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Administrative data

Description of key information

No data on acute toxicity by oral route is available for the substance reaction mass of amines, hydrogenated tallow alkyl and azelaic acid and lithium hydroxide. Read across from dilithium azelate and reaction mixture of hydrogenated tallow alkyl amines with sebacic acid and lithium hydroxide is used to complete this endpoint. 

The LD50 value for reaction mixture of hydrogenated tallow alkyl amines with sebacic acid and lithium hydroxide was >2000 mg/kg bw. For dilithium azelate, the oral LD50 value is within the range 300 mg/kg bw - 2000 mg/kg bw.

 

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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
Study period:
16 April to 11 June 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-compliant, guideline study, available as an unpublished report.
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Further information is included under 'Attached justification' in IUCLID section 13 and 'Cross-reference'.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
- Source: Charles River Deutschland, Sulzfeld, Germany. Animals were 8 to 10 weeks old and nulliparous and non-pregnant.
- Acclimatisation: The acclimatization period was at least 5 days before the start of treatment under laboratory conditions and animals were individually housed for the pilot study and group housed for the main study.
- Housing: Individual housing of animals in the pilot study and group housing of four animals per cage in the main study in labeled Makrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material and paper as cage-enrichment. The rats had free access to pelleted rodent diet and tap water.
- Environmental conditions: Temperature and relative humidity were set to achieve limits of 18 to 24 deg C, and 40 to 70% humidity. Rate of air exchange was at least 10 changes per hour and there was a 12 hour light/12 hour dark cycle.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
- Preparation: The preparations (w/w) were kept at room temperature protected from light and were dosed within 4 hours after adding the vehicle to the test substance. Homogeneity was obtained to visually acceptable levels.
- Dosing: Oral gavage, using plastic feeding tubes. The test item preparations were stirred on a magnetic stirrer during dosing. The concentration of the test substance in vehicle was varied to allow constant dosage volume in terms of mL/kg body weight.
- Fasting: Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test substance. Water was available.
Doses:
In the absence of any other toxicity information a "Pilot study" was conducted in which a single female rat was orally dosed with the test substance at 2000 mg/kg body weight. Based on the Pilot results, a fixed dose level of 2000 mg/kg body weight was then selected for the main study which was conducted in a stepwise approach on three animals. One animal at a time was treated at 2000 mg/kg body weight. When two animals were found dead, five animals were treated at a lower dose level of 300 mg/kg body weight.
No. of animals per sex per dose:
For the main study four female rats were treated at 2000 mg/kg body weight, and five female rats were subsequently treated at 300 mg/kg body weight.
Control animals:
no
Details on study design:
- Observations: Clinical observations were made on the day of dosing and then once daily until Day 15. Morbidity and viability checks were made twice daily and individual body weights were recorded on days 0, 8 and 15. At the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.
Statistics:
The Fixed Dose Procedure does not require any statistical analyses of the data.
Preliminary study:
In the preliminary study in one animal at 2000 mg/kg bw no mortality occurred. Hunched posture, piloerection and ptosis were noted between Days 1 and 12. The animal showed body weight loss between Days 1 and 8 and showed body weight gain again between Days 8 and 15. No findings were noted during macroscopic post mortem examination.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 mg/kg bw
Based on:
test mat.
Mortality:
At 2000 mg/kg, two animals were found dead, on Day 4 and 5 of the study.
At 300 mg/kg, no mortality occurred.
Clinical signs:
At 2000 mg/kg, hunched posture, piloerection and/or chromodacryorrhoea (snout) were noted for the animals between Days 1 and 4.
At 300 mg/kg, no clinical signs were noted for any of the animals.
Body weight:
At 2000 mg/kg, one of the surviving animals (pilot animal) showed bodyweight loss between Days 1 and 8 and showed body weight gain again between Days 8 and 15. The other surviving animal showed a normal body weight gain during the study period.
At 300 mg/kg, the mean body weight gain shown by the animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain.
Gross pathology:
At 2000 mg/kg, abnormalities of the stomach (glandular mucosa: focus/foci, several, black-brown) were found in one of the animals found dead. Macroscopic post mortem examination of the other animal that died during the study and of the surviving animals at termination did not reveal any abnormalities. Autolysis was noted for both animals found dead. This was considered not toxicologically relevant.
At 300 mg/kg, no abnormalities were found at macroscopic post mortem examination of the animals.
Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The highest dose level of Dilithium azelate that did not produce mortality in Wistar rats was established as 300 mg/kg body weight and the estimated minimum lethal dose level was 2000 mg/kg body weight. Based on the mortality rate at 2000 mg/kg body weight, it was concluded that the oral LD50 value of Dilithium azelate was within the range of 300-2000 mg/kg body weight. Based on these results Dilithium azelate should be classified as Category 4.
Executive summary:

