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Description of key information

The test substance was practically non toxic in rats after a single dose oral or a 24 hour dermal exposure to the test substance, each route producing an LD50 greater than 2,000 mg/kg bw in male and female animals.

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:
2007
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)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no
Specific details on test material used for the study:
- Name of test substance (as cited in study report): Bumetrizol
- Analytical purity: 99.9% w/w
- Lot/batch No.: 01721IW4
- Stability under test conditions: Stable
- Storage condition of test material: Stored sealed in a cabinet at 20.0 - 25.3 deg C
Species:
rat
Strain:
Crj: CD(SD)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Japan (Hino Breeding center)
- Age at study initiation: 7 weeks (8 weeks at administration)
- Weight at study initiation: 182 - 204 g (185 - 201 g at administration)
- Fasting period before study: 18.5 - 19 hours before and up to 6 hours after administration
- Housing: Stainless steel cage
- Diet: CRF-1 (Oriental Yeast Co.); ad libitum
- Water: ad libitum
- Acclimation period: 5 days quarantine, 2 days acclimation

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 24
- Humidity (%): 41 - 46
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
methylcellulose
Remarks:
0.5 % w/v solution
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 20 % w/v
- Amount of vehicle (if gavage): 10 mL/kg

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Information available from company literature that LD50 > 2000 mg/kg bw
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6 females (3 in test 1 and 3 in test 2)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: General signs and death were observed up to 6 hours on the day of administration (0 - 30 min, 2, 4 and 6 hours after administration), then once per day from the following day during the observation period. Body weights were taken on the administration day (just before administration) and 1, 3, 7, 10 and 14 days after administration.
- Necropsy of survivors performed: yes
Statistics:
Mean and standard deviation calculated for body weights.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No animal died.
Mortality:
No mortality occurred during the study period.
Clinical signs:
No clinical signs of toxicity were observed up to the end of the 14-day observation period.
Body weight:
No effect on body weight was noted.
Gross pathology:
Necropsy examination revealed no substance-related findings.

Body weights (g):

