1,1'-(methylenedi-p-phenylene)bismaleimide

Endpoint summary

Description of key information

The substance BMI is non-toxic via oral route but toxic by inhalation. The oral LD50 in rats is >2000 mg/kg/body weight. The inhalation LC50 in rats is >0.515 <1 mg/L air (4 hr exposure). No test data regarding dermal exposure are available. Testing of dermal exposure was waived as scientifically unjustified due to the availability of the oral  and inhalation data and the fact that BMI is a skin sensitiser.

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:

23 March 2012 - 03 July 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Version / remarks:

2008

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

2001

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

2002

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, Acute oral toxicity (2-1-1), 12 Nousan No 8147, Agricultural Production Bureau, November 24, 2000.

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

d.d. 12-12-11

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

other: Crl:CD "SD"

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 8 - 12 weeks prior to dosing
- Weight at study initiation: 211 to 249 g
- Fasting period before study: Food supply was withdrawn overnight before dosing, and for 4 hours after dosing
- Housing: Solid bottomed polycarbonate cages with stainless steel lids.
- Diet (e.g. ad libitum): Free access to diet, except during fasting period described above
- Water (e.g. ad libitum): free access
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 23°C
- Humidity (%): 40 to 70%
- Photoperiod (hrs dark / hrs light): 12 hours light per 24 hours

IN-LIFE DATES: From: 17 April 2012 (Date of first treatment) To: 10 May 2012 (date of last necropsy)

Route of administration:

oral: gavage

Vehicle:

other: 1% (w/v) Aqueous methylcellulose

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 or 200 mg/mL (Depending on dose level)
- Amount of vehicle (if gavage): 10 mL/kg bodyweight

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: As no previous toxicological information was available, 300 mg/kg was chosen as the starting dose, in compliance with the test guidelines.

Doses:

300 mg/kg, 2000 mg/kg

No. of animals per sex per dose:

6 females per dose group (2x3 females)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed at least twice daily after dosing. Bodyweights were recorded on days 1 (prior to dosing), 8, and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, macroscopic examination of organs

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

There were no deaths during the study

Clinical signs:

other: There were no clinical signs of reaction to treatment throughout the study

Gross pathology:

No abnormalities were noted in any animal at the macroscopic examination at study termination on day 15

Interpretation of results:

other: Not classified

Remarks:

According to Regulation (EC) No 1272/2008

Conclusions:

The acute median lethal oral dose (LD50) to rats of BMI was demonstrated to be greater than 2000 mg/kg bodyweight.

Executive summary:

An acute oral toxicity study in rats was performed by oral gavage according to internationally accepted guidelines and in accordance with GLP principles. Following a preliminary dose at 300 mg/kg/bw that showed no lethality, a limit test was conducted at 2000 mg/kg/bw. No mortality or adverse signs were observed. This results in an LD50 >2000 mg/kg/bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

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:

10 May 2012 - 28 September 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

d.d. 12/12/11

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

other: Crl:CD (SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 8 to 10 weeks
- Weight at study initiation: 326 to 376 g (Males) or 215 to 257 g (Females)
- Housing: Polycarbonate cages with stainless steel mesh lids.
- Diet (e.g. ad libitum): Free access to diet whilst in home cage.
- Water (e.g. ad libitum): Free access to potable water.
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 23°C
- Humidity (%): 40 to 70%
- Photoperiod (hrs dark / hrs light): 12 hours / 12 hours.

IN-LIFE DATES: From: 14 May 2012 To: 31 July 2012

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Snout-only inhalation chamber
- Exposure chamber volume: Approximately 30 litres; a chamber liner was added filling 9.9 liters, giving a final volume of 20.1 liters.
- Method of holding animals in test chamber: Restraining tubes
- Source and rate of air: Compressed air, 25 litres/minute
- Method of conditioning air: Filtered and dried
- System of generating particulates/aerosols: Wright Dust Feed (WDF)
- Method of particle size determination: Atmosphere samples from chamber were drawn through a Cascade Impactor using a pump.
- Treatment of exhaust air: Extraction system incorporated a filtration system to remove particulate material.
- Temperature, humidity, pressure in air chamber: Mean temperature = 23.8°C (group 1), 22.6°C (group 2), 22.6°C (group 3). Mean relative humitidy = 48.3% (group 1), 16.6% (group 2), 9.7% (group 3).

TEST ATMOSPHERE
- Brief description of analytical method used: Gravimetric analysis of glass fibre filters over which a known volume of the test atmosphere was drawn. Mean of five measurements during exposure period was used.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.):
Group 1 (average achieved chamber concentration = 2.02 mg/L): Mean MMAD = 4.0µm; GSD = 2.33
Group 2 (average achieved chamber concentration = 1.09 mg/L): Mean MMAD = 3.8µm; GSD = 2.53
Group 3 (average achieved chamber concentration = 0.515 mg/L): Mean MMAD = 3.5µm; GSD = 2.27

Analytical verification of test atmosphere concentrations:

yes

Remarks:

See details above

Duration of exposure:

4 h

Concentrations:

Group 1: Target concentration = 2 mg/L; Average achieved chamber concentration = 2.02 mg/L
Group 2: Target concentration = 1 mg/L; Average achieved chamber concentration = 1.09 mg/L
Group 3: Target concentration = 0.5 mg/L; Average achieved chamber concentration = 0.515 mg/L

No. of animals per sex per dose:

3 males and 3 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations taken at least twice daily. Bodyweights recorded during acclimatisation, on day 1 prior to dosing, and on days 2,4,8, and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, macroscopic pathology

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 0.515 - < 1 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

2 males and 2 females died at 2.02 mg/L.
3 males and 1 female died at 1.09 mg/L.
2 males died at 0.515 mg/L.

