4,4'-Methylene-bis-(3-chloro-2,6-diethylaniline)

Endpoint summary

Description of key information

Acute oral toxicity:

The study was performed 1988 as GLP-test following EU-testing method B.1. A pretest (screening) with five groups of 1 male & 1 female per dose level (250, 500, 1000, 2000 and 5000 mg/kg) was performed as DRF-study. The used species were Wistar rats. In the main study, 5 males and 5 females were treated with a single dose of 5000 mg/kg. The test item was dissolved in 1% aqueous methyl cellulose. One male died on day 8 after showing clinical symptoms. Necropsy examination of this animal showed effects in several organs. The remaining animals shower neither clinical signs nor effects on organs. In conclusion, the acute oral LD50 on both sexes was determined to be > 5000 mg/kg.

Acute inhalation toxicity:

Based on the low amount of inhalable particles (< 10 µm) of less than 10% and the use of the substance, the potential for the generation of inhalable forms is low, the use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalation route will be unlikely to occur, and no acute inhalation test was performed.

Acute dermal toxicity:

The study was performed 1986 as GLP-test following EU-testing method B.3. The used species were Sprague-Dawley rats; 5 males and 5 females were treated with a single dose of 2000 mg/kg. The test item was moistened with distilled water and applied by occlusive dressing. Neither clinical signs nor effects on organs were noted. Body weight gains were lower than expected, particularly in females.

In conclusion, the acute dermal LD50 was determined to be > 2000 mg/kg.

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:

February 1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
- Stability under storage conditions: stable
- Stability under test conditions: stable
- Solubility and stability of the test substance in the solvent/dispersant/vehicle/test medium: stable

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd., Margate
- Weight at study initiation: Males 256 - 289 g; females 204 - 231 g.
- Fasting period before study: overnight fast prior to dosing
- Housing: groups of 5 by sex in grid floor stainless steel cages
- Diet: SQC Rat and Mouse Maintenance Diet No. 1, Expanded; Specia1 Diets Services Ltd., Witham
- Water: Mains water was provided at all times and dispensed from glass water bottles
- Acclimation period: 3 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19 - 25°C
- Humidity: 40 - 70%
- Air changes: 10 changes /hour; single air-conditioned room
- Photoperiod: 12 hours darkness; 12 hours fluorescent lightning

Route of administration:

oral: gavage

Vehicle:

other: 1% aqueous methyl cellulose

Details on oral exposure:

The test article preparations were administered once only by oral gavage using a metal stomach tube attached to a disposable plastic syringe.

Doses:

PRETEST (SCREENING):
- Dose levels of 250, 500, 1000, 2000 and 5000 mg/kg; 2 fasted rats (1 male and 1 female) per dose group

MAIN STUDY (LIMIT TEST):
- Single dose level of 5000 mg/kg; 10 fasted rats (5 males, 5 females}

No. of animals per sex per dose:

PRETEST (SCREENING):
- Five groups of 1 male & 1 female per dose level (250, 500, 1000, 2000 and 5000 mg/kg)

MAIN STUDY (LIMIT TEST):
- Group of 5 males & 5 females at a dose level of 5000 mg/kg

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes
- Frequency of observations and weighing:
All animals were observed for overt signs of toxicity or behavioural changes at 15 min, 1, 2 and 4 hours after -treatment and subsequently once daily for 14 days. All observations were recorded. Individual body weights were recorded on the day before treatment (day-1), on the day of treatment, on days 7 and 14 or at death.

Preliminary study:

The male animal receiving 5000 mg/kg died during this study. The oral LD50 was considered to be in excess of 5000 mg/kg.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

MALES:
- 5000 mg/kg bw: One male out of five was found dead on day 8. No other deaths were noted.


FEMALES:
- 5000 mg/kg bw: No mortality observed in females.