Females

mg/kg bw

Test group 1

Test group 2

2000

2000

Days after administration

0

185

199

1

203

222

3

209

230

7

220

242

10

232

255

14

239

262

Interpretation of results:
GHS criteria not met
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
Test animals given single oral dose of 2,500 or 5,000 mg/kg bw and were observed for 8 days.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test substance (as cited in study report): TK 10048
- Substance No.: GP 38771
Species:
mouse
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 17 - 19 g
No further detail given.
Route of administration:
oral: unspecified
Vehicle:
other: gum arabicum
Details on oral exposure:
TEST MATERIAL
- Concentration in vehicle: 20%
Doses:
2,500 or 5,000 mg/kg bw
No. of animals per sex per dose:
5 animals/dose (how many per sex unspecified)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 8 days
- Frequency of observations and weighing: no data
- Necropsy of survivors performed: no data
- Other examinations performed: clinical signs
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No animal died.
Mortality:
No mortality occurred during the study period.
Clinical signs:
No clinical signs of toxicity were observed up to the end of the 8-day observation period.
Body weight:
no data
Gross pathology:
no data
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
Test animals given single oral dose of 2,500 or 5,000 mg/kg bw and were observed for 8 days.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): TK 10048
- Substance No.: GP 38771
Species:
rat
Strain:
not specified
Sex:
male/female
Route of administration:
oral: unspecified
Vehicle:
other: Gum arabic
Doses:
2,500 or 5,000 mg/kg bw
No. of animals per sex per dose:
5 animals/dose, sex unspecified
Control animals:
no
Details on study design:
- Duration of observation period following administration: 8 days
- Frequency of observations and weighing: no data
- Necropsy of survivors performed: no data
- Other examinations performed: clinical signs
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No animal died.
Mortality:
No mortality occurred during the study period.
Clinical signs:
No clinical signs of toxicity were observed up to the end of the 8-day observation period.
Body weight:
no data
Gross pathology:
no data
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
(limited documentation)
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
- Name of test material (as cited in study report): Sample # 25-84
- Physical state: white liquid
- Batch No.: 108-074
- Substance No.: 25-84
- Storage: room temperature
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Additional information on strain: Albino rats
- Source: Ace Animals
- Weight at study initiation: 220 - 247 g (males) and 200 - 218 g (females)
- Fasting period before study: 16 - 20 h
- Housing: 5/cage in suspended wire mesh cages
- Diet: Purina Rat Chow (Diet #5012); ad libitum
- Water: ad libitum
- Acclimation period: at least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled (no value given)
- Humidity (%): controlled (no value given)
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 1.1 mL per animal
Doses:
5,000 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: observation for mortality, toxicity and pharmacological effects 1, 2 and 4 hours after dosing and daily for 14 days. Body weights were recorded prior to dosing and at termination of the study.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
LD50 and 95% confidence were calculated by the method of Litchfield and Wilcoxon (1949) or Horn (1956)
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No animal died.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 110 mg/kg bw
Based on:
act. ingr.
Remarks:
(42.2% of the test substance was contained in the test material)
Remarks on result:
other: No animal died
Mortality:
No mortality occurred during the study period.
Clinical signs:
The males appeared normal throughout the study. Physical signs of ptosis (2 hours - day 4) and chromodacryorrhea (day 1 - day 9) were noted in the females.
Body weight:
- Mean body weights (g, day 0 - day 14):
Males: 229.8 - 352.2
Females: 207.6 - 235.8
Body increase were normal in 9/10 animals. One female did not gain a normal amount of weight.
Gross pathology:
Necropsy results were normal in 7/10 animals. Moderate hydronephrosis of the right kidney was noted in one male, and intestinal abnormalities were noted in two females (slight to moderate).
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
(limited documentation, Photoperiod (hrs dark / hrs light): 14/10, acclimation period in some cases of only 4 days)
Principles of method if other than guideline:
5 male and 5 female rats dosed by gavage at 4,640, 6,000 or 7,750 mg/kg bw and were observed for 14 days.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): TK 10048
- Lot/batch No.: EN 26565
Species:
rat
Strain:
other: Tif:RAIf (SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: raised by the laboratory
- Weight at study initiation: 160 - 180 g
- Fasting period before study: overnight
- Housing: groups of 5 in Macrolon cages (type 3)
- Diet: NAFAG, Gossau SG; ad libitum
- Water: ad libitum
- Acclimation period: minimum of 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1
- Humidity (%): 55 ± 5
- Photoperiod (hrs dark / hrs light): 14/10
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
(PEG 400)
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30%


Doses:
4,640, 6,000 or 7,750 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: Observations at 1, 24 and 48 hours, 7 and 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 7 750 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No animal died.
Mortality:
No mortality occurred during the study period.
Clinical signs:
Within two hours after treatment, the rats in all dosage groups showed sedation, dyspnoea, curved position and ruffled fur. The animals recovered within 8 to 10 days.
Body weight:
No effect on body weight was noted.
Gross pathology:
Necropsy examination revealed no substance-related findings.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 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
Study period:
1972
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 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
(Photoperiod (hrs dark / hrs light): 10/14, occlusive treatment, 8 day-post treatment observation, no necropsy examinations)
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
- Name of test material (as cited in study report): TK 10048
- Lot/batch No.: Dated 16.10.71
Species:
rat
Strain:
other: CFE (RAC; SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Local suppliers
- Age at study initiation: no data
- Weight at study initiation: 123 - 133 g
- Fasting period before study: no data
- Housing: groups of 5 in macrolon cages (type 3)
- Diet: Nafag; ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1
- Humidity (%): 55 ± 5
- Photoperiod (hrs dark / hrs light): 10/14


Type of coverage:
occlusive
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
(0.5% in water)
Details on dermal exposure:
TEST SITE
- Area of exposure: 100 cm²/kg bw
- Type of wrap if used: occlusive dressing held in place with an adhesive elastic bandage

