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Diss Factsheets

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
02-10-2018 to 26-10-2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study performed under GLP. All relevant validity criteria were met.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.52 (Acute Inhalation Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
p-benzoquinone dioxime
EC Number:
203-271-5
EC Name:
p-benzoquinone dioxime
Cas Number:
105-11-3
Molecular formula:
C6H6N2O2
IUPAC Name:
N-[(1Z,4Z)-4-(hydroxyimino)cyclohexa-2,5-dien-1-ylidene]hydroxylamine
Test material form:
solid
Details on test material:
- Physical state: Solid
- Storage condition of test material: In refrigerator (2-8°C) container flushed with nitrogen
- Other: Brown powder

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Crl:WI(Han)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Recognised supplier
- Females (if applicable) nulliparous and non-pregnant: Yes.
- Age at study initiation: approximately 10 weeks
- Weight at study initiation: Approximately the same age and body weight variation did not exceed +/- 20% of the sex mean. Females: 188-219 g and Males: 285 – 326 g
- Fasting period before study: None.
- Housing: Group housing of five animals per sex per cage in labelled Makrolon cages (type IV), containing sterilised sawdust bedding and paper cage enrichment.
- Diet (e.g. ad libitum): Certified diet from recognised supplier, provided ad libitum (except for exposure period period)
- Water (e.g. ad libitum): mains drinking water, ad libitum (except for exposure period period)
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24 (Actual: 20 to 21°C).
- Humidity (%): 40 to 70 (Actual: 50 to 73%, not considered to adversely impact the study).
- Air changes (per hr): > 10 per hour
- Photoperiod (hrs dark / hrs light): 12 h light / 12 h dark

IN-LIFE DATES: From: 02-10-2018 To: 26-10-2018

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
clean air
Mass median aerodynamic diameter (MMAD):
>= 3.3 - <= 4.1 µm
Geometric standard deviation (GSD):
>= 1.7 - <= 2.2
Remark on MMAD/GSD:
MMAD and GSD relate to the following for individual concentrations:
0.5 mg/L: MMAD was 4.1 µm, GSD 2.0 and 3.3 µm, GSD 2.1
1.0 mg/L: MMAD was 3.9 µm, GSD 1.7 and 3.6 µm, GSD 1.9
5.0 mg/L: MMAD was 4.0 µm, GSD 2.2 and 3.9 µm GSD 1.8
At 5 mg/L, three measurements were performed because one measurement did not show a normal distribution over the filter stages and the particle size could not be determined.
Applicant assessment indicates that the range of MMAD and GSD was within the range 1-4 µm and 1.5 to 3.0, respectively. It was considered that the atmosphere targets were achieved.
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The test item was administered in an exposure atmosphere via a stream of pressurized air using a combination of a wright dust feeder. This generated a dust. The dust was passed through a series of two cyclones, allowing larger particles to settle, and diluted with pressurized air (at the 0.5 and 1 mg/L exposure group levels) before it entered the exposure chamber. Mean total airflows were 47, 30 and 13 L/min. for the 0.5, 1 and 5 mg/L groups, respectively.
- Exposure chamber volume: Not reported. Was consistent with Am. Ind. Hyg Assoc. J. 44(12): 923-928, 1983.
- Method of holding animals in test chamber: Restraining tubes.
- Source and rate of air: filtered air
- Method of conditioning air: Compressed air was supplied by means of an oil free compressor and passed through a water trap and respiratory quality filters before it was introduced to the atmosphere generation apparatus.
- System of generating particulates/aerosols: Wright dust feeder and dual cyclones; the chamber mean total flow rate were 47, 30 and 13 L/min. for the 0.5, 1 and 5 mg/L groups, respectively.
- Method of particle size determination: Particle size was determined using a cascade impactor. The device consisted of eight impactors stages containing fiber glass filters.
- Treatment of exhaust air: From the exposure chamber the test atmosphere was passed through a filter before it was released to the exhaust of the fume hood.
- Temperature, humidity, in air chamber: The temperature and relative humidity inside the exposure chamber were measured by an electronic thermometer/humidity meter: 21.7-22.8°C, 10-15% humidity. This was considered appropriate for the relative short 4 hour exposure duration.

TEST ATMOSPHERE
- Brief description of analytical method used: Actual concentration was determined through 19, 25 and 23 representative samples taken for determination of the actual concentration at 0.5, 1 and 5 mg/L, respectively during the exposure period. Samples were drawn from the test atmosphere through a tube mounted in one of the free animal ports of the middle section of the exposure chamber. The collected amount of the test item in the air sample was measured gravimetrically. Sample volumes were measured by means of a dry gas meter. The time-weighted mean concentration with the standard deviation was calculated. Full details of the analytical method are provided in the full study report.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: The particle size of the generated atmosphere inside the exposure chamber was determined two times during each exposure period using a cascade impactor. The particle size distribution for each group is reported in table 1.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): The Mass Median Aerodynamic Diameter (MMAD) was determined and is reported for each group in table 1.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: The starting exposure level was selected based on the available test item data and was one expected not to cause mortality. The exposure levels were selected based on the EC and UN classification and labelling guidelines.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
0.5 mg/L (nominal), time weighted mean concentration: 0.52 ± 0.01 mg/L with a generation efficiency of 46%.
1.0 mg/L (nominal), time weighted mean concentration: 1.20 ± 0.03 mg/L with a generation efficiency of 49%.
5.0 mg/L (nominal), time weighted mean concentration: 5.00 ± 0.11 mg/L with a generation efficiency of 20%.
No. of animals per sex per dose:
3 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, twice daily. Clinical signs three times during exposure and on day one at one and three hours and then once daily. Any evidence of mortality or overt toxicity was recorded at each observation. Individual body weights were recorded on arrival, prior to treatment on the day of exposure and on Days 1, 2, 4, 8 and 15 or after mortality.
- Necropsy of survivors performed: yes (and in the event of any mortalities)
- Other examinations performed: clinical signs, body weight, organ weights, and any other relevant toxicological effects were reported.
Statistics:
No statistical analysis was performed.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5 mg/L air (analytical)
Based on:
test mat.
Remarks:
atmosphere stability was monitored during the study and deemed 'stable'. The time weighted mean concentration was: 5.0 ± 0.11 mg/L at nominal 5.0 mg/L.
Exp. duration:
4 h
Mortality:
No mortality.
Clinical signs:
other: 0.5 mg/L, no clinical signs of systemic toxicity were noted during exposure. Lethargy, hunched posture, slow breathing (score = 1) were seen during the observation period on day 1 through 3 post exposure. Piloerection and/or staining of the fur was observ
Body weight:
Body weight gain in males and females was within the expected range. One male exposed to 5 mg/L showed body weight loss between Days 4 and 8. This male gained body weight between Days 8 and 15, no toxicological significance was attached to this finding.
Gross pathology:
No abnormalities were found during macroscopic examination.
Other findings:
- Other observations: The respiratory tract was subjected to a detailed macroscopic examination for signs of irritancy or local toxicity during necropsy.

Any other information on results incl. tables

Table 1.0 : Characteristics of the achieved atmosphere

Group Number

Nominal Concentration (mg/L)

Time-weighted mean actual concentration (mg/L)

Mean Mass Median Aerodynamic Diameter (µm)

Geometric Standard Deviation

Comments

1

1.10

0.52 ± 0.01

3.3 – 4.1

2.0 – 2.1

n=19 samples ; generation efficiency (ratio of actual and nominal concentration) of 46%

2

2.40

1.20 ± 0.03

3.6 – 3.9

1.7 – 1.9

n=25 samples; generation efficiency of 49%

3

25.0

5.00 ± 0.11

3.9 – 4.0

1.8 – 2.2

n=23 samples; generation efficiency of 20%

 

 

 

 

 

 

 

Table 2.0 : Mortality data

Group Number

Nominal Concentration (mg/L)

Time-weighted mean actual concentration (mg/L)

Mortalities

 

 

 

Female

Male

1

1.10

0.52 ± 0.01

0/3

0/3

2

2.40

1.20 ± 0.03

0/3

0/3

3

25.0

5.00 ± 0.11

0/3

0/3

 

 

 

 

 

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the study, the inhalation 4h-LC50 (male/female) was considered to be > 5.0 mg/L within the Crl:WI(Han) rat.
Executive summary:

The study was performed according to OECD TG 436 guideline in accordance with GLP to assess the test item acute inhalation toxicity. The test item was administered as a dust by nose only inhalation for 4 hours to three groups of three male and three female Wistar rats at target concentrations of 0.5, 1 and 5 mg/L. Mortality and clinical signs were observed daily during the observation period and body weights were determined on Days 1, 2, 4, 8 and 15. Macroscopic examination was performed after terminal sacrifice (Day 15). The time-weighted mean actual concentrations were0.52 ± 0.01 mg/L, 1.2 ± 0.03 mg/L and 5.0 ± 0.11 mg/L, respectively. The concentration was measured at several time points that were equally distributed over the exposure period, the results of which demonstrated that the exposure concentrations were sufficiently stable. The characteristics of the test atmospheres were as follows for MMAD and GSD: 0.5 mg/L: MMAD 4.1 µm, GSD 2.0 to 3.3 µm, GSD 2.1 and 1.0 mg/L: MMAD 3.9 µm, GSD 1.7 to 3.6 µm, GSD 1.9 and 5.0 mg/L: MMAD 4.0 µm, GSD 2.2 to 3.9 µm GSD 1.8. There was no mortality. At 0.5 mg/L, no clinical signs of systemic toxicity were noted during exposure. Lethargy, hunched posture, slow breathing (score = 1) were seen during the observation period on day 1 through 3 post exposure. Piloerection and/or staining of the fur was observed post exposure (score = 1). Orange discolouration of urine was seen on day 3 (score = 1). At 1.0 mg/L, no clinical signs of systemic toxicity were noted during exposure. Hunched posture was seen during the observation period on day 1 through 3 post exposure. Staining of the fur was observed post exposure (score = 1). At 1.0 mg/L, slow and fast breathing was seen during exposure. Hunched posture, slow breathing, laboured respiration and gasping was seen during the observation period on day 1 through 2 and/or day 3 post exposure. Piloerection was observed on day 1 through 2 (score = 1). Staining of the fur was observed post exposure (score = 1). Green and/or Orange discolouration of urine was seen on day 1 through 7 (score = 1). One male that showed rales present on day 6 and 7 (score = 1). Body weight gain in males and females was within the expected range. One male exposed to 5 mg/L showed body weight loss between Days 4 and 8. This male gained body weight between Days 8 and 15, no toxicological significance was attached to this finding. No abnormalities were found at macroscopic post mortem examination.Under the conditions of this study, the inhalation 4h-LC50 (male/female) was considered to be > 5.0 mg/L within the Wistar: Crl:WI(Han) rat.