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Repeated dose toxicity: inhalation

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Administrative data

short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: experimental result, precedes establishment of guideline and GLP. Documentation is limited.

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
no guideline available
Principles of method if other than guideline:
Study precedes establishment of guideline protocols and GLP. Guinea pigs are exposed (full body) to dust of BTDA for 6 hours/day, 5 days per week for 14 days. Animals are euthanized and organs are examined. Specific attention is paid to the immune response in lung and lymph tissue.
GLP compliance:
preceeds establishment of GLP
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
Benzophenone-3,3':4,4'-tetracarboxylic dianhydride
EC Number:
EC Name:
Benzophenone-3,3':4,4'-tetracarboxylic dianhydride
Cas Number:
Molecular formula:
Test material form:
solid: crystalline

Test animals

guinea pig
other: English short-hair
not specified
Details on test animals or test system and environmental conditions:
200-300 g body weight.
1530 liter exposure chamber, full body exposure.
The animals were group-housed in metal cages suspended above the droppings. Food and water were available ad libitum.

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
not specified
Remarks on MMAD:
MMAD / GSD: no data
Details on inhalation exposure:
Exposure occurred in a 1530 liter stainless steel inhalation chamber. The total air flow through the system was 50 liters per minute.
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
No attempt was made to determine the actual chamber concentration during the exposure. The mean theoretical concentration was calculated from the air flow and net loss of material.
Duration of treatment / exposure:
6 hours/day
Frequency of treatment:
daily for 5 days/week, for two continuous weeks.
Doses / concentrations
Dose / conc.:
136 mg/m³ air (nominal)
Theoretical, as calculated. Ranges up to 251 mg/m3
No. of animals per sex per dose:
Control animals:
not specified
Details on study design:
During the 6 hour exposure period, all animals were continuously observed for mortality and toxic effects. Following exposures, the animals were observed daily for possible latent effects. After sacrifice, the animals underwent a necropsy.


Observations and examinations performed and frequency:
clinical signs, signs of toxicity, death
Sacrifice and pathology:
Theoretical doses were calculated from air flow and net loss of material.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
2 of 10 animals showed marked dyspnea and cyanosis, and later died; survivors displayed sneezing and muscle spasms.
mortality observed, treatment-related
Description (incidence):
2 of 10 animals showed marked dyspnea and cyanosis, and later died; survivors displayed sneezing and muscle spasms.
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Marked to severe but reversible granulomatous pneumonia and hyperplasia of mediastinal lymph nodes. Also moderate diffuse granulomatous mediastinitis.
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not examined
Details on results:
Survivors displayed sneezing, muscle spasms and slight dyspnea. Two of ten animals showed marked dyspnea and cyanosis and later died. Animals showed marked to severe but reversible granulomatous pneumonia and hyperplasia of mediastinal lymph nodes. Moderate diffuse granulomatous mediastinitis was also observed.

Effect levels

Key result
Dose descriptor:
Effect level:
136 mg/m³ air (nominal)
Based on:
test mat.
not specified
Basis for effect level:
other: Death and toxicity observed. Doses ranged from 136 to 251 mg/m3.

Target system / organ toxicity

Key result
Critical effects observed:
Lowest effective dose / conc.:
136 mg/L air (nominal)
other: granulomatous pneumonia and hyperplasia of mediastinal lymph nodes
lymph node
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Applicant's summary and conclusion

Guinea pigs were exposed by inhalation (whole body) to the dust of 1,3-Isobenzofurandione, 5,5'-carbonylbis- (BTDA), 6 hours per day, five days per week (whole body) for two continuous weeks. Two of twenty animals died, and severe but reversible granulomatous pneumonia, moderate diffuse granulomatous mediastinitis and hyperplasia of lymph nodes was found on necropsy. No NOAEL could be determined, but is presumed lower than 136 mg/m3, (LOAEC), under conditions of this study.