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Description of key information

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:
key study
Study period:
1988
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
Purity : 73.1%
PROXEL Press Paste
Reference ADH374793, Bx973
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
other: 0.5% aqueous polysorbate 80
Doses:
0, 100, 300, 500 and 900 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
670 mg/kg bw
Based on:
test mat.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
490 mg/kg bw
Based on:
act. ingr.
Mortality:
There were no deaths in animals dosed with 100 or 300 mg/kg. One female dosed with 500 mg/kg was killed in extremis on Day 2. All the males and three females dosed with 900 mg/kg died or were killed in extremis on Days 1 or 2.
Clinical signs:
There were no signs of toxicity at any time in the animals dosed with 100 mg/kg. Signs of slight toxicity in those dosed with 300 mg/kg were piloerection and upward curvature of the spine, neither of which persisted after Day 3. Surviving animals dosed with 500 mg/kg also showed signs of slight toxicity until Day 3. These were of a slightly higher incidence than those seen following dosing with 300 mg/kg, and included dehydration, piloerection and upward curvature of the spine. Signs of marked toxicity were observed in the animals dosed with 900 mg/kg. The most common abnormalities were upward curvature of the spine, piloerection, sides pinched-in, dehydration, hypothermia and decreased activity. Two animals appeared cyanosed prior to death. The two surviving females had recovered by days 6 or 7.
Body weight:
The overall weight gain, throughout the study, was similar at all dose-levels.
Gross pathology:
There were no macroscopic abnormalities in any animal at necropsy.

The acute oral median lethal dose value was 670 mg/kg (approximate 95% confidence limits 500, 900) to male rats and 784 mg/kg (lower 95% confidence limit 475) to female rats.

Conclusions:
Materials and methods
Groups of five male and five female rats were given a single oral dose of 100, 300, 500 or 900 mg/kg of PROXEL press paste, as preparations in 5% (w/v) aqueous polysorbate 80. The animals were weighed and observed for fourteen days after dosing. PROXEL press paste (wet) is a 73.1% BIT technical grade material.
The methodology employed was equivalent to those described in guidelines OECD401, EC B.1.

Results and discussion There were no deaths and no signs of toxicity at 100 mg/kg and no deaths but signs of slight toxicity at 300 mg/kg. One female dosed with 500 mg/kg was killed in extremis and there were signs of slight toxicity in the survivors. Following dosing with 900 mg/kg there were signs of marked toxicity and all the males and three females died or were killed in extremis on Days 1 or 2. There were no macroscopic abnormalities in any animal at necropsy.
The acute oral median lethal dose value was 670 mg/kg (approximate 95% confidence limits 500, 900) to male rats and 784 mg/kg (lower 95% confidence limit 475) to female rats.
Executive summary:

A study was conducted to determine the acute oral toxicity of the substance according to a method similar to OECD Guideline 401. Groups of five male and five female rats were administered a single oral dose of 0, 100, 300, 500 or 900 mg/kg bw of the substance in a 0.5% (w/v) aqueous polysorbate 80 suspension. The animals were weighed and observed for fourteen days after dosing. There was no mortality at 100 and 300 mg/kg. One female at 500 mg/kg bw was sacrificed in extremis. At 900 mg/kg bw there were signs of marked toxicity and all the males and three females died or were sacrificed in extremis on Day 1 or 2. There were no macroscopic abnormalities in any animal at necropsy. Under the study conditions, the acute oral LD50 of the substance was determined to be 670 mg/kg bw (490 mg a.i./kg bw) in rats (Leah, 1988).

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1994
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
Specific details on test material used for the study:
Batch No. GK 100 B
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
other: T52-003:Aqueous 0.5% w/v methylcellulose
Doses:
0, 202, 320 and 506 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Only male animals were tested at the three dose levels. Females were included at the lowest dose level to show that females were not more sensitive than male animals.
Statistics:
Probit analysis by the method of Finney (1971) was used to determine the acute median lethal dosage, 95% confidence interval and slope of the dose response curve of the test material.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
454 mg/kg bw
Based on:
test mat.
Mortality:
Two male animals treated at 506 mg/kg died within the first hour after dosing and another animal was found dead two hours later. One animal treated at 320 mg/kg died during the first overnight period.
There was no death at the low dosage of 202 mg/kg.
Clinical signs:
Ante mortem signs comprised lethargy, underactivity, staggering gait, prone position, pallor, hyperpnoea, piloerection, hunched posture and pupil dilation.
Signs of reaction to treatment in the surviving animals in all dose levels included underactivity, staggering gait, piloerection, hunched posture and salivation. The majority of animals were overtly normal five days after dosing.
Body weight:
The surviving animals achieved expected bodyweight gains
Gross pathology:
Necropsy findings for the decedents were unremarkable.
Necropsy of the surviving animals, on Day 15, revealed no significant macroscopic lesion.
Conclusions:

Materials and methods
Young adult rats (CD strain, remote Sprague-Dawley origin) were held in a limited-access facility kept at slight positive pressure relative to the outside. Target values for temperature and humidity were 21°C (range 19O-25°C) and 55% R.H. (range 40%-70% R.H.), respectively. A commercially-available complete pelleted rodent diet was fed ad libitum.
The main study was carried out using three groups of five male rats (one group at each concentration level) and one group of five female rats (at the lowest dose level). Each group was given a single oral administration of BIT at dosages of 202, 320 or 506 mg/kg, at a constant volume-dosage of 20 mL/kg in aqueous 0.5% w/v methylcellulose.
Animals were inspected regularly and the bodyweight of each animal was recorded on the day before dosing and on Days 1, 8 and 15. The test was terminated on the morning of Day 15.
All animals were examined for abnormality of tissues or organs. All body cavities were opened, larger organs were sectioned and the gastro-intestinal tract was opened at intervals for examination of the mucosal surfaces. All abnormalities were described or the normal appearance of major organs was confirmed.
The methodology employed was as described in guidelines OECD401, EC B.1.

Results and discussion
Two male animals treated at 506 mg/kg died within the first hour after dosing and another animal was found dead two hours later. One animal treated at 320 mg/kg died during the first overnight period.
There was no death at the low dosage of 202 mg/kg.
Ante mortem signs comprised lethargy, underactivity, staggering gait, prone position, pallor, hyperpnoea, piloerection, hunched posture and pupil dilation.
Signs of reaction to treatment in the surviving animals in all dose levels included underactivity, staggering gait, piloerection, hunched posture and salivation. The majority of animals were overtly normal five days after dosing.
There was no sign of reaction to treatment in female animals.
Necropsy findings for the decedents were unremarkable. Necropsy of the surviving animals, on Day 15, revealed no significant macroscopic lesion.
The surviving animals achieved expected bodyweight gains.
♂ LD50 = 454 mg/kg (95% confidence limits 306, 601 mg/kg)
♀ The female animals treated at 202 mg/kg showed no sign of reaction to treatment, indicating the test material was not more toxic to female rats.
Executive summary:

Results and discussion       

Two male animals treated at 506 mg/kg died within the first hour after dosing and another animal was found dead two hours later. One animal treated at 320 mg/kg died during the first overnight period.

There was no death at the low dosage of 202 mg/kg.

Ante mortem signs comprised lethargy, underactivity, staggering gait, prone position, pallor, hyperpnoea, piloerection, hunched posture and pupil dilation.

Signs of reaction to treatment in the surviving animals in all dose levels included underactivity, staggering gait, piloerection, hunched posture and salivation. The majority of animals were overtly normal five days after dosing.

There was no sign of reaction to treatment in female animals.

Necropsy findings for the decedents were unremarkable. Necropsy of the surviving animals, on Day 15, revealed no significant macroscopic lesion.

The surviving animals achieved expected bodyweight gains.

♂       LD50 = 454 mg/kg (95% confidence limits 306, 601 mg/kg)

♀       The female animals treated at 202 mg/kg showed no sign of reaction to treatment, indicating the test material was not more toxic to female rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
490 mg/kg bw

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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes
Specific details on test material used for the study:
Batch number: GK 100 B
Species:
rat
Strain:
other: CD strain (remote Sprague-Dawley origin)
Sex:
male/female
Type of coverage:
occlusive
Vehicle:
water
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Details on study design:
The acute percutaneous toxicity of BIT was investigated in a group of five male and five female CD rats. The test material was applied to the closely-clipped dorsum of each animal at a dosage of 2000 mg/kg bodyweight and was covered by an occlusive dressing for 24 hours. Mortality, systemic and local signs of reaction to treatment were recorded during a subsequent 14-day period of observation. The animals were killed on the following day and subjected to necropsy.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There was no death and there were no systemic signs of reaction to treatment.
Clinical signs:
Local signs comprised very slight or well-defined erythema, slight exfoliation and eschar formation.
Body weight:
The animals achieved expected bodyweight gains
Gross pathology:
necropsy revealed no significant macroscopic lesion.
Under the conditions of this study, the acute percutaneous median lethal  dosage (LD50) of the test material was greater than 2000 mg/kg. 

