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Administrative data

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:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
2008
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
2001
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
2002
Deviations:
no
Qualifier:
according to
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. certificate)
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 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- Fasting period before study: Food supply was withdrawn overnight before dosing, and for 4 hours after dosing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:
There were no clinical signs of reaction to treatment throughout the study
Body weight:
All animals were considered to have achieved satisfactory bodyweight gains 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:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
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 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:
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 females at 2.02 mg/L, one animal was noted as having deep breathing and both animals were observed as having reduced activity with a hunched posture and closed eyelids. At 1.09 mg/L all males died on the day of dosing, clinically these males were noted as having a reduced body temperature, reduced activity with irregular, fast or deep breathing. One female exposed to 1.09 mg/L died at 237 minutes into the exposure, this animal was noted to be struggling in the restraint tube, the animal was righted but continued to struggle; the animal was removed from the tube
and died shortly after. There were two decedent males at 0.515 mg/L; these animals were observed to have had irregular or deep breathing and partially closed eyelids. The macroscopic examinations performed on decedent animals revealed a number of findings in the lungs; these included dark discoloration, incomplete collapse and firmness.

The two surviving animals at 2.02 mg/L were noted to have reduced activity, closed eyelids, hunched posture and unsteady gait. From Day 3 and throughout the observation period both animals were considered normal. The two surviving females at 1.09 mg/L were noted to have reduced body temperature, reduced activity and fast breathing; from Day 5 onwards both animals were considered normal. The surviving male at 0.515 mg/L was noted as having irregular breathing, partially closed eyelids, reduced activity and a hunched posture, from Day 6 and for the remainder of the observation period this male was considered normal. Females exposed to 0.515 mg/L were observed to have red staining to the snout and jaw irregular breathing and hunched posture, from Day 4 onwards all females were considered normal.
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
Dose descriptor:
LC50
0.515 mg/m³

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/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.

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/mL for BMI. Therefore BMI is included in Category 3, according to Regulation (EC) No 1272/2008.