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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
repeated dose toxicity: inhalation
Remarks:
other: subacute/neurotoxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998
Report Date:
1998

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Qualifier:
according to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
28-days instead of 90
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Butindiol
- Analytical purity: 99.5 %
- Lot/batch No.: 41-0701
- Storage condition of test material: in closed containers covered with N2, cool and dark

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, FRG
- Housing: type MD III of Becker & Co., Castrop-Rauxel, FRG
- Diet (e.g. ad libitum):ad libitum
- Water (e.g. ad libitum):ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
nose/head only
Vehicle:
air
Remarks on MMAD:
MMAD / GSD: 0.81 - 0.99 um/ 2.0-2.2
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Method of holding animals in test chamber: rats were restrained in glass exposure tubes with their snouts projected into the inhalation chamber.
- Temperature, humidity, pressure in air chamber: measured continuously by an automated measuring system.
- Method of particle size determination: metal collecting discs and backup particle filter were eluted individually with bidistilled water into graduated flsks, filled up to the calibration mark and analyzed.

TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatograph
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 days
Frequency of treatment:
6 hours per working day
Doses / concentrations
Remarks:
Doses / Concentrations:
0.5; 5; 25 mg/m3
Basis:

No. of animals per sex per dose:
8 male / 8 female
Control animals:
yes
Details on study design:
Post-exposure period: 2 days
Positive control:
no

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: on exposure days before, during and after exposure. During preflow period and on post exposure day clinical findings were recorded once each working day

BODY WEIGHT: Yes
- Time schedule for examinations:at the beginning of the preflow, on the first exposure day and then once a week.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations:prior to and at the end of the exposure period
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the exposure period
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- How many animals: 5 animals per sex
- Parameters checked in table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the exposure period
- Animals fasted: Yes / No / No data
- How many animals: 5 animals/sex
- Parameters checked in table 2 were examined.

URINALYSIS: Yes / No / No data
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table 3 were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations:
- Dose groups that were examined: 3 animals per sex and test group
- Battery of functions tested: functional observational batteries and motor activity measurements

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (see table 4)

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
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:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
focal squamous metaplasia of larynx, focal inflammation of trachea,
Histopathological findings: neoplastic:
no effects observed

Effect levels

open allclose all
Dose descriptor:
NOAEC
Remarks:
for systemic toxicity
Effect level:
25 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no systemic affects at the high dose
Dose descriptor:
NOAEC
Remarks:
for local toxicity
Effect level:
0.5 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: respiratory tract irritation

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

The following test substance related findings were observed in the high concentration groups (25 mg/m3):

Satellite group(10exposures):

-focal squamous metaplasia and inflammation inlevel I of the larynx

Main group (20 exposures):

-focal squamous metaplasia and inflammation in level I of the larynx

-focal inflammation at the tracheal bifurcation

In the mid concentration (5 mg/m3) satellite group focal squamous metaplasia in level I of the larynx was present. In the main group focal inflammation inlevel I of the larynx was seen additionally.

 There is some indication of increase in inflammation incidence over prolongation of exposure time, but all histopathological changes were graded minimal to slight without increase of severity.

No substance related clinical (including neurofunc-tion), clinico-pathological or pathological findingsoccurred in the low concentration group(0.5mg/m3).


Applicant's summary and conclusion

Conclusions:
The high concentration of Butindiol aerosol (25 mg/m3) caused no systemic toxicity but local irritant effects in the upper respiratory tract(larynx, trachea). Taking into account the results of the preceding 5-day study and the satellite groups of this study, there is no evidence for the accumulation of systemic toxicity over time up to concentrations of 25 mg/m3. The effects found in larynx and trachea are unspecific responses due to the local irritation caused by the deposition of Butindiol aerosol in the aerodynamic traps presented by larynx and tracheal bifurcation. The NOAEC for systemic toxicity under the conditions of this study is 25 mg/m3. The NOAEC for local toxicity in the upper respiratory tract is 0.5 mg/m3.