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Administrative data

Description of key information

Oral: measured LD50 > 2000 mg/kg bw and the estimated LD50 cut-off was considered to be > 2000 and < 5000 mg/kg bw, female rat, OECD TG 420, 2012

Inhalation: LC50 (male/female): > 3.52 mg/L, mean maximum achievable atmosphere concentration, male/female rat, OECD TG 436, 2012

Dermal: measured LD50 > 2000 mg/kg bw and the estimated LD50 cut-off value was considered to be > 5000 mg/kg bw, male/female rat, OECD TG 402, 2012

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:
17-01-2012 to 21-02-2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study performed under GLP. All relevant validity criteria were met.
Justification for type of information:
Information as to the availability of the in vivo study is provided in 'attached justification'.
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
inspected: July 2011; signature: August 2011
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Remarks:
RccHan:WIST
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Recognised Supplier
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: 157 to 170g
- Fasting period before study: Overnight before dosing and four hours after dosing.
- Housing: up to 4 in solid-floor propylene cages with woodflakes
- Diet (ad libitum): 2014C Teklad Global Rodent Diet (Recognised Supplier); provided ad libitum (except for overnight fasting period and four hours post doing).
- Water (ad libitum): ad libitum (except for fasting period)
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25
- Humidity (%): 30 to 70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12 h light / 12 h dark

IN-LIFE DATES: From: 17-01-2012 To: 21-02-2012
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30 or 200 mg/mL in the vehicle and administered at a volume of 10 mL/kg body weight
- Amount of vehicle (if gavage): Administered at a volume of 10 mL/kg body weight
- Justification for choice of vehicle: Test item did not dissolve/suspend in water

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bodyweight

DOSAGE PREPARATION (if unusual): Not applicable.
Doses:
300 and 2000 mg/kg
No. of animals per sex per dose:
1 female at 300 mg/kg
5 females at 2000 mg/kg
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Cages were checked at least twice daily for any mortalities. Clinical observations were made ½, 1, 2, and 4 hours after dosing and then daily for fourteen days. Individual body weights were recorded on Day 0 (prior to dosing) and on Days 7 and 14 or at mortality. Individual weekly body weight changes and group mean body weights were calculated.
- Necropsy of survivors performed: yes
Preliminary study:
No signs of systemic toxicity or effect on body weight were recorded in the female dosed at 300 mg/kg
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
300 mg/kg bw: No mortality.
2000 mg/kg bw: No mortality.
Clinical signs:
other: 300 mg/kg bw: No signs of systemic toxicity were noted during the observation period. 2000 mg/kg bw: Signs of systemic toxicity noted were hunched posture, lethargy, ataxia, pilo-erection, ptosis, prostration and increased lachrimation. All females appear
Gross pathology:
300 mg/kg bw: No abnormalities were noted at necropsy.
2000 mg/kg bw: No abnormalities were noted at necropsy.
Interpretation of results:
GHS criteria not met
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this study the oral LD50 was established to exceed 2000 mg/kg bw in female Wistar (RccHan™: WIST) rats. Applicant assessment indicates, under the conditions of this study and according to the OECD TG 420 criteria, the LD50 cut-off value was considered to be greater than 2000 mg/kg body weight and less than 5000 mg/kg body weight.
Executive summary:

The study was performed according to OECD TG 420 and EU Method B.1 bis guidelines for Acute Toxicity Oral: fixed dose method and in accordance with GLP. The objective of the study was to assess the acute oral toxicity of the test material following a single oral administration in the female Wistar (RccHan™: WIST) strain rat by the fixed dose method. The test item was formulated in arachis oil BP vehicle at 30 mg/mL and then administered by single oral gavage in a sighting test to one fasted female at 300 mg/kg bw. In the absence of toxicity, an additional fasted female was treated with 30 mg/mL test item in arachis oil BP at 2000 mg/kg bw. In the absence of mortality, a further four fasted females were treated. Clinical signs and bodyweight development were monitored during the study and were subsequently subjected to gross necropsy. There were no mortalities. Clinical observations were absent at 300 mg/kg bw. Clinical observations at 2000 mg/kg bw included hunched posture, lethargy, ataxia, pilo-erection, ptosis, prostration and increased lachrimation. All signs ceased by day 3. All females showed expected gains in bodyweight during the study period and there was no abnormal necropsy findings. Under the conditions of this study the oral LD50 was established to exceed 2000 mg/kg bw in female Wistar (RccHan™: WIST) strain rat. Applicant assessment indicates, under the conditions of this study and according to the OECD TG 420 criteria, the LD50 cut-off value was considered to be greater than 2000 mg/kg body weight and less than 5000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 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:
19-03-2012 to 16-04- 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study performed under GLP. All relevant validity criteria were met; with some generally acceptable deviations in accordance with the specifications of the guidelines.
Justification for type of information:
Information as to the availability of the in vivo study is provided in 'attached justification'.
Qualifier:
according to guideline
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Deviations:
yes
Remarks:
It was not possible to generate a MMAD < 4 µm atmosphere and maintaining the concentration at 2 mg/L despite attempts to generate such an atmosphere. Therefore expert judgement was used to apply study to classification and lablleing
GLP compliance:
yes (incl. QA statement)
Remarks:
inspected: July 2011; signature: August 2011
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Remarks:
RccHan: WIST
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Recognised supplier
- Age at study initiation: 8 to 12 weeks
- Weight at study initiation: 200 to 250g
- Fasting period before study: yes
- Housing: groups of up to 5 by sex in solid-floor polypropylene cages with stainless steel lids, furnished with softwood flakes and cage enrichment (wooden chew blocks and cardboard fun tunnels).
- Diet (ad libitum): 2014C Harlan Rodent Diet from recognised supplier, provided ad libitum (except for exposure period period)
- Water (ad libitum): mains drinking water, ad libitum (except for exposure period period)
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25
- Humidity (%): 30 to 70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12 h light / 12 h dark

IN-LIFE DATES: From: 19-03-2012 To: 16-04-2012
Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
clean air
Mass median aerodynamic diameter (MMAD):
5.56 µm
Geometric standard deviation (GSD):
3.07
Remark on MMAD/GSD:
MMAD/GSD relates to: 47.6 mg/L (nominal), 3.52 mg/L (maximum mean attainable concentration) dose
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Dust atmosphere was produced from the test item using a SAG 410 Solid Aerosol Generator located adjacent to the exposure chamber. The generator was connected to a metered compressed air supply
- Exposure chamber volume: approximately 30 litres (dimensions: 28 cm diameter x 50 cm high)
- Method of holding animals in test chamber: Prior to the day of exposure each rat was acclimatized (for approximately 2 hours) to a tapered polycarbonate restraining tube. During the exposure period, each rat was individually held in a tapered, polycarbonate restraining tube fitted onto a single tier of the exposure chamber and sealed by means of a rubber ‘O’ ring. Only the nose of each animal was exposed to the test atmosphere.
- Source and rate of air: filtered air; chamber flow rate was maintained at 60 L/min providing 120 air changes per hour.
- 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 Solid Aerosol Generator.
- System of generating particulates/aerosols: The concentration within the chamber was controlled by adjusting the air flow settings and test item feed rate from the SAG 410. The chamber flow rate was maintained at 60 L/min providing 120 air changes per hour.
- Method of particle size determination: Particle size was determined using a cascade impactor. The device consisted of six impactors stages. The mean amount for each stage was used to determine the cumulative amount below each cut-off point size to calculate the proportional (%) aerosol of defined size ranges. The resulting values were converted to probits and plotted against Log10 cut-point size. From this plot, the Mass Median Aerodynamic Diameter (MMAD) was determined (as the 50% point) and the geometric standard deviation was calculated. In addition the proportion (%) of aerosol less than 4 μm (considered to be the inhalable fraction) was determined.
- Treatment of exhaust air: The extract from the exposure chamber passed through a ‘scrubber’ trap and was connected with a high efficiency filter to a metered exhaust system. The chamber was maintained under negative pressure. A schematic of the dynamic (continuous flow) system is presented in the full study report.
- Temperature, humidity, in air chamber: The temperature and relative humidity inside the exposure chamber were measured by an electronic thermometer/humidity meter: 19-20°C, 50-51% humidity.

