Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
April to June 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981
Report Date:
1981

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
not specified
Qualifier:
equivalent or similar to
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Deviations:
not specified
GLP compliance:
not specified
Test type:
traditional method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid

Test animals

Species:
rat
Strain:
Wistar
Remarks:
TNO/W 74
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Recognised supplier
- Age at study initiation: not specified
- Weight at study initiation: 150-200g
- Fasting period before study: 16h
- Housing: Makrolon cages (type III/II)
- Diet (e.g. ad libitum): Altromin-R rat and mouse maintenance diet, provided ad libitum (except for exposure period)
- Water (e.g. ad libitum): water, ad libitum (except for exposure period)
- Acclimation period: not specified; study reports state that animals were "soberly handled" (implies handled carefully/gently)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): not specified
- Humidity (%): not specified
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): not specified

IN-LIFE DATES: April - June 1980.

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: vapour-enriched clean air
Remark on MMAD/GSD:
No specific mention of MMAD/GSD in study report; 200 L/h air was supplied with 150 g heated (melted), dynamically-evaporated test-item.
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The test item was heated to 55-57 °C, in order to melt it. The melted test item was then "dynamically evaporated" into a 200 L/hour flow of moisture-enriched, clean air.
- Exposure chamber volume: 10 L PVC box for whole-body exposure.
- Method of holding animals in test chamber: Not applicable; animals were in chamber for whole-body exposure.
- Source and rate of air: Unspecified source; 200L/h flow-rate.
- Method of conditioning air: moisture-enrichment.
- System of generating particulates/aerosols: Not specified; some sort of atomiser/nebuliser is implied by the test ("dynamic evaporation").
- Method of particle size determination: Not reported.
- Treatment of exhaust air: Not reported.
- Temperature, humidity, in air chamber: Not reported.

TEST ATMOSPHERE
- Brief description of analytical method used: Not reported; total exposure is calculated or inferred from the quantity of test item vapourised into the air stream entering the test chamber.
- Samples taken from breathing zone: Not reported.

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: Not reported.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): Not reported.
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
7 h
Concentrations:
200 L/h air was supplied with ~150g test item, indicating a concentration of ~0.11 g/L test item.
No. of animals per sex per dose:
5 per sex per dose.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality, daily. Clinical signs during exposure and over the course of day one, followed by daily. Any evidence of mortality or overt toxicity was recorded at each observation. Individual body weights were recorded prior to treatment on the day of exposure and once weekly thereafter.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, and any other relevant toxicological effects were reported.
Statistics:
Where necessary, lethal dose calculations (mean) and confidence intervals were calculated with "Probit-Analyse" (Fink & Hund, Arzneimittelforschung 15, 624, 1965).

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LCLo
Effect level:
> 110 mg/L air
Based on:
test mat.
Exp. duration:
7 h
Remarks on result:
not determinable
Remarks:
All animals survived for 14 days after a 7h exposure to approximately 0.11g/L (110mg/L) of the test item.
Mortality:
No mortalities occurred during the study period.
Clinical signs:
other: During exposure, excited states were observed for all animals, accompanied by slight irritation of the nasal mucous membranes. No other clinical signs were seen for the animals.
Body weight:
All animals showed expected gains in bodyweight.
Gross pathology:
At autopsy, 2/5 male and 1/5 female rats had "lung-changes" (dark red or grey discolouration with "bloomed" areas). The other rats "appeared normal".
Other findings:
- Organ weights: Not reported.
- Histopathology: Not reported.
- Potential target organs: Not applicable.
- Other observations: Not applicable.

Any other information on results incl. tables

Additional comments regarding test atmosphere generation:

Due to the solid state of the test item at standard temperature and pressure, the test item had a tendency to condense on the walls of the delivery tubing and test chamber. Solidified test-item had to be periodically re-evaporated by pouring warm water over the affected areas of tubing or test-chamber wall.

 

Table 1. Mortality data summary:

Group Number

Estimated Atmosphere Concentration (mg/L)

Mortalities

 

 

Female

Male

Total

1

110

0/5

0/5

0/10

 

 

 

 

 

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the study, the inhalation 7h-LC50 (male/female) was considered to be >110 mg/L within the TNO/W 74 Wistar rat.
Executive summary:

The study was performed historically according to a method similar to OECD TG 403 and EU Method B.2, to assess the acute inhalation toxicity of the test item. A single group of ten Wistar: TNO/W 74 strain rats (five males and five females) were exposed to an aerosol atmosphere of the test item. The groups were exposed for seven hours using a full-body exposure system, followed by a fourteen day observation period. The estimated mean atmosphere concentration was 110 mg/L. Mean Mass Median Diameter (particle size) and geometric Standard Deviation were not reported. There were no mortalities in the estimated 110 mg/L achieved atmosphere concentration. Some nasal mucous membrane irritation and "excited states" in the rats were observed. After exposure, no clinical signs were observed for any animals, and the study authors remark that following exposure they all appeared to "meet the physiological norm" and show expected gains in bodyweight. 2/5 male and 1/5 female rats showed lung abnormalities at macroscopic post-mortem examination (dark red or grey discolouration with "bloomed" areas). No abnormalities were found at macroscopic post-mortem examination in the other rats. Under the conditions of this study, the inhalation 7h-LC50 (male/female) could not be determined, and was therefore considered to be >110 mg/L within the Wistar: TNO/W 74 rat.