REMOVAL OF TEST SUBSTANCE
- Washing: yes
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): no data
- Constant volume or concentration used: yes (50%)
- For solids, paste formed: yes

VEHICLE
- Amount(s) applied (volume or weight with unit): no data
- Concentration (if solution): 0.5%
Duration of exposure:
24 hours
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: 8 days
- Frequency of observations and weighing: daily observations, weighed at end of study
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs, body weight
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No animal died.
Mortality:
No mortality occurred during the study period.
Clinical signs:
No clinical signs of toxicity were observed up to the end of the 8-day observation period.
Body weight:
Average body weight increased from 126 g to 171 g during the test.
Gross pathology:
not performed
Interpretation of results:
GHS criteria not met
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw

Additional information

Acute toxicity: oral

In an acute toxic class toxicity study, 2 groups containing three Crj: CD(SD) female rats (8 weeks old) were each administered the test substance (99.9% pure) via gavage after a ca. 19 hour fasting period. The test substance was administered at the limit dose of 2,000 mg/kg bw in 0.5% (w/v) methylcellulose solution. Animals were subsequently observed for a period of 14 day in which time clinical signs of toxicity, body weights changes and cases of mortality were noted. 

Death did not occur in either group. Hence, the LD 50 is higher than 2,000 mg/kg bw. No clinical signs of toxicity were observed up to the end of the 14-days observation period. Body weight development was normal and at necropsy, no deviations from normal morphology were found (Nihon Bioresearch Center Inc., 2007).

This study is suitable for assessment of acute oral toxicity as it was performed under GLP and according to the protocol of OECD 423.

 

In a standard acute oral toxicity study, the test substance (no data on purity) was administered via gavage to groups of five overnight fasted Tif Raif (SPF) rats per sex per dose. Treatment was performed as a single dose application at dose levels of 4,640, 6,000 or 7,750 mg/kg bw in polyethylene glycol (PEG 400). Animals were subsequently observed for a period of 14 day in which time clinical signs of toxicity, body weights changes and cases of mortality were noted. 

Death did not occur at any dose level. Hence the LD 50 is higher than 7,750 mg/kg bw. Registered clinical signs of toxicity seen in all groups were sedation, dyspnoea, curved position and ruffled fur. The animals recovered within 8 to 10 days. Body weight development was normal and at necropsy, no deviations from normal morphology were found (Ciba Geigy Ltd. 1978).

This study is suitable for assessment of acute oral toxicity as it was performed using a protocol which is similar and equivalent to the delete OECD 401 guideline.

 

Acute toxicity: dermal

In an acute dermal toxicity study, groups of five young adult CFE (RAC; SPF) rats per sex per dose were dermally exposed to the test substance (no data on purity in 0.5 % (w/v) carboxymethyl cellulose (aqueous) for 24 hours to a skin surface of 100 cm2/kg bw at the limit dose of 2,000 mg/kg bw. Substance application was performed under occlusive dressing. Animals were then observed for 8 days. 

No mortalities occurred. LD 50 thus lies higher than 2,000 mg/kg bw. No clinical signs of toxicity were observed up to the end of the 8-day observation period. There were no treatment related changes in body weight. Necropsy of surviving animals was not performed (Ciba Geigy Ltd. 1972). 

This study does not fully satisfy the requirement of OECD 402 for Acute Dermal Toxicity data as treatments were performed under occlusive conditions and necropsy of surviving animals was not performed. In addition, there is limited data provided on test substance (e.g. there is no data on test substance purity).

 

Acute toxicity: inhalation

There are no reliable data available covering this endpoint.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. No mortality occurred at the limit dose of 2000 mg/kg bw. As a result, the substance is not considered to be classified for acute oral or dermal toxicity under Regulation (EC) No. 1272/2008, as amended for the thirteenth time in Regulation (EC) No. 2018/1480.