TEST ATMOSPHERE
- Brief description of analytical method used: The test atmosphere was sampled seventeen times during the exposure period. The actual chamber concentration was measured at regular intervals during the exposure period. The Gravimetric Method used glass fibre filters placed in a filter holder. The holder was temporarily sealed in a vacant port in the exposure chamber in the animals’ breathing zone and a suitable, known volume of exposure chamber air was drawn through the filter using a vacuum pump. Each filter was weighed before and after sampling in order to calculate the weight of collected test item. The difference in the two weights, divided by the volume of atmosphere sampled, gave the actual chamber concentration. The nominal chamber concentration was calculated by dividing the mass of test item used by the total volume of air passed through the chamber. The nominal concentration is 1353% of the actual mean achieved atmosphere concentration and shows that keeping the aerosol airborne was extremely difficult.
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 three 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: maximum achievable
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
4 h
Concentrations:
3.52 mg/L
No. of animals per sex per dose:
3 per sex per dose. Full details are provided in table 2.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical signs at hourly intervals during exposure, immediately on removal from the restraining tubes at the end of exposure, one hour after termination of exposure and subsequently once daily for up to fourteen days. 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, 3, 7 and 14 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.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 3.52 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Mortality:
No mortality.
Clinical signs:
other: Hunched posture, piloerection and red/brown staining around eyes or snout and wet fur noted when animals removed from restraint tubes and considered associated with restraint procedure. Increased respiratory rate noted during and 1 hour after exposure. Al
Body weight:
Slight loss of body weight noted for 3 males and 1 female on day after exposure. Slight body weight loss also noted for 1 female between Days 1 and 3. All males and females gained weight during the study.
Gross pathology:
Dark patches on lungs noted for 1/3 males and 1/3 females.

Additional comments regarding test atmosphere generation:

It was noted that four samples were outside 20% of the mean achieved atmosphere concentration (two low and two high). The test item was generated at the maximum speed that the generation system could run at in order to achieve the maximum attainable atmosphere concentration during the exposure. The nominal concentration (47.6 mg/L) also shows that keeping the aerosol airborne was extremely difficult. These deviations were therefore considered to be unavoidable.

 

It is also noted that the particle size distribution and the GSD that were achieved during this study were outside of the ranges specified in the test guidelines (1 - 4μm and 1.5-3.0). It was, preferable to expose the animals to a concentration of test item as close to 5 mg/L as possible, even though this may have increased the MMAD as this was considered to result in the animals being exposed to the highest possible concentration of particles < 4μm. During the formal exposure the percentage of particles < 4μm was found to be 38.4%, which means that approximately 1.35 mg/L of test atmosphere could be considered to be in the inhalable range of the test animals (< 4μm). In order to achieve this concentration of particles < 4 μm at 2 mg/L the particle size achieved would have needed to be approximately to 2.5 μm. Even with substantial grinding this would have been impossible to achieve with this particular test item. Even when reducing the achieved concentration to below 2 mg/L during the characterisation phase of the study and by adding particle selection devices into the generation system a particle size <4 μm could not be achieved.

 

Further testing was not considered appropriate given the results and the nature of the test item, within the study.

