Pyrrolo[3,4-c]pyrrole-1,4-dione, 2,5-dihydro-3,6-bis(4-methylphenyl)-

Endpoint summary

Description of key information

A single dose of the test item was administered orally or dermally to Wistar rats at concentrations of 2000 mg/kg bw. No mortality occurred. Clinical examiniation and gross necropsy did not reveal any findings. The LD50 after oral and dermal administration is therefore considered to be > 2000 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1994-12-20 to 1995-01-03

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP and guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

adopted February 24, 1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Version / remarks:

92/69/EEC, 31-Jul-1992

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OTS 798.1175 (Acute Oral Toxicity)

Version / remarks:

Revised as of July 01, 1991

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Testing Methods for New Chemical Substances according to the Revised Japanese Chemical Substance Law (March 31, 1987)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: BRL, Biological Research Laboratories Ltd., Wolferstrasse 4, 4414 Füllinsdorf / Switzerland
- Age at study initiation: males: 8 weeks, females: 10 weeks
- Weight at study initiation: males: 199.6 - 210.9 g, females: 176.3 - 187.6 g
- Fasting period before study: yes, fasting for approximately 16 hours
- Housing: Groups of five per sex in Makrolon type-4 cages with autoclaved standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz).
- Diet: Pelleted standard Kliba 343, Batch no. 82/94 rat maintenance diet ("Kliba", Klingentalmuehle AG, CH-4303 Kaiseraugst) available ad libitum (except for the overnight fasting period prior to application).
- Water: Community tap water from Füllinsdorf, available ad libitum.
- Acclimation period: One week under laboratory conditions, after health examination.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-20.5
- Humidity (%): 46-62
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1994-12-13 To: 1995-01-03

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 ml/kg bw
- Justification for choice of vehicle: standard vehicle according to guideline

Doses:

single dose of 2000 mg/kg bw

No. of animals per sex per dose:

5 males and 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality / Viability: Four times during test day 1 and daily for surviving animals during days 2-15.
Body Weights: On test day 1 (pre-administration), 8 and 15 for surviving animals.
Clinical Signs: Each animal was examined for changes in appearance and behaviour four times during day 1, and once daily for surviving animals during days 2-15. All abnormalities were recorded.
- Necropsy of survivors performed: yes
At the end of the observation period all surviving animals were anesthetized by intraperitoneal injection of NARCOREN (Rhone Merieux GmbH, D-88471 Laupheim, Germany) at a dose of at least 2.0 mL/kg body weight (equivalent to at least 320 mg sodium pentobarbitone/kg bw) and sacrificed by exsan- guination. The animals were examined macroscopically and all abnormalities recorded.

Statistics:

No statistical assessment was performed due to lack of mortality.

Preliminary study:

No preliminary study.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths as a result of treatment with the test article.

Clinical signs:

other: No clinical signs of toxicity were observed during the observation period.

Gross pathology:

No organ abnormalities were observed at necropsy.

Other findings:

None

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Quality of whole database:

Valid without restriction

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1994-12-20 to 1995-01-03

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP and guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

adopted February 24, 1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Version / remarks:

92/69/EEC, 31-Jul-1992

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OTS 798.1100 (Acute Dermal Toxicity)

Version / remarks:

Revised as of July 01, 1991

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Testing Methods for New Chemical Substances according to the Revised Japanese Chemical Substance Law (March 31, 1987).

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: BRL, Biological Research Laboratories Ltd., Wölferstrasse 4, 4414 Füllinsdorf / Switzerland
- Age at study initiation: males: 8 weeks, females: 11 weeks
- Weight at study initiation: males: 223.5 - 239.7 g, females: 197.0 - 219.4 g
- Fasting period before study: no
- Housing: During acclimatization in groups of five per sex in Makrolon type-4 cages with autoclaved standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz). During treatment and observation individually in Makrolon type-3 cages with autoclaved standard softwood bedding.
- Diet: Pelleted standard Kliba 343, Batch no. 82/94 rat maintenance diet ("Kliba", Klingentalmuehle AG, CH-4303 Kaiseraugst) available ad libitum.
- Water: Community tap water from Füllinsdorf, available ad libitum.
- Acclimation period: One week under laboratory conditions, after health examination.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-20.5
- Humidity (%): 46-62
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1994-12-13 To: 1995-01-03

Type of coverage:

semiocclusive

Vehicle:

other: corn oil

Details on dermal exposure:

TEST SITE
- Area of exposure: back
- % coverage: 10 % of the total body surface
- Type of wrap if used: semi-occlusive dressing: The dressing was wrapped around the abdomen and fixed with an elastic adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing: Twenty-four hours after the application the dressing was removed and the skin was washed with lukewarm tap water and dried with disposable paper towels.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied: 500 mg/mL
- Constant volume or concentration used: yes

VEHICLE
- Amount(s) applied: 4.0 mL/kg bw

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 male and 5 female animals

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality / Viability: Four times during test day 1 and daily for surviving animals during days 2-15.
Body Weights: On test days 1 (pre-administration), 8 and 15 for surviving animals.
Clinical Signs: Each animal was examined for changes in behaviour and appearance (with special emphasis on the application area, except for the time when the semi-occlusive dressing was in place) four times during day 1, and once daily during days 2-15. All abnormalities were recorded.
- Necropsy of survivors performed: yes
At the end of the observation period all animals were anesthetized by intraperitoneal injection of NARCOREN (Rhone Merieux GmbH, D -88471 Laupheim, Germany) at a dose of at least 2.0 mL/kg bw (equivalent to at least 320 mg/kg sodium pentobarbitone/kg bw) and sacrificed by exsanguination. The animals were examined macroscopically and all abnormalities recorded.

Statistics:

No statistical assessment was performed due to lack of mortality.

Preliminary study:

No preliminary study

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths as a result of treatment with the test article.

Clinical signs:

other: Clinical signs of systemic toxicity were observed in one female and local effects of the test article on the skin at the application site (red skin, back) were observed in all animals during the observation period. Discoloration of the skin at the applica

Gross pathology:

No organ abnormalities were observed at necropsy.

Other findings:

None

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Quality of whole database:

Valid without restriction

Additional information

A single dose of the test item was administered by gavage to female Wistar rats at concentrations of 2000 mg/kg bw. The animals were observed for 14 days. Mortality, body weight and clinical signs were recorded continuously. Organ weighing and gross necropsy was performed after scheduled sacrifice.

A single dose of the test item was applied onto skin of male and female Wistar rats at concentrations of 2000 mg/kg bw. The animals were observed for 14 days. Mortality, body weight and clinical signs were recorded continuously. Organ weighing and gross necropsy was performed after scheduled sacrifice.

No mortality occurred, body weight and body weight gain were comparable to control animals. Clinical signs of toxicity were not observed and gross necropsy did not reveal any findings. The LD50 is therefore considered to be > 2000 mg/kg bw.

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. As a result the substance is not considered to be classified for acute toxicity under Directive 67/548/EEC.

                               

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for acute toxicity under Regulation (EC) No. 1272/2008.