mat.
95% CL:
>= 1 102 - <= 2 298
Mortality:
- A summary of animal deaths can be seen in Table 1.
- At 600 mg/kg no animals died.
- At 800 mg/kg 3/10 animals died.
- At 1200 mg/kg 3/10 animals died.
- At 1700 mg/kg 5/10 animals died.
- At 2500 mg/kg 7/10 animals died.
Clinical signs:
Several animals were hypoactive on the day of dosing and some exhibited wet rales, soft stool and/or faecal staining. Within 24 hours after dosing several abnormalities were apparent in all dose groups. These, most notably, included ataxia; prostration; decreased activity; decreased food consumption; unthrifty coats; soft stool; faecal and urinary staining; oral, nasal and ocular discharge.
A few survivors continued to exhibit abnormalities throughout much of the 21-day post-dose observation period. These abnormalities included hypoactivity, decreased food consumption, unthrifty coat, faecal staining, soft stool and alopecia. Most animals were free of significant abnormalities by study termination.
On Day 4 one animal (female No. 4624, 800 mg/kg) was noted to have a mass in the lower abdomen. The mass was approximately 5 mm in diameter on Day 4 and grew to approximately 34x38 mm by Day 21. The presence of a rapidly-growing mass of this type is highly unusual in an animal of this age; this appears to be a spontaneously occurring abnormality. Its presence in a single animal in one of the lower dose groups in this study is not considered to represent an effect of test material administration.
Body weight:
Animals which died exhibited substantial antemortem weight losses.
All surviving animals in the 1700 and 2500 mg/kg groups and a few survivors in other groups lost weight at Day 7. All animals gained weight at Days 14 and 21.
Gross pathology:
Post-mortem examination of animals found dead revealed a variety of changes primarily in the lungs (discolouration, red foci), liver (discoloured, accentuated lobular pattern) and gastrointestinal tract (stomach and intestinal walls discoloured, black or red fluid in intestine or stomach). These changes appeared to represent post-mortem autolysis, antemortem stress and/or an irritant or corrosive effect of the test material on the gastrointestinal mucosa.
Two animals in the 2500 mg/kg and one animal in the 1700 mg/kg group had red fluid in the urinary bladder.
Postmortem observations of animals which survived throughout the study confirmed the presence of the mass seen in the animal No. 4264 (female, 800 mg/kg) during the antemortem phase. The mass consisted of soft yellow-tan tissue with a cavernous centre containing thick dark red fluid. Changes seen in other animals killed after 21 days were generally similar to those seen in control animals killed by carbon dioxide inhalation, or were considered to represent normal physiological variation.
Other findings:
The study was planned for 14 days but because signs of toxicity were still present at Day 14, the study was extended for one week (to Day 21).

Table 1: Summary of mortalities throughout the study

Dose level (mg/kg)

Mortality

Time of death

Male

Female

Total

600

0/5

0/5

0/10

-

800

0/5

3/5

3/10

Day 2

1200

1/5

2/5

3/10

Day 2

1700

1/5

4/5

5/10

Days 2 to 6

2500

2/5

5/5

7/10

23 hr to Day 3

Table 2: Summary of study results

 

Male

Female

Total

LD50 (mg/kg)

3100

980

1700

95 % confidence limits (mg/kg)

1079 to 5121

647 to 1313

1102 to 2298

 

Interpretation of results:
other: Category 4 in accordance with EU criteria
Conclusions:
Under the conditions of this study the acute oral LD50 value to CDR Sprague Dawley rats was 1700 mg/kg.
Executive summary:

The potential of the test material to cause acute oral toxicity to rats was investigated in a study conducted largely in accordance with EPA OPP 81-1 using the CDR Sprague Dawley strain of rat.

Five animals per sex per dose were treated orally with the test material at five concentration levels (600, 800, 1200, 1700 and 2500 mg/kg) and then observed for 21 days.

No mortality was seen in the 600 mg/kg treatment group. At 800 mg/kg 3/10 animals died, at 1200 mg/kg 3/10 animals died, at 1700 mg/kg 5/10 animals died and at 2500 mg/kg 7/10 animals died. Animals which died exhibited substantial antemortem weight losses. All surviving animals in the 1700 and 2500 mg/kg groups and a few survivors in other groups lost weight at Day 7. All animals gained weight at Days 14 and 21.

Post-mortem examination of animals found dead revealed a variety of changes primarily in the lungs (discoloration, red foci), liver (discoloured, accentuated lobular pattern) and gastrointestinal tract (stomach and intestinal walls discoloured, black or red fluid in intestine or stomach). These changes appeared to represent post-mortem autolysis, antemortem stress and/or an irritant or corrosive effect of the test material on the gastrointestinal mucosa. Two animals in the 2500 mg/kg and one animal in the 1700 mg/kg group had red fluid in the urinary bladder. Postmortem observations of animals which survived throughout the study confirmed the presence of a mass seen in an animal that died during the study, during the antemortem phase. The mass consisted of soft yellow-tan tissue with a cavernous centre containing thick dark red fluid. Changes seen in other animals killed after 21 days were generally similar to those seen in control animals killed by carbon dioxide inhalation, or were considered to represent normal physiological variation.

Under the conditions of this study the acute oral LD50 value to CDR Sprague Dawley rats was determined to be 1700 mg/kg.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Not stated
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)
GLP compliance:
no
Remarks:
This study pre-dates the inception of GLP.
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Tif.RAI
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Animals were bred in house
- Age at study initiation: 6 to 7 weeks
- Weight at study initiation: 160 to 180 g
- Fasting period before study: rats were starved for one night before the start of treatment
- Housing: The males and females were segregated and housed in Macrolon cages (Type 3) in groups of 5
- Diet: ad libitum
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 1 °C
- Humidity: approximately 50 %
Route of administration:
oral: unspecified
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
VEHICLE: 2 % carboxymethylcellulose

DOSAGE PREPARATION: The test material was weighed into an Erlenmeyer flask on a Mettler balance. It was diluted at 30 and 50% with carboxymethylcellulose (2%).

Doses:
3590, 4640 and 7750 mg/kg
No. of animals per sex per dose:
5 animals per sex per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations: 1, 24 and 48 hours and 7 days
- Necropsy of survivors performed: yes after 7 days
Statistics:
Total animals = 30
Number of doses, K = 3
(Chi)² = 3.37 (total x number of animals / number of doses)
Degrees of Freedom, n = K - 2 = 1
(Chi)² for n of 1 = 3.84 (3.37 is less than 3.84 therefore the data are not significantly heterogeneous)
LD 84 mg/kg = 8750
LD 50 mg/kg = 5000
LD 16 mg/kg = 2850
S = [(LD 84/LD 50) + (LD 50/LD 16)] / 2 = (1.75 + 1.75) / 2 = 1.75
N' = 30 (the total number of animals used between 16 % to 84 % expected effects)
Exponent= 0.506
fLD 50 = 1.33
LD 50/fLD 50 = 3760
LD 50 x fLD 50 = 6650
LD 50 and 19/20 confidence limits: 5000 (3760-6650) mg/kg
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 19/20 CL 3760-6650 mg/kg
Mortality:
- 3590 mg/kg: 2/10 animals died during the observation period.
- 4640 mg/kg: 4/10 animals died during the observation period.
- 7750 mg/kg: 9/10 animals died during the observation period.
Clinical signs:
The rats in all dosage groups showed dyspnoea, sedation, exophthalmos, curved position and ruffled fur. These symptoms became more accentuated as the dose was increased.
The surviving animals had recovered within 6 to 7 days.
Body weight:
Not specified
Gross pathology:
No test material related gross organ changes were seen.

Table 1: Deaths during the study observation period

Dose (mg/kg)

Concentration of A.S

No. of animals

Number of deaths within

1 hour

24 hours

48 hours

7 days

M

F

M

F

M

F

M

F

M

F

3590

30

5

5

0

0

0

2

0

2

0

2

4640

50

5

5

0

0

1

3

1

3

1

3

7750

50

5

5

0

0

2

5

2

5

4

5

M = male, F = female

Interpretation of results:
other: Not classified in accordance with EU criteria
Conclusions:
Under the conditions of the study the LD50 of the test material was 5000 mg/kg.
Executive summary:

The acute oral toxicity of the test material was investigated in a study broadly similar to the OECD 401 guideline using Tif.RAI rats.