 

Table 1. Characteristics of the achieved atmosphere:

Mean Maximum Attainable Concentration (mg/L)

Mean Mass Median Aerodynamic Diameter (μm)

Inhalable Fraction

(% <4 μm)

Geometric Standard Deviation

3.52

5.56

38.4

3.07

 

 

 

 

 

Table 2. Achieved atmosphere concentrations:

Atmosphere Concentration

Mean Maximum Attainable (mg/L)

Standard Deviation

Nominal (mg/L)

3.52

0.54

47.6

 

 

 

 

Table 3. Mortality data summary:

Mean Maximum Attainable Concentration (mg/L)

Male Mortalities

Female Mortalities

Total Mortalities

3.52

0/3

0/3

0/6

 

 

 

 

Interpretation of results:
GHS criteria not met
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this study, the mean maximum attainable atmosphere concentration over 4 hours was 3.52 mg/L. The inhalation 4h-LC50 (male/female) was considered to be > 3.52 mg/L within the Wistar (RCCHan: WIST) strain rat.
Executive summary:

The study was performed according to OECD TG 436 guideline in accordance with GLP to assess the acute inhalation toxicity of the test item. A single group of six Wistar (RccHan : WIST) strain rats (three males and three females) were exposed to an dust atmosphere of the test item. The groups were exposed for four hours using a nose only exposure system, followed by a fourteen day observation period. The mean maximum attainable atmosphere concentration was follows: 3.52 mg/L based on a nominal concentration of 74.6 mg/L. The characteristics of the achieved atmosphere where Mean Mass Median Diameter (particle size) and Inhalable Fraction < 4 μm were: 5.56 μm and 38.4% with geometric Standard Deviation 3.07. There was no male and female mortalities in the 3.52 mg/L maximum attainable atmosphere concentration. Common abnormalities noted during the study included increased respiratory rate, hunched posture, pilo-erection, red/brown staining around the eyes or snout and wet fur. All males and females recovered to appear normal from Days 3 to 5 post-exposure. All males and one female exhibited slight bodyweight losses on the first day post-exposure. Reasonable bodyweight development was noted for all males and females during the remainder of the recovery period with the exception of one female animal which exhibited a slight bodyweight loss from Days 1 to 3 post-exposure. All males and females gained weight during the study. Dark patches on the lungs were detected amongst one female and one male at necropsy. All other findings were normal. No mortality occurred and there was no indications of significant toxicity in a group of six rats exposed to a mean maximum attainable atmosphere concentration of 3.52 mg/L for four hours. Under the conditions of this study, the acute inhalation median lethal concentration 4 hr-LC50 was > 3.52 mg/L in the male/female RccHanTM : WIST strain rat.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating conc.
Value:
3 520 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
Type of information:
experimental study
Adequacy of study:
key study
Study period:
01-02-2012 to 15-02-2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study performed under GLP. All relevant validity criteria were met.
Justification for type of information:
Information as to the availability of the in vivo study is provided in 'attached justification'.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
inspected: July 2011; signature: August 2011
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Remarks:
RccHan: WIST
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Recognised Supplier
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: Female: 213 - 230 g; Male: 272 – 300 g; The weight variation did not exceed ±20% of the mean weight per sex at the start of treatment.
- Fasting period before study: Not applicable.
- Housing: suspended solid floor polypropylene cages furnished with woodflakes; the animals were housed individually during the 24 hour exposure period. Then in groups of five by sex, for the remainder of the study.
- Diet (ad libitum): 2014C Teklad Global Rodent Diet (Recognised Supplier); provided ad libitum
- Water (ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25
- Humidity (%): 30 to 70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12 h light / 12 h dark