Clinical signs:

other: At 2.02 mg/L two males died on the day of the exposure, clinically they were observed to have deep or noisy breathing; in addition one male was noted as having reduced activity with a hunched posture and closed eyelids. There were also two decedent female

Body weight:

Bodyweight losses were observed in the surviving males from Groups 1 and 3 up until Day 4, after which growth was observed until Day 15.

Bodyweight losses were observed in all surviving females on the day following the exposure; recovery was evident by the next weighing occasion after which growth continued until Day 15.

In all decedent animals the terminal bodyweights were lower than the weights recorded prior to the start of the exposure.

Gross pathology:

The macroscopic examinations performed revealed a number of findings in the lungs. These comprised dark discoloration, incomplete collapse, firmness, adhesions and some pale areas in animals treated with 2.02 or 1.09 mg/L, many of which were found dead. Associated findings such as fluid in the thorax and gaseous distension of the gastrointestinal tract were also seen in some animals at these exposure levels.

A few pale areas in the lungs were observed in the four terminal animals treated with 0.515 mg/L. Enlargement of the tracheobronchial lymph nodes was also noted in these animals. The two decedent animals at 0.515 mg/L showed dark discoloration, incomplete collapse and firmness of the lungs consistent with the findings observed in the other groups.

Interpretation of results:

other: Category 3

Remarks:

according to Regulation (EC) No 1272/2008

Conclusions:

Under the conditions of this study the LC50 (4-hour) of BMI is in excess of 0.515 mg/L but not exceeding 1 mg/L for male and female rats.

Executive summary:

An acute inhalation toxicity was performed according to internationally accepted guidelines and in accordance with GLP principles. Group 1 animals were exposed to BMI at a target concentration of 2 mg/L for a period of 4 hours. Due to a high mortality rate (4/6 animals), Group 2 animals were exposed to BMI at a target concentration of 1 mg/L. Following a high mortality rate (4/6 animals), Group 3 animals were exposed to BMI at a target concentration of 0.5 mg/mL. At this exposure level the mortality rate was 2/6 animals and effects observed in surviving animals included pale areas in the lungs and enlargement of the tracheobronchial lymph nodes. The LC50 (4 -hour) of BMI was found to be in excess of 0.515 mg/L but not exceeding 1 mg/L for male and female rats.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral Route

The key study for acute oral toxicity in rats was performed by oral gavage (Huntingdon Life Sciences, 2012) according to internationally accepted guidelines and in accordance with GLP principles. Following a preliminary dose at 300 mg/kg bw that showed no lethality, a limit test was conducted at 2000 mg/kg bw. No mortality or adverse signs were observed. This results in an LD50 >2000 mg/kg bw.

Inhalation Route

The key study for acute inhalation toxicity was performed (Huntingdon Life Sciences, 2012) according to internationally accepted guidelines and in accordance with GLP principles. Group 1 animals were exposed to BMI at a target concentration of 2 mg/L for a period of 4 hours. Due to a high mortality rate (4/6 animals), Group 2 animals were exposed to BMI at a target concentration of 1 mg/L. Following a high mortality rate (4/6 animals), Group 3 animals were exposed to BMI at a target concentration of 0.5 mg/L. At this exposure level the mortality rate was 2/6 animals and effects observed in surviving animals included pale areas in the lungs and enlargement of the tracheobronchial lymph nodes. The LC50 (4-hour) of BMI was found to be in excess of 0.515 mg/L but not exceeding 1 mg/L for male and female rats.

Dermal Route

This study was waived as being scientifically unjustified due to the existence of oral and inhalation data and the fact that BMI is a skin sensitiser.

Justification for selection of acute toxicity – oral endpoint

This study was carried out in accordance with GLP and to OECD guidelines and has been designated as the key study.

Justification for selection of acute toxicity – inhalation endpoint

This study was carried out in accordance with GLP and to OECD guidelines and has been designated as the key study.

Justification for selection of acute toxicity – dermal endpoint

Study waived on the basis that acute oral toxicity and acute inhalation toxicity studies are available therefore a further study is scientifically unjustified. Also the substance is a skin sensitiser therefore steps would be taken to minimise skin contact during use.

Justification for classification or non-classification

The oral LD50 exceeded 2000 mg/kg bw and no classification is warranted for BMI.

The LC50 (4-hour) for the inhalation route was found to be >0.515 but <1 mg/L for BMI. Therefore BMI is included in Category 3, according to Regulation (EC) No 1272/2008.