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Acute Toxicity: inhalation

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acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No guideline was mentioned. It was not specified whether the study did follow GLP. The study was however well-documented and of scientific acceptability.

Data source

Reference Type:
study report

Materials and methods

Principles of method if other than guideline:
No guideline given.
GLP compliance:
not specified
not specified

Test material

Test material form:
solid: particulate/powder
migrated information: powder
Details on test material:
Purity 99.7%

Test animals

Details on test animals and environmental conditions:
Animals source: Charles River (UK) Ltd., Margate
Weight range for both, males and females: 180 – 200 g
Age: about 6 to 8 weeks
The chamber temperature and the relative humidity for the control and the treated groups ranged between 15 and 19 °C and between 30 to 89%. The air flow rate was 15 litres/min. for the control group and between 13 to 18 litres/min. for the treated groups. The oxygen concentrations were within the range of 21 to 22 % for all groups.

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose/head only
other: filtered air
Duration of exposure:
4 h
Analytical concentrations: 0, 0.038, 0.089, 0.588 mg/l
Nominal concentrations: 0, 1.80, 2.59, 23.23 mg/l
No. of animals per sex per dose:
Control animals:
Details on study design:
The test was conducted with 3 test groups and one control group. Each test group (defined as group 2, 3 and 4) comprised 5 male and 5 female Sprague-Dawley rats. For test atmosphere preparation and in order to get an adequate preparation in terms of particle size and respirability, the test substance was milled by means of an ultracentrifugal mill prior to use. The test atmospheres were then prepared in a Perspex chamber (capacity: ca. 10 litres) by means of a Wright duct feed generator. The test substance was conducted continuously into the chamber with filtered air at flow rate of 13 - 18 litres/min; the air flow rate was monitored and recorded at 30 minute-intervals. The nominal test concentrations were 0, 1.80, 2.59, 23.23 mg/l; the corresponding measured concentrations were 0, 0.038, 0.089 and 0.588 mg/l. The animals were nose-head exposed to the test atmosphere for a period of 4 hours; the control animals received filtered air without test substance. The rats were observed hourly during the exposure and once a day over the observation period of 14 days for mortality and clinical signs of toxicity. Body weight was assessed prior test initiation, at the end of the 4 hour-exposure, once daily between day 1 and 7 of observation, on day 14 and prior sacrifice. Animals that died were subjected to gross pathological examination as well as histopathology. The surviving rats were sacrificed at the end of the observation period and were also subjected to gross pathology and histopathology. Particular attention was given to the nasal passages, the cranial cavity and the respiratory tract. Lungs, bronchi, trachea and nasal passages were examined; lungs, liver, kidney and skin samples from 2 animals were fixed in 10% neutral buffered formalin for the purpose of histopathological examination.

Results and discussion

Effect levels
Dose descriptor:
Effect level:
>= 0.588 mg/L air
Exp. duration:
4 h
Of the high dose group (0.588 mg/l) one male animal was found dead on the day following exposure; and 2 more animals (one male and one female) were killed for humane reasons because they suffered from inflammation of the eyes. The authors attribute the deaths of 3 animals at this level only to the local irritancy of bronopol. However, symptoms of local irritation only occured at concentrations causing lethality. Thus, acute inhalation toxicity is the predominant effect.No deaths occurred in the control groups or at concentrations of 0.038 or 0.089 mg/l.
Clinical signs:
other: High dose group (0.588 mg/l): nasal discharge, red staining from the eyes, staining of the head and inflammation of the eyes was observed on the day of exposure in most animals, sometimes accompanied by swelling of the head, throat and/or forepaws. Thes
Body weight:
Small body weight losses were observed for both control and treated animals. Almost all animals had returned to their pre-exposure body weight by day 4 of the observation period, and body weight gains were normal thereafter. The initial body weight losses were similar in treated and control groups and were attributed to the restraint procedure and not to the exposure to bronopol.
Gross pathology:
There were no treatment-related gross or histopathological findings in the kidneys, livers or lungs of the high dose level group animals. Local dermatitis and ulceration were seen in 2 high dose animals and were attributed to dermal exposure, but not to inhalation.
Other findings:
All the mean mass median diameters indicated that the test atmosphere was respirable. In fact, the reported mean values were 1.31, 1.99 and 6.66 µm respectively for the 0.038, the 0.089 and the 0.588 mg/L groups.

Any other information on results incl. tables

The NOEC was about 0.038 mg/L.

The ratio between measured and nominal test concentrations indicated a low efficiency in the generation of the test aerosol. However, the authors indicated that such a low efficiency is not unusual for aerosol generation from powder using the Wright dust feed generator and mainly is due to losses within the chamber.

Applicant's summary and conclusion

Interpretation of results:
Category 3 based on GHS criteria
The acute inhalation LC50 in rats was >0.588 mg/L. The classification is based on a weight of evidence approach additionally considering the LC50 > 0.120 - < 1.140 mg/m3 determined in the study by Dow (2003).