IN-LIFE DATES: From: 01-02-2012 To: 15-02-2012
Type of coverage:
semiocclusive
Vehicle:
arachis oil
Details on dermal exposure:
TEST SITE
- Area of exposure: the day before treatment the back and flanks were clipped free of hair. Dorsal area application.
- % coverage: Approximately 10% of total body surface
- Type of wrap if used: The area of application was covered piece of surgical gauze was placed over the treatment area and semi occluded with a piece of self adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The treated skin and surrounding hair wiped with cotton wool moistened with arachis oil BP to remove any residual test item
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount applied: 2000 mg/kg bw
- Constant volume or concentration used: Not applicable.
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 per sex per dose (5 male/5 female); treated sequentially following application to 1 sentinel per sex per dose .
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations and mortality checks were conducted at approximately 0.5, 1, 2, and 4 hours and subsequently once daily for 14 days. Local effects were examined once daily for 14 days after the completion of the 24-hour exposure period. Full details on the scoring and criteria (consistent with Draize) are given in the full study report. Individual bodyweights were recorded prior to application of the test item on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality was observed.
Clinical signs:
other: - Clinical observations: No signs of systemic toxicity were noted during the observation period. - Dermal reactions: Very slight erythema was noted at the test site of four females (maximum score = 1; in 5 females and 5 males at days 1 to 2 only). Test si
Gross pathology:
No abnormalities were noted at necropsy
Interpretation of results:
GHS criteria not met
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this study the dermal LD50 was established to exceed 2000 mg/kg bw in male/female Wistar (RccHan: WIST) strain rat. Applicant assessment indicates, under the conditions of this study, and according to the GHS criteria, the LD50 cut-off value was considered to be greater than 5000 mg/kg body weight.
Executive summary:

The study was performed according to OECD TG 402 and EU Method B.3 Acute Toxicity (Dermal) and in accordance with GLP to assess the acute dermal toxicity of the test substance in the Wistar (RccHan: WIST) strain rat. A group of ten animals (five males and five females) was given a single, 24 hour, semi-occluded dermal application of the undiluted test item to intact skin at a dose level of 2000 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy. There was no mortality during the study. There were no signs of system toxicity or abnormalities on necropsy. All males and females showed expected gains in body weight during the study, except for two females which showed no gain or a slight loss (1 gram) in body weight during the first week with expected gain in body weight during the second week. However, this was still considered to be within the historical range for this strain. Very slight erythema was noted at the test site of four females (maximum score = 1; in 5 females and 5 males at days 1 to 2 only). Test sites appeared normal two or three days after dosing. No other signs of dermal irritation were noted. Under the conditions of this study, the dermal LD50 was established to exceed 2000 mg/kg bw in male/female Wistar (RccHan: WIST) strain rat. Applicant assessment indicates, under the conditions of this study, and according to the GHS criteria, the LD50 cut-off value was considered to be greater than 5000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
The available information as a whole meets the tonnage driven information requirements of REACH.

Additional information

ORAL: OECD TG 420, 2012 - The study was performed according to OECD TG 420 and EU Method B.1 bis guidelines for Acute Toxicity Oral: fixed dose method and in accordance with GLP. The objective of the study was to assess the acute oral toxicity of the test material following a single oral administration in the female Wistar (RccHan™: WIST) strain rat by the fixed dose method. The test item was formulated in arachis oil BP vehicle at 30 mg/mL and then administered by single oral gavage in a sighting test to one fasted female at 300 mg/kg bw. In the absence of toxicity, an additional fasted female was treated with 30 mg/mL test item in arachis oil BP at 2000 mg/kg bw. In the absence of mortality, a further four fasted females were treated. Clinical signs and bodyweight development were monitored during the study and were subsequently subjected to gross necropsy. There were no mortalities. Clinical observations were absent at 300 mg/kg bw. Clinical observations at 2000 mg/kg bw included hunched posture, lethargy, ataxia, pilo-erection, ptosis, prostration and increased lachrimation. All signs ceased by day 3. All females showed expected gains in bodyweight during the study period and there was no abnormal necropsy findings. Under the conditions of this study the oral LD50 was established to exceed 2000 mg/kg bw in female Wistar (RccHan™: WIST) strain rat. Applicant assessment indicates, under the conditions of this study and according to the OECD TG 420 criteria, the LD50 cut-off value was considered to be greater than 2000 mg/kg body weight and less than 5000 mg/kg body weight.