Conclusions:
There was no death and there were no systemic signs of reaction to treatment.

Local signs comprised very slight or well-defined erythema, slight exfoliation and eschar formation.
The animals achieved expected bodyweight gains and necropsy revealed no significant macroscopic lesion.
Accordingly, BIT was assigned to the class ‘low percutaneous toxicity’.
Executive summary:

A study was conducted to determine the acute dermal toxicity of the substance in rats according to OECD Guideline 402. The test substance was applied to the closely-clipped dorsum of a group of five male and five female rats at a dosage of 2000 mg/kg  bodyweight and was covered by an occlusive dressing for 24 hours. Mortality, systemic and local signs of reaction to treatment were recorded during a subsequent 14-day period of observation. The animals were sacrificed on Day 15 and subjected to necropsy. There was no mortality and no systemic signs of reaction to treatment. Local signs comprised of very slight or well-defined erythema, slight exfoliation and eschar formation. The animals achieved expected bodyweight gains and necropsy revealed no significant macroscopic lesion. Under the study conditions, the acute dermal LD50 of the substance in rats was determined to be greater than 2000 mg/kg bw (Rees, 1994).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Additional information

Oral:

A study was conducted to determine the acute oral toxicity of the substance according to a method similar to OECD Guideline 401. Groups of five male and five female rats were administered a single oral dose of 0, 100, 300, 500 or 900 mg/kg bw of the substance in a 0.5% (w/v) aqueous polysorbate 80 suspension. The animals were weighed and observed for fourteen days after dosing. There was no mortality at 100 and 300 mg/kg. One female at 500 mg/kg bw was sacrificed in extremis. At 900 mg/kg bw there were signs of marked toxicity and all the males and three females died or were sacrificed in extremis on Day 1 or 2. There were no macroscopic abnormalities in any animal at necropsy. Under the study conditions, the acute oral LD50 of the substance was determined to be 670 mg/kg bw (490 mg a.i./kg bw) in rats (Leah, 1988).

Dermal:

A study was conducted to determine the acute dermal toxicity of the substance in rats according to OECD Guideline 402. The test substance was applied to the closely-clipped dorsum of a group of five male and five female rats at a dosage of 2000 mg/kg  bodyweight and was covered by an occlusive dressing for 24 hours. Mortality, systemic and local signs of reaction to treatment were recorded during a subsequent 14-day period of observation. The animals were sacrificed on Day 15 and subjected to necropsy. There was no mortality and no systemic signs of reaction to treatment. Local signs comprised of very slight or well-defined erythema, slight exfoliation and eschar formation. The animals achieved expected bodyweight gains and necropsy revealed no significant macroscopic lesion. Under the study conditions, the acute dermal LD50 of the substance in rats was determined to be greater than 2000 mg/kg bw (Rees, 1994).

A study was conducted to determine the acute dermal toxicity of the substance in rats according to US EPA Guideline OPP 81 -2. The test substance was applied to the closely-clipped dorsum of a group of five male and five female rats at a dosage of 2000 mg/kg  bodyweight and was covered by an occlusive dressing for 24 hours. Mortality, systemic and local signs of reaction to treatment were recorded during a subsequent 14-day period of observation. The animals were sacrificed on Day 15 and subjected to necropsy. There was no mortality and no systemic signs of reaction to treatment. Local signs of slight skin irritation were observed which persisted throughout the study. Under the study conditions, the acute dermal LD50 of the substance in rats was determined to be greater than 2000 mg/kg bw (Leah, 1988).

Justification for classification or non-classification

Based on the acute oral, inhalation and dermal toxicity studies with the substance, a classification as Acute Tox 4 (H302 -Harmful if swallowed) is warranted according to EU CLP (1272/2008) criteria.