p-benzoquinone dioxime

Endpoint summary

Description of key information

Oral: Weight of Evidence: LD50 > 300 and < 2000 mg/kg bw, 2018

1. Oral: LD50(rat) = 464 mg/kg bw rat, equiv. or sim. to OECD 401, 1973

2. Oral: LD50(mouse) = 1420 mg/kg bw mouse, equiv. or sim. to OECD 401, 1964

3. Supporting information: Oral: LD50(rat) = < 500 mg/kg bw rat, based on 6 out of 8 lethality at 48 hours: single dose of substance at 500 mg/kg bw in 0.3% Methrocel K15M Premium vehicle via oral gavage), within eq. or similar to OECD TG 474 - Mammalian Erythrocyte Micronucleus Test, Westmoreland et al., 1992

Inhalation: LC50 (rat) = > 5.0 mg/L (male/female) time-weighted mean concentration, OECD TG 436, 2018

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1973

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

The principles of the method would be generally in accordance with the US 16 CFR 1500.3 definitions. (jurisdiction where the test was conducted).

Deviations:

yes

Remarks:

Absence of gross pathology and/or assessment in the other sex - not deemed to impact reliability of the study.

Principles of method if other than guideline:

- Principle of test: The principles of the method would be generally in accordance with the US 16 CFR 1500.3 definitions. (jurisdiction where the test was conducted).
- Short description of test conditions: According to US CFR 1500.3: the test would be conducted on 10 laboratory white rats (weighing between 200 and 300 grams), and the LD50 would be determined to determine the toxicity class.
- Parameters analysed / observed: Lethality and clinical signs

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Not reported.
- Age at study initiation: Not reported.
- Weight at study initiation: 200 - 300 g according to US CFR 1500.3 defintiions
- Fasting period before study: Not reported
- Housing: Not reported.
- Diet: rat chow ad libitum (details Not reported).
- Water: ad libitum
- Acclimation period: Not reported.

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

Route of administration:

oral: unspecified

Vehicle:

not specified

No. of animals per sex per dose:

10 (details on sex not specified)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days according to US CFR 1500.3 definitions.
- Frequency of observations and weighing: At least once daily for 14 days.
- Necropsy of survivors performed: No.

Sex:

not specified

Dose descriptor:

LD50

Effect level:

464 mg/kg bw

Based on:

test mat.

Mortality:

Mortalities occurred.

Clinical signs:

other: Details of toxic effects not reported other than lethal dose value

Gross pathology:

Not examined

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

EU criteria met

Conclusions:

Under the conditions of this study the LD50 was determined to be 464 mg/kg bw in the rat.

Executive summary:

The study was performed following a method equivalent or similar to OECD TG 401 to assess the acute oral toxicity potential of the test substance to rats. The test item was administered as a single oral dose to group of 10 male rats orally. Under the conditions of this study the LD50 was determined to be 464 mg/kg bw.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1964

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

Non-preferred rodent species (mouse)

Deviations:

not specified

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

mouse

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Not reported.
- Age at study initiation: Not reported.
- Weight at study initiation: Not reported.
- Fasting period before study: Not reported
- Housing: Not reported.
- Diet: Not reported.
- Water: Not reported.
- Acclimation period: Not reported.

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

Route of administration:

oral: unspecified

Vehicle:

not specified

No. of animals per sex per dose:

Not reported.

Control animals:

no

Sex:

not specified

Dose descriptor:

LD50

Effect level:

1 420 mg/kg bw

Based on:

test mat.

Mortality:

Mortalities occurred.

Clinical signs:

other: Details of toxic effects not reported other than lethal dose value

Gross pathology:

Not examined

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

EU criteria met

Conclusions:

Under the conditions of this study the LD50 was determined to be 1420 mg/kg bw in the mouse.

Executive summary:

The study was performed following a method equivalent or similar to OECD TG 401 to assess the acute oral toxicity potential of the test substance to the mouse. Under the conditions of this study the LD50 was determined to be 1420 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

464 mg/kg bw

Quality of whole database:

The available information as a whole meets the tonnage driven information requirements of REACH.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

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.

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

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

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.

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.

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

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

5 000 mg/m³ air

Quality of whole database:

The available information as a whole meets the tonnage driven information requirements of REACH.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because skin contact in production and/or use is not likely

other:

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
In accordance with REACH Regulation (EC) No. 1907/2006 Annex VII, column 2 section 8.5 (as amended by Commission Regulation (EU) 2016/863) the acute dermal toxicity (OECD TG 402) study does not need to be conducted based on available information. In addition to the oral route, the information required in sub-section 8.5.2 and 8.5.2 should be provided for at least one other route. The data via the oral route indicates that the acute oral toxicity LD50 < 2000 mg/kg bw. The data in an available inhalation (OECD TG 436) study indicates that the LC50 > 5.0 mg/L. Testing via the dermal route is not deemed required as sufficient information has been provided for the information requirement and exposure to humans via the dermal route is considered unlikely during use. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7a: Endpoint Specific Guidance, R.7.4, July 2017) the study does not need to be conducted.

Clinical signs:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute Oral:

1. Eq. or similar to OECD TG 401, 1973: The study was performed following a method equivalent or similar to OECD TG 401 to assess the acute oral toxicity potential of the test substance to rats. The test item was administered as a single oral dose to group of 10 male rats orally. Under the conditions of this study the LD50 was determined to be 464 mg/kg bw.

2. Eq. or similar to OECD TG 401, 1964: The study was performed following a method equivalent or similar to OECD TG 401 to assess the acute oral toxicity potential of the test substance to the mouse. Under the conditions of this study the LD50 was determined to be 1420 mg/kg bw.

3. Supporting information: Westmoreland et al., Eq. or similar to OECD TG 474 - Mammalian Erythrocyte Micronucleus Test, 1992: Oral: LD50(rat) = < 500 mg/kg bw rat, based on 6 out of 8 lethality at 48 hours: single dose of substance at 500 mg/kg bw in 0.3% Methrocel K15M Premium vehicle via oral gavage. Clinical signs and bodyweights were not reported.

 

Conclusion: The weight of evidence is that the substance has an Oral : LD50 > 300 and < 2000 mg/kg bw.

Acute Inhalation:

Key study: OECD TG 436, 2018 : 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.

Acute Dermal:

In accordance with REACH Regulation (EC) No. 1907/2006 Annex VII, column 2 section 8.5 (as amended by Commission Regulation (EU) 2016/863) the acute dermal toxicity (OECD TG 402) study does not need to be conducted based on available information. In addition to the oral route, the information required in sub-section 8.5.2 and 8.5.2 should be provided for at least one other route. The data via the oral route indicates that the acute oral toxicity LD50 < 2000 mg/kg bw. The data in an available inhalation (OECD TG 436) study indicates that the LC50 > 5.0 mg/L. Testing via the dermal route is not deemed required as sufficient information has been provided for the information requirement and exposure to humans via the dermal route is considered unlikely during use. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7a: Endpoint Specific Guidance, R.7.4, July 2017) the study does not need to be conducted.

Justification for classification or non-classification

The substance meets classification criteria under Regulation (EC) No 1272/2008 for acute toxicity: oral - category 4: H302: Harmful if swallowed

 

The substance does not meet classification criteria under Regulation (EC) No 1272/2008 for acute toxicity: dermal

 

The substance does not meet classification criteria under Regulation (EC) No 1272/2008 for acute toxicity: inhalation