Freitag, 26. Februar 2016

Repeated dose toxicity: inhalation.001 to 008

Repeated dose toxicity: inhalation.001


Administrative data

Study result type:
experimental result
Study period:
no data
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
Study not performed acording to a guideline and not GLP. No details concerning material and method and few details on results are available. Animals were exposed by 2 to 4 sessions of 15 minutes. Actual concentration in air was not determined. Urinalysis, clinical chemistry, ophthalmic and food and water analyses were not performed. Statistical analysis is not reported.

Data source

Reference
Reference Type:
publication
Title:
Action of a discontinuous exposure to chlorine dioxide (ClO2) on the rat
Author:
Paulet, G. and Desbrousses, S.
Year:
1974
Bibliographic source:
Archives des Maladies Professionnelles, de Médecine du Travail et de Sécurité Sociale (Paris), 35(9):797-807

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Rats were exposed to chlorine dioxide in air (at 5, 10 or 15 ppm) for 2 to 4 session per day, for 1 month. Clinical signs were monitored daily. Body weights were determined. Blood analyses were performed at the beginning and the end of the tests. All animals were sacrificed at study termination and subjected to histopathological analysis of the lungs and liver.
GLP compliance:
no
Test type:
subacute
Limit test:
no

Test materials

Identity of test material same as for substance defined in section 1 (if not read-across):
yes
Test material identityopen allclose all
Details on test material:
No data

Test animals

Species:
rat
Strain:
no data
Sex:
no data
Details on test animals and environmental conditions:
No data

Administration / exposure

Route of administration:
inhalation: gas
Type of inhalation exposure:
no data
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: dynamic intoxication chamber
- Air flow rate: 15 L/min
No other information
Analytical verification of doses or concentrations:
no data
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
Duration of treatment: 1 month
Frequency of treatment:
15 minutes per session, 2 or 4 sessions per day
Doses / concentrationsopen allclose all
MMAD / GSD:
No data
No. of animals per sex per dose:
15 ppm ClO2, 2 exposures/day: 10 rats
15 ppm ClO2, 4 exposures/day: 15 rats
10 ppm ClO2, 2 exposures/day: 10 rats
10 ppm ClO2, 4 exposures/day: 10 rats
5 ppm ClO2, 2 exposures/day: 10 rats
5 ppm ClO2, 4 exposures/day: 10 rats
Control animals:
yes, sham-exposed
Details on study design:
No data
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
CLINICAL SIGNS AND MORTALITY: Yes
- Time schedule: regularly

BODY WEIGHT: Yes
- Time schedule for examinations: regularly

FOOD CONSUMPTION: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: beginning and end of the study
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all animals
- Parameters examined: red blood cell count, white blood cell count

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, viscera
HISTOPATHOLOGY: Yes, liver and lungs were examined in all animals
Organs were not weighted.
Other examinations:
No data
Statistics:
No data

Results and discussion

Effect levelsopen allclose all

Results of examinations

Clinical signs and mortality:
yes
Body weight and weight gain:
yes
Food consumption:
not examined
Food efficiency:
not examined
Water consumption:
not examined
Ophthalmoscopic examination:
not examined
Haematology:
yes
Clinical chemistry:
not examined
Urinalysis:
not examined
Neurobehaviour:
not examined
Organ weights:
not examined
Gross pathology:
yes
Histopathology: non-neoplastic:
yes
Histopathology: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
15 ppm: animals have an ocular-nasal catarrh with excretion of mucous. No other adverse clinical signs were noted.
One death occurred in each 15 ppm dose groups.

BODY WEIGHT AND WEIGHT GAIN
Body weight gains were noted to be reduced in the 15 and 10 ppm dose groups.

HAEMATOLOGY (See Table 7.5.1/1)
Significant changes were not reported in the blood parameters in any dose group. 

GROSS PATHOLOGY and HISTOPATHOLOGY
No effects were noted in the 5 ppm dose group.
10 ppm: the lung is the location of bronchitis and bronchiolitis characterised with signs of alveolar irritation, less marked than in the 15 ppm series.
15 ppm: the lungs were congested and a histological examination showed lesions of alveolitis with catarrh with peribronchiolar infiltrations more marked in the 4 exposure per day series; after ending of the exposures these lesions heal, and after 15 days, the condition of the lungs is comparable to that of the lungs of the control group. The liver appeared normal.
Any other information on results incl. tables:
Table 7.5.3/1: Changes in blood cell counts in repeated dose toxicity study
Parameter
Number of daily exposures
Control group (%)
5 ppm (%)
10 ppm (%)
15 ppm (%)
dose-response
+/-
Red blood cell count
2
-5
+3
+15
+6
4
+9
+10
+11
+8
White blood cell count
2
+17
+27
+4
+12
4
+20
+32
+7
+15

Applicant's summary and conclusion

Conclusions:
The LOAEC in this study is 28 mg/m3 based on lung damage and the NOAEC is 14 mg/m3.
Executive summary:
In a subacute repeat-dose study, rats were exposed to Chlorine Dioxide by gas inhalation at dose level of 5, 10 or 15 ppm (14, 28 and 41 mg/m3), 15 minutes per session, 2 or 4 sessions per day, for one month. Control animals were sham-exposed.
During the experiment period, rats were observed for clinical signs, mortality and haematology. At the end of the experiment, all dose group animals were sacrified and gross and histopathology were performed.
One death occurred in the 15 ppm dose group. Animals in this group have an ocular-nasal catarrh with excretion of mucous.
Body weight gains were noted to be reduced in the 15 and 10 ppm dose groups.
Significant changes were not reported in the blood parameters in any dose group.
Gross pathology and histopathology showed no effect of Chlorine Dioxide in 5 ppm dose group rats. In the 10 ppm dose group, the lung was the location of bronchitis and bronchiolitis characterised with signs of alveolar irritation, less marked than in the 15 ppm series. In the high dose group (15 ppm), the lungs were congested and a histological examination showed lesions of alveolitis with catarrh with peribronchiolar infiltrations more marked in the 4 exposure per day series. After ending of the exposures these lesions heal, and after 15 days, the condition of the lungs is comparable to that of the lungs of the control group. The liver appeared normal.
Based on these observation, the LOAEC in this study is 28 mg/m3 and the NOAEC is 14 mg/m3.
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