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Diss Factsheets

Administrative data

Description of key information

A number of acute oral studies were included as part of NONS registrations. Acute oral toxicity studies were conducted on four MDI category members; A mixture of: 3,3'-dicyclohexyl-1,1'-methylenebis(4,1-phenylene)diurea; 3-cyclohexyl-1-(4-(4-(3-octadecylureido)benzyl) phenyl)urea; 3,3'-dioctadecyl-1,1'-methylenebis(4,1-phenylene)diurea (PU10; A002; PU18; EC 406-530-2); 3,3'-dicyclohexyl-1,1'-methylenebis(4,1-phenylene)diurea (R95; EC 406-370-3); N,N''-(methylenedi-4,1-phenylene) bis[N'-octyl]urea (A124; EC 445-760-8); and 3,3'-dioctadecyl-1,1'-methylenebis(4,1-phenylene)diurea (PU12/A123; EC 406-690-3). The results from these studies showed no evidence of acute toxicity up to the highest dose tested in any study (2000 or 5000 mg/kg test item in either cellulose or corn oil).


Additionally, as part of an updated testing program, acute oral studies were conducted on: Reaction product of MDI, Octadecylamine and Magnesium Hydroxide (PU05; EC 944-730-6); Reaction product of MDI and p-toluidine (PU07; EC 926-809-7); and Polyurea, produced by reacting diphenylmethane diisocyanate with octylamine and dodecyl amine (R03; EC 812-490-0. The results from these studies showed no evidence of acute toxicity up to the highest dose tested (2000 mg/kg body weight). Therefore, there is no evidence of a relevant intrinsic acute oral toxicity requiring classification or substance specific risk management measures.


 


A number of acute dermal studies were also included as part of NONS registrations. Acute dermal studies were conducted on four MDI category members: A mixture of: 3,3'-dicyclohexyl-1,1'-methylenebis(4,1-phenylene)diurea; 3-cyclohexyl-1-(4-(4-(3-octadecylureido)benzyl) phenyl)urea; 3,3'-dioctadecyl-1,1'-methylenebis(4,1-phenylene)diurea (PU10; A002; PU18; EC 406-530-2);3,3'-dicyclohexyl-1,1'-methylenebis(4,1-phenylene)diurea (R95; EC 406-370-3);N,N''-(methylenedi-4,1-phenylene) bis[N'-octyl]urea (A124; EC 445-760-8);and3,3'-dioctadecyl-1,1'-methylenebis(4,1-phenylene)diurea (PU12/A123; EC 406-690-3). The results from these studies showed no evidence of acute toxicity at the only dose tested in any study (2000 mg/kg test item). There is no evidence of a relevant intrinsic acute dermal toxicity requiring classification or substance specific risk management measures.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
This study is included in a NONS registration and therefore has been evaluated by a relevant competent authority and is considered to be reliable.
Qualifier:
according to guideline
Guideline:
other: Annex V
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
10 male and 10 female rats
Route of administration:
oral: unspecified
Vehicle:
corn oil
Doses:
2000 mg/kg b.w.
No. of animals per sex per dose:
10 animals per sex per dose
Control animals:
not specified
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
not specified
Mortality:
Male: 2000 mg/kg bw ; Number of animals: 10; Number of deaths: 0
Female: 2000 mg/kg bw ; Number of animals: 10; Number of deaths: 0
Clinical signs:
other: other: No deaths and no signs of toxicity were observed.
Gross pathology:
No effects on organs
Interpretation of results:
GHS criteria not met
Conclusions:
The LD50 for the test item was determined to be > 2000 mg/kg b.w., the only concentration tested. No deaths and no signs of toxicity were observed.
Executive summary:

The acute oral toxicity of the test item to Crj(CD)SD rats was determined in a limit test conducted according to international guidelines. The LD50 was determined to be > 2000 mg/kg b.w., the only concentration tested. No deaths and no signs of toxicity were observed.

The study is a GLP compliant, guideline study and is acceptable with restrictions.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
This study is included in a NONS registration and therefore has been evaluated by a relevant competent authority and is considered to be reliable.
Qualifier:
according to guideline
Guideline:
other: Annex V
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Remarks:
Albino
Sex:
male/female
Details on test animals or test system and environmental conditions:
5 male and 5 female rats
Route of administration:
oral: unspecified
Vehicle:
corn oil
Doses:
2000 mg/kg b.w.
No. of animals per sex per dose:
5 animals per sex per dose
Control animals:
not specified
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Male: 2000 mg/kg bw ; Number of animals: 5; Number of deaths: 0
Female: 2000 mg/kg bw ; Number of animals: 5; Number of deaths: 0
Clinical signs:
other: other: No deaths and no signs of toxicity were observed.
Gross pathology:
No treatment-related macroscopic findings were observed.
Interpretation of results:
GHS criteria not met
Conclusions:
The LD50 for the test item to albino Wistar rats was determined to be > 2000 mg/kg b.w., the only concentration tested. No signs of toxicity were observed, and the gross pathological examination revealed no treatment-related findings.
Executive summary:

The acute oral toxicity of the test item to albino Wistar rats was determined in a limit test conducted according to international guidelines. The LD50 was determined to be > 2000 mg/kg b.w., the only concentration tested. No signs of toxicity were observed, and the gross pathological examination revealed no treatment-related findings.

The study is a GLP compliant, guideline study and is acceptable with restrictions.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
This study is included in a NONS registration and therefore has been evaluated by a relevant competent authority and is considered to be reliable.
Qualifier:
according to guideline
Guideline:
other: Annex V
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: unspecified
Vehicle:
corn oil
Remarks:
at 0.5 %
Doses:
5000 mg/kg b.w.
No. of animals per sex per dose:
5 animals per sex per dose
Control animals:
not specified
Details on study design:
The total dose of 5000 mg/kg was given as two doses of 2500 mg/kg administered within a 24 hour period.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
not specified
Mortality:
Male: 5000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 5000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Clinical signs:
other: other: Signs of toxicity related to dose levels: No clear toxicologically significant effects were seen.
Gross pathology:
Effects on organs: None.
Interpretation of results:
GHS criteria not met
Conclusions:
The LD50 for the test item was determined to be > 5000 mg/kg b.w. No signs of toxicity were observed, and the gross pathological examination revealed no effects on organs.
Executive summary:

The acute oral toxicity of the test item to male and female Wistar rats was determined in a study conducted according to EU Annex V guidelines. The test item was administered to 5 male and 5 female rats, with the 5000 mg/kg/b.w. dose administered as two doses of 2500 mg/kg/b.w. in a 24 hour period. The LD50 was determined to be > 5000 mg/kg b.w. No signs of toxicity were observed, and the gross pathological examination revealed no effects on organs.

The study is a GLP compliant, guideline experimental study and is acceptable with restrictions.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
This study is included in a NONS registration and therefore has been evaluated by a relevant competent authority and is considered to be reliable.
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
6 male and 3 female rats
Route of administration:
oral: unspecified
Vehicle:
methylcellulose
Remarks:
at 0.5 %
Doses:
200 and 2000 mg/kg b.w.
No. of animals per sex per dose:
3 animals per sex per dose
Control animals:
not specified
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
not specified
Mortality:
Male: 200 mg/kg bw ; Number of animals: 3; Number of deaths: 0
Male: 2000 mg/kg bw ; Number of animals: 3; Number of deaths: 0
Female: 2000 mg/kg bw ; Number of animals: 3; Number of deaths: 0
Clinical signs:
other: other: At doses of 200 and 2000 mg / kg, no clinical signs and no mortality were observed in the animals.
Gross pathology:
No apparent abnormality is observed on macroscopic examination of the main organs of animals sacrificed at the end of the study.
Interpretation of results:
GHS criteria not met
Conclusions:
The LD50 for the test item was determined to be > 2000 mg/kg b.w. No signs of toxicity were observed, no effects on body weight were observed and the gross pathological examination revealed no treatment-related findings.
Executive summary:

The acute oral toxicity of the test item to Sprague-Dawley rats was determined in a study conducted according to OECD 423 and EU method B.1 guidelines. The LD50 was determined to be > 2000 mg/kg b.w. No signs of toxicity or effects on body weight were observed, and the gross pathological examination revealed no treatment-related findings.

 

The study is a GLP compliant, guideline experimental study and is acceptable with restrictions.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
02/11/2021 - 14/10/2022
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Version / remarks:
2001
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Version / remarks:
2008
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
other:
Remarks:
Crl:WI(Han)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd., Margate
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: 8 to 10 weeks old
- Weight at study initiation: 151 to 200 grams
- Fasting period before study: Period of fasting from the evening of the day prior to dosing (Day -1) until approximately 3 hours after dosing.
- Housing: Animals housed in groups of 6 in cages
- Diet: 5LF2 EU Rodent Diet 14% provided ad libitum
- Water: Water provided ad libitum
- Acclimation period: 7 to 15 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25 °C
- Humidity (%): 40 to 70 %
- Air changes (per hr): 15 per hour
- Photoperiod (hrs dark / hrs light): 12 hours light / 12 hours dark
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
DOSE VOLUME APPLIED: 10 mL/kg

Doses:
Sighting study: 300 and 2000 mg/kg
Main study: 2000 mg/kg
No. of animals per sex per dose:
Sighting study: 1
Main study: 4
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical signs were recorded immediately post-dose, at approximately 15 and 30 minutes post dose, hourly between 1 and 4 hours post-dose (inclusive), twice daily on Days 2, 3 and 4 and once daily from the fifth to last day of the observation period. Rats were weighed on Day -1 (day before dosing) and on Days 1, 4, 8 and 15.
- Necropsy of survivors performed: Yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: All animals were observed at the beginning and the end of the working day for signs of ill health or overt toxicity.
Preliminary study:
No deaths observed.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Remarks on result:
not determinable due to absence of adverse toxic effects
Mortality:
No mortality observed.
Clinical signs:
other: other: other: Piloerection was noted in the animal treated at 300 mg/kg, developing from 2 hours after dosing and lasting up to 3 hours after dosing. No clinical signs were seen in animals treated at 2000 mg/kg.
Body weight:
other body weight observations
Gross pathology:
No abnormalities were noted at necropsy.

Table 1       Mortality Data

Dose Level (mg/kg)   Mortality Ratio
 300  0/1
 2000  0/5

Table 2       Clinical Signs Following Treatment

Dose level: 300 mg/kg

 Animal Number    Clinical Sign   Sign Noted after Dosing on Day 1 (hours)          Sign noted on Day:          
 Imm  1/4  1/2  1  2  3  4  2  3  4  5  6  7  8  9 to 15
 784  Piloerection          +  +                  

Key:

Imm: Immediately post-dose

+: Sign present (if no entry sign absent)

Dose Level: 2000 mg/kg

Clincal Sign  Animal Number
 785  786  787  788  789
 No observations  X  X  X  X  X

Key:

X: No clincal signs seen throughout the observation period

Table 3       Individual Body Weights and Weekly Increments

 Dose Level (mg/kg)  Animal Number  Body Weight (g) at:  Increment (g)
 Day -1  Day 1  Day 4  Day 8  Day 15  Day 1 to 8  Day 8 to 15
 300  784  163  151  168  176  193  25  17
 2000  785  214  200  219  231  248  31  17
 786  190  173  195  203  219  30  16
 787  202  186  199  203  213  17  10
 788  177  163  177  184  194  21  10
 789  173  160  173  175  186  15  11

Table 4       Necropsy Findings

Dose Level: 300 mg/kg

 Animal Number  Time and Manner of Death (Day)  Necropsy Comments
 784  15T  No macroscopic changes

Dose Level: 200 mg/kg

 Animal Number  Time and Manner of Death (Day)  Necropsy Comments
 785  15T  No macroscopic changes
 786  15T  No macroscopic changes
 787  15T  No macroscopic changes
 788  15T  No macroscopic changes
 789  15T  No macroscopic changes

T       Animal killed by exsanguination under deep inhalation anaesthesia at completion of observation period

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
The acute oral toxicity of the test item was tested and the oral LD50 was determined to exceed 2000 mg/kg body weight.
Executive summary:

The acute oral toxicity of the test item was determined in an OECD 420 and EU Method B1 bis Acute Toxicity (Oral) guideline study. The test item was tested at 2000 mg/kg formulation in corn oil, orally by gavage using a metal canula. Clinical signs were recorded immediately post-dose, at approximately 15 and 30 minutes post dose, hourly between 1 and 4 hours post-dose (inclusive), twice daily on Days 2, 3 and 4 and once daily from the fifth to last day of the observation period. All animals were observed at the beginning and the end of the working day for signs of ill health or overt toxicity. Additionally the animal body weights were determined on Day -1 (day before dosing) and on Days 1, 4, 8 and 15.

In a preliminary study, one adult female rat was dosed at 300 mg/kg test item and one adult female rate was dosed at 2000 mg/kg test item, and no mortalities, effects on body weight or adverse findings during necropsy were observed, therefore four further female rats were dosed with 2000 mg/kg test item. No deaths or signs of systematic toxicity or adverse findings during necropsy were observed during the main study and the test animals achieved the expected weight gains during the study. The acute oral median lethal dose (LD50) of the test item was estimated to be greater than 2000 mg/kg body weight. 

The study is a GLP compliant guideline experimental study and is acceptable without restrictions for assessment of this endpoint.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
06/10/2021 - 14/10/2022
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Version / remarks:
2001
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Version / remarks:
2008
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
other:
Remarks:
Crl:WI(Han)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd., Margate
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: 8 to 10 weeks old
- Weight at study initiation: 166 to 184 grams
- Fasting period before study: Period of fasting from the evening of the day prior to dosing (Day -1) until approximately 3 hours after dosing.
- Housing: Animals housed in groups of 6 in cages
- Diet: 5LF2 EU Rodent Diet 14% provided ad libitum
- Water: Water provided ad libitum
- Acclimation period: 7 to 15 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25 °C
- Humidity (%): 40 to 70 %
- Air changes (per hr): 15 per hour
- Photoperiod (hrs dark / hrs light): 12 hours light / 12 hours dark
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
DOSE VOLUME APPLIED: 10 mL/kg
Doses:
Sighting study: 300 and 2000 mg/kg
Main study: 2000 mg/kg
No. of animals per sex per dose:
Sighting study: 1
Main study: 4
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical signs were recorded immediately post-dose, at approximately 15 and 30 minutes post dose, hourly between 1 and 4 hours post-dose (inclusive), twice daily on Days 2, 3 and 4 and once daily from the fifth to last day of the observation period. Rats were weighed on Day -1 (day before dosing) and on Days 1, 4, 8 and 15.
- Necropsy of survivors performed: Yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: All animals were observed at the beginning and the end of the working day for signs of ill health or overt toxicity.
Preliminary study:
No deaths observed.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Remarks on result:
not determinable due to absence of adverse toxic effects
Mortality:
No mortality observed.
Clinical signs:
other: other: other: Piloerection
Body weight:
other body weight observations
Gross pathology:
No abnormalities were noted at necropsy.

Table 1       Mortality Data

Dose Level (mg/kg)  Mortality Ratio
 300  0/1
 2000  0/5

Table 2       Clinical Signs Following Treatment

Dose Level: 300 mg/kg

 Clinical Sign  Animal Number
 790
 No observations  X

Key:

X       No clinical signs seen throughout the observation period

Dose Level: 2000 mg/kg

Animal Number   Clinical Sign   Sign Noted after Dosing on Day 1 (hours)           Sign Noted on Day: 
 Imm.  1/4  1/2  1  2  3  4  2  3  4  5  6  7  8  9 to 15
 791  Piloerection                              
 792  Piloerection        +  +  +  +                
 793  Piloerection        +  +  +  +                
 794  Piloerection        +  +  +                  
 795  Piloerection          +  +                  

Key:

Imm.       Immediately post-dose

+             Sign present (if no entry is made the sign is absent)

Table 3       Individual Body Weights and Weekly Increments

Dose Level

(mg/kg)

  Animal Number  Body weight (g) at:  Increment (g)
 Day -1  Day 1  Day 4  Day 8  Day 15  Day 1 to 8  Day 8 to 15
 300  790  194  183  202  204  203  21  -1
 2000  791  171  166  179  187  202  21  15
 792  203  184  203  210  218  26  8
 793  188  181  200  201  210  20  9
 794  183  169  188  193  194  24  1
 795  190  180  198  204  212  24  8

A minus symbol [-] indicates body weight loss

Table 4       Necropsy Findings

Dose Level: 300 mg/kg

 Animal Number  Time and Manner of Death (Day)  Necropsy Comments
 790  15T  No macroscopic changes

Dose Level: 2000 mg/kg

Animal Number   Time and Manner of Death (Day)  Necropsy Comments
 791  15T  No macroscopic changes
 792  15T  No macroscopic changes
 793  15T  No macroscopic changes
 794  15T  No macroscopic changes
 795  15T  No macroscopic changes

T       Animal killed by exsanguination under deep inhalation anaesthesia at completion of observation period

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
The acute oral toxicity of the test item was tested and the oral LD50 was determined to exceed 2000 mg/kg body weight.
Executive summary:

The acute oral toxicity of the test item was determined in an OECD 420 and EU Method B1 bis Acute Toxicity (Oral) guideline study. The test item was tested at 2000 mg/kg formulation in corn oil, orally by gavage using a metal canula. Clinical signs were recorded immediately post-dose, at approximately 15 and 30 minutes post dose, hourly between 1 and 4 hours post-dose (inclusive), twice daily on Days 2, 3 and 4 and once daily from the fifth to last day of the observation period. All animals were observed at the beginning and the end of the working day for signs of ill health or overt toxicity. Additionally the animal body weights were determined on Day -1 (day before dosing) and on Days 1, 4, 8 and 15.

In a preliminary study, one adult female rat was dosed at 300 mg/kg test item and one adult female rate was dosed at 2000 mg/kg test item, and no mortalities, effects on body weight or adverse findings during necropsy were observed, therefore four further female rats were dosed with 2000 mg/kg test item. No deaths or signs of systematic toxicity or adverse findings during necropsy were observed during the study. Piloerection was noted in four animals treated at 2000 mg/kg from 1 hour after dosing and lasted up to 4 hours after dosing. The test animals all gained weight during the first and second weeks of the observation period, except for the animal treated at 300 mg/kg, which showed slight body weight loss during the second week of the observation period. The acute oral median lethal dose (LD50) of the test item was estimated to be greater than 2000 mg/kg body weight.

The study is a GLP compliant guideline experimental study and is acceptable without restrictions for assessment of this endpoint.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
24/05/2021 - 30/06/2021
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Version / remarks:
2001
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Version / remarks:
2008
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
other:
Remarks:
Crl:WI(Han)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd., Margate
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: 8 to 10 weeks old
- Weight at study initiation: 150 to 185 grams
- Fasting period before study: Period of fasting from the evening of the day prior to dosing (Day -1) until approximately 3 hours after dosing.
- Housing: Animals housed in groups of 6 in cages
- Diet: 5LF2 EU Rodent Diet 14% provided ad libitum
- Water: Water provided ad libitum
- Acclimation period: 14 to 22 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25 °C
- Humidity (%): 40 to 70 %
- Air changes (per hr): 15 per hr
- Photoperiod (hrs dark / hrs light): 12 hrs light / 12 hrs dark
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
DOSE VOLUME APPLIED: 10 mL/kg
Doses:
Sighting study: 300 and 2000 mg/kg
Main study: 2000 mg/kg
No. of animals per sex per dose:
Sighting study: 1
Main study: 4
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical signs were recorded immediately post-dose, at approximately 15 and 30 minutes post dose, hourly between 1 and 4 hours post-dose (inclusive), twice daily on Days 2, 3 and 4 and once daily from the fifth to last day of the observation period. Rats were weighed on Day -1 (day before dosing) and on Days 1, 4, 8 and 15.
- Necropsy of survivors performed: Yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: All animals were observed at the beginning and the end of the working day for signs of ill health or overt toxicity.
Preliminary study:
No deaths observed.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Remarks on result:
not determinable due to absence of adverse toxic effects
Mortality:
No mortality observed.
Body weight:
other body weight observations
Gross pathology:
No abnormalities were noted at necropsy.

Table 1      Mortality Data

Dose Level (mg/kg)  Mortality Ratio
 300  0/1
 2000  0/5

Table 2      Clinical Signs Following Treatment

Dose Level: 300 mg/kg

 Clinical Sign  Animal Number
 421
 No observations  X

Key:

X       No clinical signs seen throughout the observation period

Dose Level: 2000 mg/kg

 Clinical Sign  Animal Number
 422  423  424  425  426
 No observations  X  X  X  X  X

Key:

X       No clinical signs seen throughout the observation period

Table 3      Individual Body Weights and Weekly Increments

Dose Level

(mg/kg)

  Animal Number  Body weight (g) at:  Increment (g)
 Day -1  Day 1  Day 4  Day 8  Day 15  Day 1 to 8  Day 8 to 15
 300  421  176  163  184  190  205  27  15
 2000  422  166  159  172  178  194  19  16
 423  173  163  180  185  195  22  10
 424  172  163  186  198  203  35  5
 425  194  185  200  212  222  27  10
 426  162  150  169  174  183  24  9

Table 4      Necropsy Findings

Dose Level: 300 mg/kg

 Animal Number  Time and Manner of Death (Day)  Necropsy Comments
 421  15T  No macroscopic changes

Dose Level: 2000 mg/kg

Animal Number   Time and Manner of Death (Day)  Necropsy Comments
 422  15T  No macroscopic changes
 423  15T  No macroscopic changes
 424  15T  No macroscopic changes
 425  15T  No macroscopic changes
 426  15T  No macroscopic changes

T       Animal killed by exsanguination under deep inhalation anaesthesia at completion of observation period

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
The acute oral toxicity of the test item was tested and the oral LD50 was determined to exceed 2000 mg/kg body weight.
Executive summary:

The acute oral toxicity of the test item was determined in an OECD 420 and EU Method B1 bis Acute Toxicity (Oral) guideline study. The test item was tested at 2000 mg/kg formulation in corn oil, orally by gavage using a metal canula. Clinical signs were recorded immediately post-dose, at approximately 15 and 30 minutes post dose, hourly between 1 and 4 hours post-dose (inclusive), twice daily on Days 2, 3 and 4 and once daily from the fifth to last day of the observation period. All animals were observed at the beginning and the end of the working day for signs of ill health or overt toxicity. Additionally the animal body weights were determined on Day -1 (day before dosing) and on Days 1, 4, 8 and 15.

In a preliminary study, one adult female rat was dosed at 300 mg/kg test item and one adult female rat 2000 mg/kg test item, and no mortalities, effects on body weight or adverse findings during necropsy were observed, therefore four further female rats were dosed with 2000 mg/kg test item. In the main study, no deaths or signs of systematic toxicity or adverse findings during necropsy were observed during the study and the test animals achieved the expected weight gains during the study. The acute oral median lethal dose (LD50) of the test item was estimated to be greater than 2000 mg/kg body weight.

The study is a GLP compliant guideline experimental study and is acceptable without restrictions for assessment of this endpoint.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
> 2 000 mg/kg bw
Quality of whole database:
NONS data evaluated for the MDI category have been conducted following standard guidelines and have been previously submitted for regulatory purposes; and therefore they are deemed acceptable for evaluation. Data from the updated testing program are guideline, GLP studies.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
This study is included in a NONS registration and therefore has been evaluated by a relevant competent authority and is considered to be reliable.
Qualifier:
according to guideline
Guideline:
other: Annex V
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
not specified
Sex:
male/female
Type of coverage:
occlusive
Vehicle:
corn oil
Duration of exposure:
24 hours
Doses:
2000 mg/kg b.w.
No. of animals per sex per dose:
5 male and 5 female per dose
Control animals:
not specified
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
not specified
Mortality:
Male: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Clinical signs:
other: other: No deaths or signs of toxicity were observed.
Gross pathology:
No treatment-related effects on organs were observed
Other findings:
Signs of toxicity (local): At the site of treatment, spots with crusts were noted in 2 females on day 8 and 1 female on day 15
Interpretation of results:
GHS criteria not met
Conclusions:
The LD50 for the acute dermal exposure of rats to the test item was determined to be > 2000 mg/kg b.w., the only concentration tested.
Executive summary:

The acute dermal toxicity of the test item was determined in a guideline limit test with male and female wistar rats at a dose level of 2000 mg/kg b.w. The LD50 was determined to be > 2000 mg/kg b.w., the only concentration tested. No deaths or effects on organs were observed. At the site of treatment, spots with crusts were noted in 2 females on day 8 and 1 female on day 15. The test item does not meet the GHS criteria and is not classified.

The study is a GLP compliant, guideline study suitable for use for assessment of this endpoint, with restrictions.

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
This study is included in a NONS registration and therefore has been evaluated by a relevant competent authority and is considered to be reliable.
Qualifier:
according to guideline
Guideline:
other: Annex V
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Type of coverage:
occlusive
Vehicle:
corn oil
Duration of exposure:
24 hours
Doses:
2000 mg/kg b.w.
No. of animals per sex per dose:
5 male and 5 female per dose
Control animals:
not specified
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Male: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Clinical signs:
other: other: No deaths or signs of toxicity were observed. Slight erythema was observed at the site of application in one female on day 2.
Gross pathology:
No treatment-related macroscopic findings were observed
Interpretation of results:
GHS criteria not met
Conclusions:
The LD50 for the acute dermal exposure of Wistar rats to the test item was determined to be > 2000 mg/kg b.w., the only concentration tested.
Executive summary:

The acute dermal toxicity of the test item was determined in a guideline limit test with male and female Wistar rats at a dose level of 2000 mg/kg b.w. The LD50 was determined to be > 2000 mg/kg b.w., the only concentration tested. No deaths, gross pathological findings or signs of toxicity were observed, except slight erythema at the site of application in one female on day 2. Therefore, the test item does not meet the GHS criteria and is not classified.

The study is a GLP compliant, guideline study suitable for use for assessment of this endpoint with restrictions.

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
This study is included in a NONS registration and therefore has been evaluated by a relevant competent authority and is considered to be reliable.
Qualifier:
according to guideline
Guideline:
other: Annex V
Version / remarks:
Version not reported
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Type of coverage:
occlusive
Vehicle:
corn oil
Duration of exposure:
24 hours
Doses:
2000 mg/kg b.w.
No. of animals per sex per dose:
5 male and 5 female per dose
Control animals:
not specified
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
not specified
Mortality:
Male: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Clinical signs:
other: other: Lethargy was noted in 1 male and 1 female during the treatment period.
Gross pathology:
No treatment-related effects on organs were observed.
Other findings:
Signs of toxicity (local): Slight erythema of treated skin was noted in one male on days 5 and 8 and scaliness in 1 male on day 5.
Interpretation of results:
GHS criteria not met
Conclusions:
The LD50 for the acute dermal exposure of rats to the test item was determined to be > 2000 mg/kg b.w., the only concentration tested.
Executive summary:

The acute dermal toxicity of the test item was determined in a limit test conducted at a dose of 2000 mg/kg b.w., with male and female Wistar rats, according to EU Annex V guidelines. The LD50 was determined to be > 2000 mg/kg b.w., the only concentration tested.

No deaths and effects on organs were observed. Lethargy was noted in 1 male and 1 female during the treatment period. Slight erythema of treated skin was noted in one male on days 5 and 8 and scaliness in 1 male on day 5. The test item does not meet the GHS criteria and is not classified.

The study is a GLP compliant, guideline experimental study and is suitable for use for assessment of this endpoint with restrictions.

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
This study is included in a NONS registration and therefore has been evaluated by a relevant competent authority and is considered to be reliable.
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Remarks:
The substance was moistened with reverse osmosis purified water.
Duration of exposure:
24 hours
Doses:
2000 mg/kg b.w.
No. of animals per sex per dose:
5 male and 5 female per dose
Control animals:
not specified
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
not specified
Mortality:
Male: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Clinical signs:
other: other: No clinical signs were observed.
Gross pathology:
No treatment-related effects on organs were observed
Other findings:
Signs of toxicity (local): No skin reaction is observed. A white coloring of the skin, due to the substance, could mask a very slight erythema and is noted in all the animals at day 2 only.
Interpretation of results:
GHS criteria not met
Conclusions:
The LD50 for the acute dermal exposure of the test item was determined to be > 2000 mg/kg b.w., the only concentration tested.
Executive summary:

The acute dermal toxicity of the test item was determined in a guideline limit test with male and female Sprague-Dawley rats at 2000 mg/kg b.w. The LD50 was determined to be > 2000 mg/kg b.w., the only concentration tested. No deaths and no effects on organs were observed. A slower body weight gain or a slight decrease in body weight is noted in 2/5 females between days 1 and 8 and in 1/5 females between days 8 and 15. The body weight gain of other animals is similar to that of historical control animals. No local skin reaction was observed, however a white colouring of the skin, due to the substance, could mask a very slight erythema is noted in all the animals at day 2 only. The test item does not meet the GHS criteria and is not classified.

The study is a GLP compliant, guideline experimental study and is suitable for use for assessment of this endpoint with restrictions.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
All studies evaluated for the MDI category have been conducted following standard guidelines and have been previously submitted for regulatory purposes; and therefore they are deemed acceptable for evaluation.

Additional information

Justification for classification or non-classification

The oral and dermal LD50 values are greater than 2000 mg/kg bw in all studies conducted on the MDI category; therefore, the existing data supports the justification for non-classification.