15 male and 15 female rats were treated with a single oral dose at three concentrations of the test material (5 animals per sex per dose). Animals were observed for a period of 7 days before being terminated and autopsy performed.

In the lowest concentration group (3590 mg/kg) 2/10 animals died, in the middle group (4640 mg/kg) 4/10 animals died and in the high group (7750 mg/kg) 9/10 animals died. The rats in all dosage groups showed dyspnoea, sedation, exophthalmos, curved position and ruffled fur. These symptoms became more accentuated as the dose was increased. The surviving animals had recovered within 6 to 7 days. Autopsy on surviving animals showed no test material related gross organ changes.

Under the conditions of the study the LD50 of the test material was determined to be 5000 mg/kg.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
16 October 1969 to 13 November 1969
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)
GLP compliance:
no
Remarks:
This study pre-dates the inception of GLP.
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Animals were bred by Dr. Hagermann
- Weight at study initiation: 85 to 105 g
- Fasting period before study: 18 hours before treatment
- Housing: 1 animal per cage in a Type II macrolide cage, grated bottom
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature: 21 to 23 °C
- Humidity: 55 to 65 %
Route of administration:
oral: unspecified
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
VEHICLE: 0.5 g of carboxymethyl cellulose was added to 100 mL of distilled water to prepare the vehicle

DOSAGE PREPARATION: 10 g of test material was added to 100 mL of vehicle to form an emulsion

Doses:
4.0 g/kg
No. of animals per sex per dose:
10 males
Control animals:
no
Details on study design:
- Duration of observation period following administration: 22 days following dosing on day 1 at 9.00 to 11.00 am
- Frequency of observations: 1 and 4 hours post application, then daily thereafter.
- Necropsy of survivors performed: yes. The following body regions, orifices, cavities and organs were investigated by means of inspection and/or palpation with the use of appropriate tools: Pelage, Skin, Eye and eyelid conjunctiva, Nose, Mouth, Ear, Anus, Preputial opening, Vulva, Subcutaneous connective tissue, Abdominal cavity, Pelvic cavity, Peritoneum, Oesophagus, Stomach, Small intestine, Large intestine, Mesenteric lymph nodes, Liver, Pancreas, Spleen, Kidneys, Urinary bladder, Seminal vesicle, Prostate, Testicles, Epididymis, Ovaries, Uterus, Vaginas, Thoracic cavity, Pleura, Heart, Lungs, Trachea, Thymus, Cerebrum, Middle ear and Application point.
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
> 4 000 mg/kg bw
Based on:
test mat.
Mortality:
1 animal died on the second day of the observation period.
Clinical signs:
Low grade apathy was observed throughout the first 10 days of observations.
Body weight:
Not specified
Gross pathology:
- In the animal that died during the observation period emphysema and passive hypermia were found during the necropsy.
- In the 9 surviving animals that were terminated on day 22 there were no findings during necropsy.
Interpretation of results:
other: Not classified in accordance with EU criteria
Conclusions:
Under the conditions of this study, the oral LD50 value in male Wistar rats was established to exceed 4000 mg/kg body weight.
Executive summary:

The acute oral toxicity of the test material was investigated in a study broadly similar to OECD 401 using Wistar rats.

10 male rats were treated with a single oral dose of the test material at the concentration of 4.0 g/kg. Animals were observed for a period of 22 days before being terminated and autopsy performed.

Low grade apathy was observed throughout the first 10 days of observations. One animal died on the second day of the observation period, emphysema and passive hypermia were found during the necropsy on this animal. In the 9 surviving animals that was terminated on day 22 there were no findings during necropsy. In the 9 surviving animals that was terminated on day 22 there were no findings during necropsy.

Under the conditions of this study, the oral LD50 value in male Wistar rats was established to exceed 4000 mg/kg body weight.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Not reported
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)
GLP compliance:
no
Remarks:
This study pre-dates the inception of GLP
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 120 to 160 g
- Housing: 2 animals per cage
- Diet: ad libitum
- Water: ad libitum
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
2.23, 2.5, 2.76, 3.04, 3.34, 5.0, 7.5 mL/kg
No. of animals per sex per dose:
5 males per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 21 days
- Necropsy performed: yes (on animals that spontaneously died)
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
2.85 mL/kg bw
Based on:
test mat.
95% CL:
>= 2.63 - <= 3.03
Mortality:
The death of animals occurred within 18 to 40 hours. A summary of animal deaths can be seen in Table 1.
Clinical signs:
Test animals showed apathy, fretlessness, shaggy fur and thirst. No nervous symptoms (restlessness, cramps or paralysis) were seen.
Body weight:
Not specified
Gross pathology:
The sections did not show macroscopically any peculiarities of the internal organs in spontaneously deceased rats.

