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Description of key information

The acute oral LD50 for BTDA is 12,800 mg/kg bw in rats.  The acute dermal toxicity for BTDA is > 3160 mg/kg bw in rabbits.   The acute inhalation LC50for BTDA is > 4.44 mg/l (1400 ppm) in rats, mice and guinea pigs after a single dose, and is 3.0 mg/l in guinea pigs after a 5-day exposure.

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Valid scientific study, precedes guideline and GLP. Documentation is limited.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Principles of method if other than guideline:
Test method is not described for this study, but a method is available for a concurrent study on a structural analogue (BTA) of this substance (BTDA) commissioned in the same laboratory. Therefore, it is likely that the method for the BTDA is identical to that of BTA, and therefore this method is described in the following record. Both studies precede the establishment of OECD methods and GLP.
GLP compliance:
no
Remarks:
precedes establishment of GLP
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: albino Mason Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Food was withheld from all animals for 3 to 4 hours prior to dosing. Food and water were available ad libitum throughout the observation period. The animals were housed separately suspended above the droppings for the 13 day period of observation.
Route of administration:
oral: gavage
Vehicle:
other: 1% methyl cellulose
Details on oral exposure:
The test material was administered as a single dose by oral gavage. The substance was administered as a suspension in 1% methylcellulose (Methocel). The volumes administered to each respective group of rats varied in relation to the individual animal body weight and each respective dose level.
Doses:
6 doses, ranging from 5000 to 14700 mg/kg body weight.
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
The animals were observed for mortality and pharmacodynamic and/or toxic effects at the following intervals after compound administration: immediately; at 1, 4 and 24 hours; and once daily for 13 days thereafter. At the termination of the observation period, all surviving animals were weighed, sacrificed by decapitation and necropsied.
Statistics:
no data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
12 800 mg/kg bw
Based on:
test mat.
95% CL:
> 11 400 - < 14 500
Other findings:
At doses of 10,000 mg/kg or higher, BTDA produced gastrointestinal irritation and hemorrhage.
Interpretation of results:
study cannot be used for classification
Remarks:
Migrated information
Conclusions:
The acute oral LD50 for 1,3-Isobenzofurandione, 5,5'-carbonylbis- (BTDA) is 12,800 mg/kg bw in male rats.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
12 800 mg/kg bw
Quality of whole database:
acceptable

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Precedes establishment of guidelines and GLP. Documentation is limited.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 433 draft (Acute Inhalation Toxicity: Fixed Concentration Procedure) (not officially approved)
GLP compliance:
not specified
Test type:
fixed concentration procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male
Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Vehicle:
clean air
Details on inhalation exposure:
stainless steel inhalation chamber, 1530 L. Total air flow through the system was 50 liters per minute. The actual chamber concentration was not determined during the exposure. The mean theoretical concentration was calulated from the air flow and net loss of material was 4.72 mg per liter.
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
6 h
Control animals:
no
Details on study design:
During the exposure, all animals were continuously observed for mortality and toxic effects. Following exposures, the animals were group-housed in metal cages suspended above droppings. Food and water were freely available during the pre-exposure period of adjustment to the laboratory environment and the post-exposure period. During the 14 day post-exposure period, the animals were observed daily for possible latent effects. Necropsies were performed following the sacrifice of the test animals at the termination of the study.
Statistics:
no data
Key result
Sex:
male
Dose descriptor:
LC0
Effect level:
4.44 mg/L air (nominal)
Based on:
test mat.
Exp. duration:
6 h
Remarks on result:
other: No deaths
Mortality:
no deaths
Clinical signs:
other: Slight evidence of lung damage such as foci of consolidation were noted at time of necropsy. As these were also noted in control animals, they were not considered to be related to the test material.
Interpretation of results:
study cannot be used for classification
Remarks:
Migrated information
Conclusions:
1,3-Isobenzofurandione, 5,5'-carbonylbis- (BTDA) was tested for acute inhalation lethality in rats in a protocol similar to OECD 433. No deaths or adverse effects occurred at concentrations of 4.44 mg/L.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
4 440 mg/m³ air
Quality of whole database:
adequate