 

INHALATION: OECD TG 436, 2012 - The study was performed according to OECD TG 436 guideline in accordance with GLP to assess the acute inhalation toxicity of the test item. A single group of six Wistar (RccHan : WIST) strain rats (three males and three females) were exposed to an dust atmosphere of the test item. The groups were exposed for four hours using a nose only exposure system, followed by a fourteen day observation period. The mean maximum attainable atmosphere concentration was follows: 3.52 mg/L based on a nominal concentration of 74.6 mg/L. The characteristics of the achieved atmosphere where Mean Mass Median Diameter (particle size) and Inhalable Fraction < 4 μm were: 5.56 μm and 38.4% with geometric Standard Deviation 3.07. There was no male and female mortalities in the 3.52 mg/L maximum attainable atmosphere concentration. Common abnormalities noted during the study included increased respiratory rate, hunched posture, pilo-erection, red/brown staining around the eyes or snout and wet fur. All males and females recovered to appear normal from Days 3 to 5 post-exposure. All males and one female exhibited slight bodyweight losses on the first day post-exposure. Reasonable bodyweight development was noted for all males and females during the remainder of the recovery period with the exception of one female animal which exhibited a slight bodyweight loss from Days 1 to 3 post-exposure. All males and females gained weight during the study. Dark patches on the lungs were detected amongst one female and one male at necropsy. All other findings were normal. No mortality occurred and there was no indications of significant toxicity in a group of six rats exposed to a mean maximum attainable atmosphere concentration of 3.52 mg/L for four hours. Under the conditions of this study, the acute inhalation median lethal concentration 4 hr-LC50 was > 3.52 mg/L in the male/female RccHanTM : WIST strain rat.

 

Applicant assessment indicates: the MMAD was > 4 µm and GSD > 3.0 (actual MMAD = 5.56 µm and GSD = 3.07) at mean maximum achieved concentration 3.52 mg/L. It was considered that within this study: the test item could not achieve an atmosphere concentration of 2 mg/L or the equivalent particle size of 2.5 μm utilising grinding or using particle size selection devices within the exposure apparatus. It was considered by expert judgement as not possible to generate an appropriate test item atmosphere of MMAD 1 – 4 μm at 2 mg/L concentration. Reducing the test concentration resulted in an inability to achieve MMAD < 4 µm as was attempted and reported within the study. Using expert judgement, the achieved concentration would be applicable for classification and labelling on the basis the test item would be generally incapable of achieving higher human exposure during realistic usage conditions. Due to its physicochemical properties.

 

References:

1. OECD TG 436 (2009)

2. OECD 39 (2009)

 

DERMAL: OECD TG 402, 2012 - The study was performed according to OECD TG 402 and EU Method B.3 Acute Toxicity (Dermal) and in accordance with GLP to assess the acute dermal toxicity of the test substance in the Wistar (RccHan: WIST) strain rat. A group of ten animals (five males and five females) was given a single, 24 hour, semi-occluded dermal application of the undiluted test item to intact skin at a dose level of 2000 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy. There was no mortality during the study. There were no signs of system toxicity or abnormalities on necropsy. All males and females showed expected gains in body weight during the study, except for two females which showed no gain or a slight loss (1 gram) in body weight during the first week with expected gain in body weight during the second week. However, this was still considered to be within the historical range for this strain. Very slight erythema was noted at the test site of four females (maximum score = 1; in 5 females and 5 males at days 1 to 2 only). Test sites appeared normal two or three days after dosing. No other signs of dermal irritation were noted. Under the conditions of this study, the dermal LD50 was established to exceed 2000 mg/kg bw in male/female Wistar (RccHan: WIST) strain rat. Applicant assessment indicates, under the conditions of this study, and according to the GHS criteria, the LD50 cut-off value was considered to be greater than 5000 mg/kg body weight.

Justification for selection of acute toxicity – oral endpoint

Only one study available.

Justification for selection of acute toxicity – inhalation endpoint

Only one study available.

Justification for selection of acute toxicity – dermal endpoint

Only one study available.

Justification for classification or non-classification

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

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

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

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