Table 1: Summary of mortalities during the study

Dose level (mL/kg)

No. of animals

No. of dead animals

% Total

7.5

5

5

100

5.0

5

5

100

3.34

5

5

100

3.04

5

3

60

2.76

5

2

40

2.5

5

1

20

2.23

5

0

0

Interpretation of results:
other: Not classified in accordance with EU criteria
Conclusions:
Under the conditions of the study the acute oral LD50 to male Wistar rats was 2.85 mL/kg.
Executive summary:

The acute oral toxicity of the test material to male Wistar rats was investigated in a study similar to OECD 401.

Five animals per dose were treated orally with the test material at the following dose levels: 2.23, 2.5, 2.76, 3.04, 3.34, 5.0, 7.5 mL/kg. Animals were observed for 21 days following administration. Test animals showed apathy, fretlessness, shaggy fur and thirst. No nervous symptoms (restlessness, cramps or paralysis) were seen.

100 % of animals in the 7.5, 5.0 and 3.34 mL/kg test groups died. 60 % in the 3.04 mL/kg, 40 % in the 2.76 mL/kg and 20 % in the 3.5 mL/kg group died, respectively. No animals died in the 2.23 mL/kg group. The death of animals occurred within 18 to 40 hours. The sections did not show macroscopically any peculiarities of the internal organs in spontaneously deceased rats.

Under the conditions of the study the acute oral LD50 to male Wistar rats was 2.85 mL/kg.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
In accordance with REACH, Annex VIII, column 2 of information requirement 8.5, in addition to the oral route, for substances other than gases, the information required under 8.5.2 to 8.5.3 shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure.

Information is provided for the dermal route which is deemed to be most appropriate as inhalation of the substance is unlikely. Testing by the inhalation route is therefore omitted.
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2nd December to 16th December 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose for cross-reference:
other: read-across target
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
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
- Age at study initiation: ca. 8 weeks old at start of study
- Weight at study initiation: 215 - 251 g. Mean weight was 237 g.
- Fasting period before study: NDA
- Housing: a maximum of 5 animals/sex per macrolon cage with sterilised wood shavings (Woody Clean) as bedding material and environmental enrichment (shreds of paper); individual housing during dermal exposure.
- Diet (e.g. ad libitum): standard laboratory diet
- Water (e.g. ad libitum): ad libitum
- Acclimation period: mimimum of 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 °C
- Humidity (%): 45-65%. Upper limit may be higher for short periods of time, because of meteorological circumstances and/or wet cleaning of the room.
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 hours light / 12 hours dark


IN-LIFE DATES: From: 2nd December 2009 To: 16th December 2009
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 20 cm²
- % coverage: at least 10 % of body surface
- Type of wrap if used: gauze affixed with tape wrapped around the trunk of the rat


REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, with water
- Time after start of exposure: ca. 24 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1.79 mL/kg bw. equivalent to 2000 mg/kg bw
- Concentration (if solution): N/A
- Constant volume or concentration used: constant concentration of test substance per kg bw.
- For solids, paste formed: N/A


VEHICLE
- N/A
Duration of exposure:
Ca. 24 hours
Doses:
2000 mg/kg bw.
No. of animals per sex per dose:
5 males, 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The body weight of each animal was recorded just prior to dosing and of each surviving animal on days 3, 7 and 14 of the study.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, dermal reactions, macroscopial findings
Statistics:
No statistics reported.
Preliminary study:
NDA
Key result
Sex:
male/female
Dose descriptor:
LD0
Effect level:
> 2 000 mg/kg bw
Mortality:
No mortality observed during the 14-day study period.
Clinical signs:
No clinical signs were observed during the 14-day study period.
Body weight:
Apart from a slight dip in body weight of some of the animals on day 3 of the study, all animals gained weight during the 14-day study (see Table 1).
Gross pathology:
Examination at necropsy of the animals did not reveal distinct treatment related gross alterations.
Other findings:
In general, no signs of skin irritation were observed during the study. On days 1 and/or 3, three females showed minor skin effects, consisting of very slight or well-defined erythema and very slight or slight scaliness.

