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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 2500 mg/kg bw, female rat, OECD TG 423, 2014

Acute Inhalation toxicity: measured LC50 > 1 mg/L and ≤ 5 mg/L (mean achieved concentration) and the LC50 cut-off was considered to be 5 mg/L, male/female rat, OECD TG 436, 2014

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, 2014

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:
23-08-2013 to 17-09-2013
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 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
inspected: March 2013 ; signature: May 2013
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Remarks:
Crl:WI (Han)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Recognised animal supplier
- Females (if applicable) nulliparous and non-pregnant: Yes.
- Age at study initiation: ca. 8 weeks (nulliparous and non-pregnant)
- Weight at study initiation: 146 - 168 g; Body weight variation did not exceed +/- 20% of the sex mean.
- Fasting period before study: Overnight and until 3-4 hours after administration of the test item.
- Housing: Group housing of 3 animals per cage containing sterilized sawdust as bedding material and paper as cage-enrichment.
- Water: ad libitum
- Acclimation period: At least five (5) days under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 ± 3.0
- Humidity (%): 40 to 70 (Deviations from the maximum level of daily mean relative humidity occurred. Laboratory historical data do not indicate an effect attributable to the deviations).
- Air changes (per hr): typically, at least 15
- Photoperiod (hrs dark / hrs light): 12 hours light/dark

IN-LIFE DATES: 23-08-2013 to 17-09-2013
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
VEHICLE
- Identity: Not applicable.
- Concentration in vehicle: Not applicable. Unchanged (no vehicle).
- Amount of vehicle (if gavage): Not applicable.
- Justification for choice of vehicle: Not applicable.

MAXIMUM DOSE VOLUME APPLIED: 2.06 mL/kg bw

DOSAGE PREPARATION (if unusual): Not applicable.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: In the absence of data suggesting the test material was toxic, 2000 mg/kg was chosen as the starting dose. The toxicity of the test substance was assessed by stepwise treatment of groups of 3 females. The first group was treated at a dose level of 2000 mg/kg. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines. The onset, duration and severity of the signs of toxicity were taken into account for determination of the time interval between the dose groups.
Doses:
2000 mg/kg
No. of animals per sex per dose:
6
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Mortality/Viability: Twice daily; Bodyweights: Days 1 (pre-administration), 8 and 15; Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. The signs were graded according to fixed scales and the time of onset, degree and duration were recorded.
- Necropsy of survivors performed: yes
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
2000 mg/kg bw: Female number 5, was sarificed in moribund condition for humane reasons on day 2. No further mortality.
Clinical signs:
2000 mg/kg bw: Clinical signs noted among the survivors between Days 1 and 3 included lethargy, hunched posture, uncoordinated movements, slow breathing, shallow respiration, piloerection, salivation, watery discharge from both eyes, and/or hypothermia. These signs were not observed in neither of surviving animals on Day 4 and thereafter. The humanely sacrificed female 5: on Day 2 showed lethargy, hunched posture, uncoordinated movements, slow breathing, piloerection, salivation, ptosis, hypothermia and yellow urine.
Body weight:
All survivors showed bodyweight gains over the study period. The body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination.
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 be > 2000 mg/kg bw in female Wistar rats. According to OECD TG 423 the LD50 cut-off value was considered to be 2500 mg/kg bw.
Executive summary:

The study was performed according to OECD TG 423 and EU Method B1 tris Acute Toxicity, US EPA OPPTS 870.1100 and Japanese JMAFF guidelines and in accordance with GLP to assess the acute oral toxicity of the test item following a single oral administration in the female Wistar strain rat by the acute class method. The test item was administered by oral gavage in a PEG 400 vehicle to two sequential groups of three female Wistar rats at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15). There was two mortalities in the second group. Lethargy, flat and/or hunched posture, piloerection, slow breathing, uncoordinated movements, dark eye and/or watery discharge from the eyes were noted in all animals between Days 1 and 6. In addition one animal showed scales and scabs on the snout during the observation period. A second dose level was then employed at 300 mg/kg bodyweight. All animals showed hunched posture and one animal showed piloerection on Day 1. No further effects were subsequently seen. The body weight gain shown by survivors over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain. No abnormalities were found at macroscopic post mortem examination of the animals at any dose level. The oral LD50 value of the test substance in Wistar rats was established to be > 300 and < 2000 mg/kg body weight. According to the OECD TG 423 test guideline, the LD50 cut-off value was considered to be 2500 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
2 500 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:
06-09-2013 to 23-01-2014
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 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Remarks:
Crl:WI(Han)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Recognised supplier
- Age at study initiation: 10 - 11 weeks
- Weight at study initiation: Approximately the same age and body weight variation did not exceed +/- 20% of the sex mean. Females: 194-215 g and Males: 284 – 332 g
- Fasting period before study: None.
- Housing: Group housing of three animals per sex per cage in labelled Makrolon cages (type IV), containing sterilised sawdust bedding and paper cage enrichment.
- Diet (e.g. ad libitum): Certified diet from recognised supplier, provided ad libitum (except for exposure period period)
- Water (e.g. ad libitum): mains drinking water, ad libitum (except for exposure period period)
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24
- Humidity (%): 40 to 70 (actual: 32 – 40% ; was considered appropriate for this study)
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12 h light / 12 h dark

IN-LIFE DATES: From: 06-09-2013 To: 30-09-2013
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
clean air
Mass median aerodynamic diameter (MMAD):
>= 3.7 - <= 4.3 µm
Geometric standard deviation (GSD):
>= 1.9 - <= 2
Remark on MMAD/GSD:
MMAD/GSD relates to:
5 mg/L (nominal), 5.10 ± 0.11 mg/L (mean achieved concentration) dose : MMAD = 4.0 GSD = 2.0 and MMAD = 3.7 GSD = 2.0
1 mg/L (nominal), 1.03 ± 0.03 mg/L (mean achieved concentration) dose : MMAD = 3.9 GSD = 1.9 and MMAD = 4.3 GSD = 1.9
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: An aerosol was generated by nebulization of the test substance by means of a nebulizer and pressurized air. The primary aerosol was diluted with pressurized air before it entered the exposure chamber
- Exposure chamber volume: Not reported. Was consistent with Am. Ind. Hyg Assoc. J. 44(12): 923-928, 1983.
- Method of holding animals in test chamber: Restraining tubes.
- Source and rate of air: filtered air
- 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 nebulizer.
- System of generating particulates/aerosols: nebulizer; the chamber mean total flow rate was maintained at 30 L/min (5 mg/L exposure level) and 33 L/min (1 mg/L exposure level).
- Method of particle size determination: Particle size was determined using a cascade impactor. The device consisted of eight impactors stages containing fiber glass filters.
- Treatment of exhaust air: From the exposure chamber the test atmosphere was passed through a filter before it was released to the exhaust of the fume hood.
- Temperature, humidity, in air chamber: The temperature and relative humidity inside the exposure chamber were measured by an electronic thermometer/humidity meter: 20.1-21.0°C, 32-40% humidity (this was considered appropriate for this study).

TEST ATMOSPHERE
- Brief description of analytical method used: Actual concentration was determined (n= 18 and 22 at 5 and 1 mg/L respectively) multiple times during the exposure period. Samples were drawn from the test atmosphere through a tube mounted in one of the free animal ports of the middle section of the exposure chamber. Samples were drawn through a glass fibre filter. The collected amount of the test substance in the air sample was measured gravimetrically. Sample volumes were measured by means of a dry gas meter. The time-weighted mean concentration with the standard deviation was calculated. Full details of the analytical method are provided in the full study report.
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle (if applicable): Not applicable.
- Concentration of test material in vehicle (if applicable): Not applicable.
- Justification of choice of vehicle: Not applicable.
- Lot/batch no. (if required): Not applicable.
- Purity: Not applicable.

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: The particle size of the generated atmosphere inside the exposure chamber was determined two 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: In accordance with the OECD TG 436 guideline).
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
- 5.0 mg/L (1.89 mg/L nominal), 5.1 mg/L (mean achieved concentration) with a generation efficiency of 63%.
- 1.0 mg/L (8.0 mg/L nominal), 1.0 mg/L (mean achieved concentration) with a generation efficiency of 53%.
No. of animals per sex per dose:
5 per sex per dose. Full details are provided in table 2.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Mortality, twice daily. Clinical signs three times during exposure and on day one at one and three hours and then once daily. 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, 4, 8 and 15 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.
Statistics:
No statistical analysis was performed.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 1 - <= 5 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
At 5 mg/L : One male was humanely terminated on day 3 ; two females were humanely terminated on day 3.
At 1 mg/L : No mortality.
Clinical signs:
other: see "Any other information on results incl. tables"
Body weight:
At 5 mg/L : Reduced body weight gain and body weight loss was noted among survivors during the first week post exposure. All animals regained weight during the second week and/or gained weight over the course of the study.
At 1 mg/L : Reduced body weight gain and body weight loss was noted among survivors during the first week post exposure. All males/females regained weight during the second week and/or gained weight over the course of the study.
Gross pathology:
At 5 mg/L : Macroscopic post mortem examination of the two females humanely terminated revealed gelatinous contents in the stomach and/or duodenum. Macroscopic examination of the other females did not reveal any abnormalities. Pelvic dilation of the right kidney, as seen in one female exposed to 5 mg/L, is occasionally seen among rats of this age and strain and was therefore considered unrelated to treatment.
At 1 mg/L : No macroscopic abnormalities were noted.
Other findings:
- Other observations: The respiratory tract was subjected to a detailed macroscopic examination for signs of irritancy or local toxicity during necropsy.

Table 1.0 : Characteristics of the achieved atmosphere

Group Number

Nominal Concentration (mg/L)

Time-weighted mean actual concentration (mg/L)

Mean Mass Median Aerodynamic Diameter (µm)

Geometric Standard Deviation

Comments

1 (1 mg/L)

1.89

1.03 ± 0.03

3.7 – 4.0

2.0

n=22 samples ; generation efficiency (ratio of actual and nominal concentration) of 53%

2 (5 mg/L)

8.0

5.10 ± 0.11

3.9 – 4.3

1.9

n=18 samples ; generation efficiency (ratio of actual and nominal concentration) of 63%

 

 

 

 

 

 

 

Table 2.0 : Mortality data

Group Number

Nominal Concentration (mg/L)

Time-weighted mean actual concentration (mg/L)

Mortalities

 

 

 

Female

Male

1 (1 mg/L)

1.89

1.03 ± 0.03

0/3

0/3

2 (5 mg/L)

8.0

5.10 ± 0.11

2/3

1/3

Clinical signs:

At 5 mg/L : slow breathing, during exposure. After exposure: lethargy, hunched posture, flat posture, uncoordinated movements, laboured respiration, ptosis, rales and/or hypothermia were observed. Surviving males/females had recovered by days 5 and 6.

At 1 mg/L : No clinical signs during or after exposure.

Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the study, the inhalation 4h-LC50 (male/female) was considered to be > 1 and ≤ 5 mg/L and/or the LC50 cut off was considered to be 5 mg/L within the Crl:WI(Han) 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 groups of six Wistar: Crl:WI(Han) strain rats (three males and three females) were exposed to an aerosol atmosphere of the test item. The groups were exposed for four hours using a nose only exposure system, followed by a fifteen day observation period. The time-weighted mean achieved atmosphere concentrations were as follows: 5.10 ± 0.11 mg/L based on a nominal concentration of 8.0 mg/L and/or 1.03 ± 0.03 mg/L based on a nominal concentration of 1.89 mg/L. The atmosphere generation efficiencies were 63% and 53%, respectively. The characteristics of the achieved atmosphere L were at 5 mg/: Mean Mass Median Diameter (particle size): > 3.7 μm and < 4.0 μm with geometric Standard Deviation 2.0 and 1 mg/L: Mean Mass Median Diameter (particle size): > 3.9 μm and < 4.3 μm with geometric Standard Deviation 1.9. At 5 mg/L, one male was humanely terminated on day 3 ; two females were humanely terminated on day 3. Slow breathing, was observed during exposure. After exposure lethargy, hunched posture, flat posture, uncoordinated movements, laboured respiration, ptosis, rales and/or hypothermia was observed. Surviving males/females had recovered by days 5 and 6. At 1 mg/L, there was no mortality and no significant clinical signs during or after exposure. Reduced body weight gain and body weight loss was noted among survivors during the first week post exposure. At all exposure levels. all animals regained weight during the second week and/or gained weight over the course of the study. At 5 mg/L, macroscopic post mortem examination of the two females humanely terminated revealed gelatinous contents in the stomach and/or duodenum. Macroscopic examination of the other females did not reveal any abnormalities. Pelvic dilation of the right kidney, as seen in one female exposed to 5 mg/L, is occasionally seen among rats of this age and strain and was therefore considered unrelated to treatment. At 1 mg/L, no macroscopic abnormalities were noted. Under the conditions of this study, the inhalation 4h-LC50 (male/female) was > 1 and ≤ 5 mg/L and the LC50 cut-off was considered to be 5 mg/L within the Wistar: Crl:WI(Han) rat.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
5 000 mg/m³
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:
17-09-2014 to 01-10-2013
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
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
inspected: March 2013 ; signature: May 2013
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Remarks:
Crl:WI (Han)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Recognised supplier
- Age at study initiation: approximately 10 weeks.
- Weight at study initiation: Female: 199 - 212 g ; Male: 302 – 318 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: Individually housed in Makrolon cages furnished with sterilized sawdust and paper cage enrichment.
- Diet (e.g. ad libitum): Certified diet from recognised supplier, provided ad libitum.
- Water (e.g. ad libitum): ad libitum.
- Acclimation period: At least 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 ± 3.0
- Humidity (%): 40 to 70
- Air changes (per hr): typically, at least 15
- Photoperiod (hrs dark / hrs light): 12 hours light/dark

IN-LIFE DATES: 17-09-2014 to 01-10-2013
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
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 occluded with a piece of aluminium foil and elastic bandage affixed with micropore tape.

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

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): dose volume: 1.98 mL/kg bodyweight.
- Concentration (if solution): 2000 mg/kg
- Constant volume or concentration used: Not applicable.

VEHICLE
- Amount(s) applied (volume or weight with unit): 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)
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Clinical observations and mortality checks were conducted periodically on day one and subsequently once daily for 15 days. Individual bodyweights were recorded prior to application of the test item on Day 0 and on Days 8 and 15.
- Necropsy of survivors performed: yes
Statistics:
No statistical analyses were performed.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality was observed.
Clinical signs:
- Clinical observations:Lethargy, hunched posture, piloerection, chromodacryorrhoea and/or ptosis were noted among all animals between Days 1 and 8. Swelling, general erythema, and/or dryness were noted on the treated skin area of all animals between Days 2 and 6. Scales were noted on the treated skin of five animals between Days 7 and 13.
- Dermal reactions: Some of observations (such as piloerection and hunched posture) may (in part) be related/secondary to the burden of dermal treatment and/or observed skin lesions, rather than being primary signs of toxicity. The clinical signs observed fully recovered by Day 14 of the observation period.
Body weight:
All males and females showed expected gains in body weight during the study.
Gross pathology:
No significant abnormalities were noted at necropsy. Pelvic dilation of the right kidney was found in female 10 at necropsy. This was considered a background finding.
Interpretation of results:
not classified
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 rat.
Executive summary:

The study was performed according to OECD TG 402, EU Method B.3 Acute Toxicity (Dermal), US EPA OPPTS 870.1100 and Japanese JMAFF guidelines in accordance with GLP to assess the acute dermal toxicity of the test item in the Wistar strain rat. A group of ten animals (five males and five females) was given a single, 24 hour, 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. Lethargy, hunched posture, piloerection, chromodacryorrhoea and/or ptosis were noted among all animals between Days 1 and 8. Swelling, general erythema, and/or dryness were noted on the treated skin area of all animals between days 2 and 6. Scales were noted on the treated skin of several animals between Days 7 and 13. Some of observations (such as piloerection and hunched posture) may (in part) be related/secondary to the burden of dermal treatment and/or observed skin lesions, rather than being primary signs of toxicity. The clinical signs observed fully recovered by Day 14 of the observation period. The body weight gain during the observation period was within the expected range. Under the conditions of this study, the dermal LD50 was established to exceed 2000 mg/kg bw in male/female Wistar 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: Key study : OECD TG 420, 2014 : The study was performed according to OECD TG 423 and EU Method B1 tris Acute Toxicity, US EPA OPPTS 870.1100 and Japanese JMAFF guidelines and in accordance with GLP to assess the acute oral toxicity of the test item following a single oral administration in the female Wistar strain rat by the acute class method. The test item was administered by oral gavage to two sequential groups of three female Wistar rats at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15). There one humane sacrifice in the second group on day 2. No further mortality occurred. The animal sacrificed in moribund condition for humane reasons on Day 2 showed lethargy, hunched posture, uncoordinated movements, slow breathing, piloerection, salivation, ptosis, hypothermia and yellow urine. Clinical signs noted among the surviving animals between Days 1 and 3 included lethargy, hunched posture, uncoordinated movements, slow breathing, shallow respiration, piloerection, salivation, watery discharge from both eyes, and/or hypothermia . These signs were not observed in neither of surviving animals on Day 4 and thereafter. The body weight gain shown by survivors over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain. No abnormalities were found at macroscopic post mortem examination of the animals at any dose level. The oral LD50 value of the test item in Wistar rats was established to be > 2000 mg/kg body weight. According to the OECD TG 423 test guideline, the LD50 cut-off value was considered to be 2500 mg/kg body weight.

INHALATION: Key study : OECD TG 436, 2014 : 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 groups of six Wistar: Crl:WI(Han) strain rats (three males and three females) were exposed to an aerosol atmosphere of the test item. The groups were exposed for four hours using a nose only exposure system, followed by a fifteen day observation period. The time-weighted mean achieved atmosphere concentrations were as follows: 5.10 ± 0.11 mg/L based on a nominal concentration of 8.0 mg/L and/or 1.03 ± 0.03 mg/L based on a nominal concentration of 1.89 mg/L. The atmosphere generation efficiencies were 63% and 53%, respectively. The characteristics of the achieved atmosphere L were at 5 mg/: Mean Mass Median Diameter (particle size): > 3.7 μm and < 4.0 μm with geometric Standard Deviation 2.0 and 1 mg/L: Mean Mass Median Diameter (particle size): > 3.9 μm and < 4.3 μm with geometric Standard Deviation 1.9. At 5 mg/L, one male was humanely terminated on day 3 ; two females were humanely terminated on day 3. Slow breathing, was observed during exposure. After exposure lethargy, hunched posture, flat posture, uncoordinated movements, laboured respiration, ptosis, rales and/or hypothermia was observed. Surviving males/females had recovered by days 5 and 6. At 1 mg/L, there was no mortality and no significant clinical signs during or after exposure. Reduced body weight gain and body weight loss was noted among survivors during the first week post exposure. At all exposure levels. all animals regained weight during the second week and/or gained weight over the course of the study. At 5 mg/L, macroscopic post mortem examination of the two females humanely terminated revealed gelatinous contents in the stomach and/or duodenum. Macroscopic examination of the other females did not reveal any abnormalities. Pelvic dilation of the right kidney, as seen in one female exposed to 5 mg/L, is occasionally seen among rats of this age and strain and was therefore considered unrelated to treatment. At 1 mg/L, no macroscopic abnormalities were noted. Under the conditions of this study, the inhalation 4h-LC50 (male/female) was > 1 and ≤ 5 mg/L and the LC50 cut-off was considered to be 5 mg/L within the Wistar: Crl:WI(Han) rat.

DERMAL: Key study : OECD TG 402, 2014 : The study was performed according to OECD TG 402, EU Method B.3 Acute Toxicity (Dermal), US EPA OPPTS 870.1100 and Japanese JMAFF guidelines in accordance with GLP to assess the acute dermal toxicity of the test item in the Wistar strain rat. A group of ten animals (five males and five females) was given a single, 24 hour, 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. Lethargy, hunched posture, piloerection, chromodacryorrhoea and/or ptosis were noted among all animals between Days 1 and 8. Swelling, general erythema, and/or dryness were noted on the treated skin area of all animals between days 2 and 6. Scales were noted on the treated skin of several animals between Days 7 and 13. Some of observations (such as piloerection and hunched posture) may (in part) be related/secondary to the burden of dermal treatment and/or observed skin lesions, rather than being primary signs of toxicity. The clinical signs observed fully recovered by Day 14 of the observation period. The body weight gain during the observation period was within the expected range. Under the conditions of this study, the dermal LD50 was established to exceed 2000 mg/kg bw in male/female Wistar 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 classification or non-classification

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

The substance meets classification criteria under Regulation (EC) No 1272/2008 for acute toxicity: inhalation: category 4: H332

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

 

The available acute inhalation study indicates that the substance will produce acute toxicity sufficient for classification and labelling under the EU criteria.

 

References:

1. OECD TG 436 (2009)

2. OECD 39 (2009)