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:
other: Precedes establishment of guideline and GLP. Documentation is limited.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
; intact and abraded skin, 4 animals rather than 5 per dose group, evaluation scale for dermal toxicity includes erythema, edema, atonia, desquamation, coriaceous injury and fissuring.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
other: albino, strain not given
Sex:
not specified
Details on test animals or test system and environmental conditions:
Individually housed in metal cages suspended above the droppings. Food and water were available ad libitum. At the end of the experiment, all rabbits were weighed, sacrificed by air embolization and necropsied. Rabbits that succumbed were necropsied also.
Type of coverage:
occlusive
Vehicle:
ethanol
Remarks:
25%
Details on dermal exposure:
TEST SITE
- Area of exposure: 5 inches by 5 inches
- Type of wrap if used: The test material, as a paste, was distributed evenly over a piece of rubber dental dam, secured with adhesive tape and held in place with an elastic bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Material was scraped from the abdomen skin; no washing was noted.
- Time after start of exposure:

TEST MATERIAL
- For solids, paste formed: yes; A semi-liquid mass was made with the powdered test material in 25% ethanol.

VEHICLE
- Concentration (if solution): 25% ethanol
Duration of exposure:
24 hours
Doses:
50, 200, 794, 3160 mg/kg
No. of animals per sex per dose:
4
Control animals:
no
Details on study design:
Skin was clipped with an electric clipper. The skin of 2 of the 4 rabbits in each group was abraded with a scalpel blade. Observation period: 14 days after removal of patch
Key result
Sex:
not specified
Dose descriptor:
LD0
Effect level:
> 3 160 mg/kg bw
Based on:
test mat.
Remarks on result:
other: no deaths
Mortality:
no deaths
Clinical signs:
other: no signs of irritation or systemic toxicity
Interpretation of results:
study cannot be used for classification
Remarks:
Migrated information
Conclusions:
1,3-Isobenzofurandione, 5,5'-carbonylbis- (BTDA) was studied in albino rabbits in an acute dermal lethality test similar to an OECD 402 protocol. No animals died during the 14-day test at the highest dose of 3160 mg/kg body weight.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 160 mg/kg bw
Quality of whole database:
adequate

Additional information

BTDA is not toxic after acute exposure via the oral or dermal route. The LC50 for inhalation toxicity (dust) is greater than 4.44 mg/l (4440 mg/m3) in rats, mice and guinea pigs. There is another inhalation toxicity study available in which guinea pigs were exposed to BTDA dust in a sub-acute setting (5 days), resulting in an LC50 of 3000 mg/m3 or 3 mg/L. This repeated dose study is considered to reflect a worst-case with regard to the acute exposure situation. However, this is a repeated exposure study and thus does not consider a single exposure to BTDA. Some data is available for BTDA "fume" or smaller particles; however, this is not offered currently as a commercial product. These data collectively are consistent with acute inhalation toxicity of BTDA dust near 5 mg/l. The substance is not classified according to Regulation EC No. 1282/2008.


Justification for selection of acute toxicity – oral endpoint
Acute oral toxicity testing showed lethality at 11400 to 14500 mg/kg bw in rats. LD50 is 12800 mg/kg bw.

Justification for selection of acute toxicity – inhalation endpoint
Acute inhalation toxicity testing showed no lethality at 4.44 mg/L in rats, mice or guinea pigs. This converts to a figure of > 4440 mg/m3 or > 1400 ppm. Data for "dust" is considered most relevant for the BTDA exposure situation.

Justification for selection of acute toxicity – dermal endpoint
Acute dermal toxicity testing showed no lethality at 3160 mg/kg bw in rabbits.

Justification for classification or non-classification

The acute oral LD50 for BTDA is 12,800 mg/kg bw in male rats. This exceeds the current threshold (2000 mg/kg bw) for classification as Acute Toxicity-oral. The acute dermal LD50 is higher than 3160 mg/kg bw in rabbits, which exceeds the threshold (2000 mg/kg bw) for classification as Acute Toxicity-dermal. The acute inhalation LD50 is higher than 4.44 mg/L in rats, mice and guinea pigs. According to the Regulation EC No. 1272, BTDA is not classified as acutely toxic by inhalation. The classification and warnings will result in risk management measures which are protective for workers.