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Respiratory sensitisation

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Administrative data

Endpoint:
respiratory sensitisation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1988
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable study with restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report date:
1989

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
One of three groups of rats was exposed (whole body) to aerosol containing the test material for 6 hours/day for 5 days. Following a 3-week rest period, the exposed rats and the 2 other groups were challenged with aerosol containing the test material for one period of 6 hours. The animals were sacrificed and lungs were examined. Specific IgG was measured in serum.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Benzophenone-3,3':4,4'-tetracarboxylic dianhydride
EC Number:
219-348-1
EC Name:
Benzophenone-3,3':4,4'-tetracarboxylic dianhydride
Cas Number:
2421-28-5
Molecular formula:
C17H6O7
IUPAC Name:
5-(1,3-dioxo-1,3-dihydro-2-benzofuran-5-carbonyl)-1,3-dihydro-2-benzofuran-1,3-dione
Constituent 2
Reference substance name:
291-348-1
IUPAC Name:
291-348-1
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, MI.
- Age at study initiation: 7 weeks
- Weight at study initiation:
- Housing: stainless steel cages 15.8 x 15.5 x 17.0 cm, suspended over excrement pans fitted with deodorizing cage boards.
- Diet (e.g. ad libitum): Purina Rodent Chow 5001 (Ralston Purina Co., St. Louis, MO) ad libitum
- Water (e.g. ad libitum): reverse-osmosis purified, ad libitum
- Acclimation period: 6 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 40
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: July 20, 1988 To: Sept. 29, 1988

Test system

Route of induction exposure:
inhalation
Remarks:
whole body
Route of challenge exposure:
inhalation
Vehicle:
other: Air filtered through HEPA filters
Concentration:
50 µg/m3
No. of animals per dose:
20; 10 males and 10 females
Details on study design:
MAIN STUDY
A. INDUCTION EXPOSURE: whole body exposure
- No. of exposures: 5
- Exposure period: 6 hours
- Test groups: 1
- Control group: 2
- Frequency of applications: once daily
- Duration: 6 hours
- Concentrations: 50 microgram/m3

B. CHALLENGE EXPOSURE: whole body exposure
- No. of exposures: 1
- Day(s) of challenge: 1
- Exposure period: 6 hours
- Test groups: 2
- Control group: 1
- Concentrations: 50 microgram/m3
- Evaluation (hr after challenge): 18

Rats were observed for morbidity and mortality twice daily on weekdays (once daily on weekends and holidays). Physical examinations were performed once prior to study initiation. Clinical observations were performed daily on weekdays during the exposure phase of the study and weekly thereafter. Body weights were measured at the initiation of the study, weekly thereafter and at the termination of the study immediately prior to sacrifice.
Test rats were fasted for appoximately 18 h following the challenge exposure and anesthetized with sodium pentobarbital. Blood samples were obtained from the femoral artery of each rat just prior to the scheduled necropsy.
Gross necropsies were performed on all rats. The lungs were removed, trimmed of excess adherent tissue, weighed and examined for external hemorrhagic foci. Lung volume was determined by liquid displacement. The lungs were perfused with 10% neutral buffered formalin and collected.
Challenge controls:
1 group of 10 animals which did not receive exposure to the test material in the induction test or the challenge test.
Positive control substance(s):
none
Negative control substance(s):
none

Results and discussion

Results:
The analytical concentrations of BTDA ranged from 20.4 to 73.5 µg/m3 during the 5 exposures and from 33.2 to 52.5 µg/m3 during the challenge exposure. The time-weighted average was 47.0 and 53.2 µg/m3 for the two scenarios. The average particle size was 2.01 microns with 99.8% of the particles being equal to or less than 10 microns in size. No test article was detected in the filtered air control chamber at any time during the study.
No deaths of animals occurred in any group. No significant clinical signs were noted in any rat during the study. There were no statistically significant effects of treatment on body weight during the study.
Small numbers of lung foci (< 10) were noted in rats of all groups and were more prevalent in males than females. Statistically, there was no significant difference in the number of lung foci between the BTDA-exposed and control rats. There were no statistically significant effects of treatment on either absolute or relative lung weights and volume.
Serum BTDA-specific IgG antibody levels were statistically significantly increased in the BTDA-exposed males and combined males/females. However, antibody levels in three of the FAC/nonchallenged females were also elevated, for unknown reasons.

Any other information on results incl. tables

Table 1: Summary of Chamber Concentrations

 

5 Exposures

Challenge

 

Filtered Air Control (FAC)

BTDA

Filtered Air Control (FAC)

BTDA

Target concentration (µg/m3)

0

50

0

50

Analytical concentration (µg/m3)

 

 

 

 

Mean ± SD

-

47.8 ± 5.7

-

43.8 ± 9.8

Min/Max

-

20.4/73.5

-

33.2/52.5

TWA

-

47.0

-

43.2

Means and standard deviations were calculated. Data were log-transformed and analyzed using multivariate and univariate two-factor ANOVA. If significant main effects were seen, Dunnett's Test (1955) was conducted. Body weights were evaluated using multivariate repeated-measures ANOVA to determine the shape of the dose-response relationship over time (Bock, 1975). All analyses were performed on a PC using SYSTAT Software (1986). A minimum significance level of p < 0.05 was used in all comparisons. Table 2: Respiratory Screen of BTDA in Rats

Group

Lung Foci

IgG Antibody

Males

 

 

BTDA

5 ± 5.1

0.313 ± 0.21*

Filtered Air control/challenged

1 ± 0.8

0.085 ± 0.05

Filtered Air control/unchallenged

1 ± 1.6

0.080 ± 0.04

Females

 

 

BTDA

1 ± 2.1

0.352 ± 0.41

Filtered Air control/challenged

2 ± 2.3

0.108 ± 0.05

Filtered Air control/unchallenged

1 ± 0.7

0.186 ± 0.17

Combined Male and Female

 

 

BTDA

3 ± 4.3

0.333 ± 0.32*

Filtered Air control/challenged

1 ± 1.8

0.096 ± 0.05

Filtered Air control/unchallenged

1 ± 1.3

0.133 ± 0.13

Applicant's summary and conclusion

Interpretation of results:
other: Inconclusive, not sufficient for classification
Conclusions:
1,3-Isobenzofurandione, 5,5'-carbonylbis- (BTDA) was tested in an in vivo respiratory sensitisation experiment with male and female CD rats at aerosol concentrations (whole body) of 50 µg/m3, 6 hours/day for 5 days. No deaths occurred and there were no statistically significant clinical or histopathological findings. While elevated levels of serum IgG, specific to BTDA, were found in exposed rats compared with filtered air-exposed control, this was also found in several control animals. There was no difference in the number of lung foci between exposed and control rats, nor between antibody levels and lung foci. BTDA cannot conclusively be considered as sensitising under the conditions of this study.
Executive summary: