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Acute Toxicity: inhalation

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acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1990-02-20 to 1990-03-06
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study.

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
according to guideline
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
Test type:
standard acute method
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
- Name of test material (as cited in study report): Isatosäureanhydrid (Isatoic anhydride)
- Physical state: solid (powder), beige, brown
- Analytical purity: 99.8%
- Impurities (identity and concentrations): no data
- Lot/batch No.: 05-0617, filling date: 1989-08-14
- Expiration date of the lot/batch: no data
- Stability under test conditions: stability was ensured for at least the study period
- Storage condition of test material: room temperature
No further data.

Test animals

Details on test animals or test system and environmental conditions:
- Source: Dr . K . Thomae GmbH, D-7950 Biberach, FRG
- Age at study initiation: 8 - 9 weeks
- Weight at study initiation: male animals (mean ± sd) 265 ± 7.6 9, female animals (mean ± sd) 190 ± 3.9 g
- Fasting period before study: no data
- Housing: 5 per cage
- Diet (ad libitum): KLIBA rat/mouse laboratory diet 24-343-4 10 mm pellets, Klingentalmühle AG, CH-4303 Kaiseraugst, Switzerland,
- Water (ad libitum): tap water
- Acclimation period: no data

- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: no data

Administration / exposure

Route of administration:
other: dust aerosol
Type of inhalation exposure:
nose/head only
other: mixing with 1wt% Aerosil
Details on inhalation exposure:
A dust aerosol was generated by means of a dosing-wheel dust generator (Gericke/BASF). The concentration was adjusted by varying the rotation of the metering disc.
- Exposure apparatus: Head-nose inhalation system INA 20 (glass-steel construction, BASF Aktiengesellschaft)
- Exposure chamber volume: ca. 55 L
- Method of holding animals in test chamber: the animals were restrained in tubes and their snouts projected into the inhalation chamber
- Source and rate of air: 1500 L/h, no further data
- Method of conditioning air: no data
- System of generating particulates/aerosols: dosing-wheel dust generator
- Method of particle size determination: Equipment: Stack Sampler Mark III (Andersen ), Vacuum Compressed Air Pump (Millipore ), Sampling probe (internal diameter 6 .9 mm), Balance: Sartorius M3P and Mettler AE 240, Evaluation unit (IBM-PC with software PGA )
- Treatment of exhaust air: By means of an exhaust air system the pressure ratios in the inhalation system were adjusted in such a way that the amount of exhaust air was about 10% lower (excess pressure). This ensured that the mixture of test substance and air was not diluted with laboratory air in the breathing zones of the animals.
- Temperature, humidity, pressure in air chamber: no data

- Brief description of analytical method used:
The nominal concentration was calculated from the amount of substance consumed and the air flow.
The inhalation atmosphere concentration was determined gravimetrically (equipment: Mettler AE 240). The preweighed filter was placed into the filtration equipment. By means of a vacuum compressed air pump a volume of the dust aerosol was drawn through the filter. The dust concentration in mg/L was calculated from the difference between the preweight of the filter and the weight of the filter after sampling, with reference to the sample volume of the inhalation atmosphere. The concentration was corrected for the amount of the added excipient.
- Samples taken from breathing zone: yes

No vehicle, but mixing with 1 wt% of Aerosil in order to achieve a more uniform dust concentration in air.

TEST ATMOSPHERE (if not tabulated)
The particle size analysis of the test group led to the following results:
The MMAD 50% = 3.0 µm (geometrical standard deviation = 3.2 ) was calculated from the results of the particle size analysis.
A respirable dust aerosol fraction that might reach the alveolar region of 81 % was obtained from the results of the particle size analysis.
Duration of exposure:
4 h
analytical concentration: 5.3 +/- 0.390 mg/L(mean +/- sd)
nominal concentration: 71 mg/L
No. of animals per sex per dose:
5 males and 5 females
Control animals:
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The body weight of the animals was checked before the beginning of the test, after 7 days and at the end of the observation period. Clinical findings were recorded several times during exposure and at least once on each workday in the observation period. A check for dead animals was made daily.
- Necropsy of survivors performed: yes
The statistical evaluation of the concentration/effect relationship was carried out on the basis of the binomial test in accordance with tables of the BASF Computer Center.
The calculation of the particle size distribution was carried out in the Department of Toxicology of BASF Aktiengesellschaft on the basis of mathematical methods for evaluating particle measurements (DIN 66141, DIN 66161).

Results and discussion

Effect levels
Dose descriptor:
Effect level:
> 5.3 mg/L air
Exp. duration:
4 h
Remarks on result:
other: statistical reliability: 99 .9%
No deaths occurred until scheduled sacrifice.
Clinical signs:
other: During exposure, the following signs were observed (maximum number of affected animals in brackets): irregular respiration (6/10), accelerated respiration (4/10), eyelid closure (10/10), attempts to escape (10/10). During post-observation, the following s
Body weight:
The body weight gain of female rats in the test group, compared with a historical control collective, was not affected by the substance over the total observation period. The body weight gain of male rats in the test group, compared with a historical control collective, was slightly retarded in the second week of the observation period. See table below.
Gross pathology:
No pathologic findings were noted.

Any other information on results incl. tables

Table: body weight data

mean body weight in [g]

test group: 5 males, 5 females

historical control group: exposure to air

  before the study after 7 days after 14 days
  male female male female male female
 test group 265 190 292 207 317 219
 control data 248 177 286 196 318 211

Applicant's summary and conclusion

Executive summary:

LC50 > 5.3 mg/L/4 h.

Five male and five female Wistar rats were exposed to a dust aerosol of the test substance for 4 hours using a head/nose exposure system, test concentration: 5.3 mg/L. After exposure, the animals were observed for 14 days. Body weight and clinical symptoms were recorded. At the end of the observation period, surviving animals were sacrificed. Both decedents and survivors were subjected to pathological examination.

No deaths occurred. Clinical signs comprised irregular and/or accelerated respiration, eyelid closure, attempts to escape, reddish smear/crusts around the nose, discoloration/contamination of the fur with the test substance and/or urine. All animals were normal at the day after exposure. Body weight gain was within historical control data for females and slightly retarded in males. Pathology revealed no abnormal findings.

The particle size analysis of the test group led to the following results:

The MMAD 50% = 3.0 µm (geometrical standard deviation = 3.2 ) was calculated.

A respirable dust aerosol fraction that might reach the alveolar region of 81 % was obtained.