Table 1. Individual and mean bodyweights, dose amounts applied and mortality data.

Animal number Sex Dose (ml) applied Bodyweights (g) recorded on day: Mortality
0 3 7 14
12 Male 0.38 215 203 230 262 -
14   0.45 251 255 281 315 -
16   0.43 238 241 266 298 -
18   0.43 241 231 260 281 -
20   0.43 242 244 267 300 -
Mean bodyweight 237 235 261 291 0/5
11 Female 0.32 180 174 191 211 -
13   0.32 181 183 199 211 -
15   0.29 163 154 177 189 -
17   0.32 180 162 188 206 -
19   0.31 174 171 190 213 -
Mean bodyweight 176 169 189 206 0/5
Interpretation of results:
other: Not classified in accordance with EU Criteria
Conclusions:
Since all animals survived the 2000 mg/kg dose level, the dermal LD50 of the test material is considered to be higher than 2000 mg/kg body weight.
Executive summary:

The test material was examined for acute dermal toxicity in an experiment with 8 week old male and female Wistar rats (limit testing), according EU Method B.3 and OECD 402, under GLP conditions. A dose level of 2000 mg per kg body weight was examined and the dermal contact period was 24 hours.

Since all animals survived the 2000 mg/kg dose level, the dermal LD50 of the test materuial is considered to be higher than 2000 mg/kg body weight.

Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted on read-across material
Justification for type of information:
Read Across to Octyltin tris(2-ethylhexylmercaptoacetate) (MOTE) (EC Number 248-227-6 and CAS No 27107-89-7) based on structural similarity and hydrolytical behaviour, see attached justification.
Reason / purpose for cross-reference:
read-across source
Key result
Sex:
male/female
Dose descriptor:
LD0
Effect level:
> 2 000 mg/kg bw
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

Oral (Bathe, 1973)

The acute oral toxicity of the test material was investigated in a study broadly similar to the OECD 401 guideline using Tif.RAI rats. The study was awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch et al. (1997).

15 male and 15 female rats were treated with a single oral dose at three concentrations of the test material (5 animals per sex per dose). Animals were observed for a period of 7 days before being terminated and autopsy performed.

In the lowest concentration group (3590 mg/kg) 2/10 animals died, in the middle group (4640 mg/kg) 4/10 animals died and in the high group (7750 mg/kg) 9/10 animals died. The rats in all dosage groups showed dyspnoea, sedation, exophthalmos, curved position and ruffled fur. These symptoms became more accentuated as the dose was increased. The surviving animals had recovered within 6 to 7 days. Autopsy on surviving animals showed no test material related gross organ changes.

Under the conditions of the study the LD50 of the test material was determined to be 5000 mg/kg.

Oral (Gunzel and Richter, 1969)

The acute oral toxicity of the test material was investigated in a study broadly similar to OECD 401 using Wistar rats. The study was awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch et al. (1997).

10 male rats were treated with a single oral dose of the test material at the concentration of 4.0 g/kg. Animals were observed for a period of 22 days before being terminated and autopsy performed.

Low grade apathy was observed throughout the first 10 days of observations. One animal died on the second day of the observation period, emphysema and passive hypermia were found during the necropsy on this animal. In the 9 surviving animals that was terminated on day 22 there were no findings during necropsy. In the 9 surviving animals that was terminated on day 22 there were no findings during necropsy.

Under the conditions of this study, the oral LD50 value in male Wistar rats was established to exceed 4000 mg/kg body weight.

Oral (Auletta, 1984)

The potential of the test material to cause acute oral toxicity to rats was investigated in a study conducted largely in accordance with EPA OPP 81-1 using the CDR Sprague Dawley strain of rat. The study was awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch et al. (1997).

During the study, five animals per sex per dose were treated orally with the test material at five concentration levels (600, 800, 1200, 1700 and 2500 mg/kg) and then observed for 21 days.

No mortality was seen in the 600 mg/kg treatment group. At 800 mg/kg 3/10 animals died, at 1200 mg/kg 3/10 animals died, at 1700 mg/kg 5/10 animals died and at 2500 mg/kg 7/10 animals died. Animals which died exhibited substantial antemortem weight losses. All surviving animals in the 1700 and 2500 mg/kg groups and a few survivors in other groups lost weight at Day 7. All animals gained weight at Days 14 and 21.

Post-mortem examination of animals found dead revealed a variety of changes primarily in the lungs (discoloration, red foci), liver (discoloured, accentuated lobular pattern) and gastrointestinal tract (stomach and intestinal walls discoloured, black or red fluid in intestine or stomach). These changes appeared to represent post-mortem autolysis, antemortem stress and/or an irritant or corrosive effect of the test material on the gastrointestinal mucosa. Two animals in the 2500 mg/kg and one animal in the 1700 mg/kg group had red fluid in the urinary bladder. Postmortem observations of animals which survived throughout the study confirmed the presence of a mass seen in an animal that died during the study, during the antemortem phase. The mass consisted of soft yellow-tan tissue with a cavernous centre containing thick dark red fluid. Changes seen in other animals killed after 21 days were generally similar to those seen in control animals killed by carbon dioxide inhalation, or were considered to represent normal physiological variation.

Under the conditions of this study the acute oral LD50 value to CDR Sprague Dawley rats was determined to be 1700 mg/kg.

Oral (Klimmer, 1969)

The acute oral toxicity of the test material to male Wistar rats was investigated in a study similar to OECD 401. The study was awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch et al. (1997).

Five animals were treated orally with the test material at the following dose levels: 2.23, 2.5, 2.76, 3.04, 3.34, 5.0, 7.5 mL/kg. Animals were observed for 21 days following administration. Test animals showed apathy, fretlessness, shaggy fur and thirst. No nervous symptoms (restlessness, cramps or paralysis) were seen.

100 % of animals in the 7.5, 5.0 and 3.34 mL/kg test groups died. 60 % in the 3.04 mL/kg, 40 % in the 2.76 mL/kg and 20 % in the 3.5 mL/kg group died, respectively. No animals died in the 2.23 mL/kg group. The death of animals occurred within 18 to 40 hours. The sections did not show macroscopically any peculiarities of the internal organs in spontaneously deceased rats.

Under the conditions of the study the acute oral LD50 to male Wistar rats was 2.85 mL/kg.

Oral

Read-across to structurally similar substance Octyltin tris(2-ethylhexylmercaptoacetate) (MOTE) (CAS No 27107-89-7)

A sample of the test material was examined for acute oral toxicity in an experiment with female rats (limit testing), according to EU Method B.1 tris and OECD 423, under GLP conditions. The study was awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch et al. (1997).

Dose levels of 2000, 300 and 50 mg per kg bodyweight were examined and animals were observed for a maximum of 14 days after dosing.

No mortality or clinical signs were observed after treatment with a 50 and 300 mg/kg/ bw dose-levels. The 2000 mg/kg bw dose-level caused mortality in one out of the 6 animals dosed. Clinical signs observed consisted of Hunching, ataxia, blepharospasm, protrusion of eyes, piloerection and an abdominal lump. Macroscopic examination of the surviving animals at the end of the observation period did not reveal any treatment related gross changes.

Since five out of six animals survived the 2000 mg/kg dose-level, the oral LD50 of the test material is considered to be between 2000 and 5000 mg/kg/day.

Inhalation

In accordance with column 2 of section 8.5.2 of REACH, the acute toxicity by inhalation study has been omitted as scientifically unjustified on the grounds that inhalation exposure to the substance is unlikely under normal conditions of use. The acute toxicity of the substance has been determined adequately by the other routes.

Dermal

Read across to Octyltin tris(2-ethylhexylmercaptoacetate) (MOTE) (CAS No 27107-89-7)

The test material was examined for acute dermal toxicity in an experiment with 8 week old male and female Wistar rats (limit testing), according EU Method B.3 and OECD 402, under GLP conditions. A dose level of 2000 mg per kg body weight was examined and the dermal contact period was 24 hours.

Since all animals survived the 2000 mg/kg dose level, the dermal LD50 of the test materuial is considered to be higher than 2000 mg/kg body weight.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does not require classification with regards to acute oral or dermal toxicity.