Clinical signs:

other: All animals appeared normal on the day of dosing and up to 5 days after treatment. On days 6 and 7, one male appeared emaciated with hunched posture and staining to the body. This animal was found dead on day 8. All other animals continued to appear norma

Gross pathology:

The male which died during the study was emaciated and at necropsy showed dark lungs and enlarged liver which also appeared pale w ith dark and yellow patches. All animals necropsied at termination were unremarkable.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute oral LD50 on Wistar rats (males and females) was found to be > 5000 mg/kg.

Executive summary:

The study was performed 1988 as GLP-test following EU-testing method B.1. A pretest (screening) with five groups of 1 male & 1 female per dose level (250, 500, 1000, 2000 and 5000 mg/kg) was performed as DRF-study.

The used species were Wistar rats. In the main study, 5 males and 5 females were treated with a single dose of 5000 mg/kg. The test item was dissolved in 1% aqueous methyl cellulose. One male died on day 8 after showing clinical symptoms. Necropsy examination of this animal showed effects in several organs. The remaining animals shower neither clinical signs nor effects on organs.

In conclusion, the acute oral LD50 on both sexes was determined to be > 5000 mg/kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

Klimisch 1; guideline study

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
Based on the low amount of inhalable particles (< 10 um) of less than 10% and the use of the substance, the potential for the generation of inhalable forms is low, the use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur, and no acute inhalation test was performed.

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:

September 1986

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
- Stability under storage conditions: stable
- Stability under test conditions: stable
- Solubility and stability of the test substance in the solvent/dispersant/vehicle/test medium: stable

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd.
- Age: 6 - 8 weeks
- Weight at study initiation: 215 - 305 g
- Housing: groups of 5 by sex in suspended polypropylene cages
- Diet: Special Diet Services Expanded Rat and Mouse Maintenance Diet No. 1
- Water: ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature: 21 - 23°C
- Humidity: mean 51%

Type of coverage:

occlusive

Vehicle:

water

Details on dermal exposure:

The test material, at a dose level of 2000 mg/kg, was applied evenly onto the prepared gauze dressing and wetted with distilled water. The dressing was then applied to the shaved back of each rat with approximately 10% of the body surface in contact with the test material. The trunk of the rat was then encircled with a strip of non-irritating tape (Sleek).

Duration of exposure:

24 h

Doses:

2000 mg/kg

No. of animals per sex per dose:

5 males and 5 females

Control animals:

no

Details on study design:

Each rat was individually housed for a contact period of 24 hours following application, after which the dressing was removed and the skin wiped with a damp tissue to remove excess material. The rats were then returned to their original cages. The rats were observed frequently on the day of dosing and for 14 days following dosing. They were weighed immediately prior to dosing, 7 days after dosing and at death or sacrifice at the end of the 14 day
observation period. At death or at the end of the observation period and sacrifice by nitrogen asphyxiation, each animal was subjected to a gross post mortem.
- ;

Preliminary study:

no pre-test performed

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

MALES:
- 2000 mg/kg bw: No mortality observed in males.


FEMALES:
- 2000 mg/kg bw: No mortality observed in females

Clinical signs:

other: No deaths and no clincal signs of toxicity observed.

Gross pathology:

No effects on organs observed.

Other findings:

No signs of local toxicity observed.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute dermal LD50 on Sprague-Dawley rats (both sexes) was found to be > 2000 mg/kg.

Executive summary:

The study was performed 1986 as GLP-test following EU-testing method B.3. The used species were Sprague-Dawley rats; 5 males and 5 females were treated with a single dose of 2000 mg/kg. The test item was moistened with distilled water and applied by occlusive dressing. Neither clinical signs nor effects on organs were noted. Body weight gains were lower than expected, particularly in females.

In conclusion, the acute dermal LD50 was determined to be > 2000 mg/kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Klimisch 1; guideline study

Justification for classification or non-classification

Based on the data available, the substance is not classified or labelled according to Regulation 1272/2008/EC (CLP).