The acute oral toxicity of Dilithium azelate to female Wistar rats was determined in a GLP-compliant, fixed-dose method study following OECD guideline 420 (Latour 2015). A preliminary study indicated no mortality of a single rat at 2000 mg/kg bw Dilithium azelate, therefore 2000 mg/kg bw was selected for the main study which was conducted in a stepwise approach on three further animals. Dilithium azelate was dosed by oral gavage and the rats were observed for mortality, systemic toxicity and bodyweight gain.When two animals were found dead at 2000 mg/kg bw, five animals were treated at a lower dose level of 300 mg/kg bw for 15 days. No deaths or significant signs of toxicity were observed at 300 mg/kg bw Dilithium azelate. The oral LD50 value is within the range 300 mg/kg bw - 2000 mg/kg bw Dilthium azelate. Based on these results Dilithium azelate should be classified as Category 4. The study is considered to be relevant and reliable for use for this endpoint.

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
16 April to 11 June 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-compliant, guideline study, available as an unpublished report.
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Further information is included under 'Attached justification' in IUCLID section 13 and 'Cross-reference'.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
- Source: Charles River Deutschland, Sulzfeld, Germany. Animals were 8 to 10 weeks old and nulliparous and non-pregnant.
- Acclimatisation: The acclimatization period was at least 5 days before the start of treatment under laboratory conditions and animals were individually housed for the pilot study and group housed for the main study.
- Housing: Individual housing of animals in the pilot study and group housing of four animals per cage in the main study in labeled Makrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material and paper as cage-enrichment. The rats had free access to pelleted rodent diet and tap water.
- Environmental conditions: Temperature and relative humidity were set to achieve limits of 18 to 24 deg C, and 40 to 70% humidity. Rate of air exchange was at least 10 changes per hour and there was a 12 hour light/12 hour dark cycle.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
- Preparation: The preparations (w/w) were kept at room temperature protected from light and were dosed within 4 hours after adding the vehicle to the test substance. Homogeneity was obtained to visually acceptable levels.
- Dosing: Oral gavage, using plastic feeding tubes. The test item preparations were stirred on a magnetic stirrer during dosing. The concentration of the test substance in vehicle was varied to allow constant dosage volume in terms of mL/kg body weight.
- Fasting: Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test substance. Water was available.
Doses:
In the absence of any other toxicity information a "Pilot study" was conducted in which a single female rat was orally dosed with the test substance at 2000 mg/kg body weight. Based on the Pilot results, a fixed dose level of 2000 mg/kg body weight was then selected for the main study which was conducted in a stepwise approach on three animals. One animal at a time was treated at 2000 mg/kg body weight. When two animals were found dead, five animals were treated at a lower dose level of 300 mg/kg body weight.
No. of animals per sex per dose:
For the main study four female rats were treated at 2000 mg/kg body weight, and five female rats were subsequently treated at 300 mg/kg body weight.
Control animals:
no
Details on study design:
- Observations: Clinical observations were made on the day of dosing and then once daily until Day 15. Morbidity and viability checks were made twice daily and individual body weights were recorded on days 0, 8 and 15. At the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.
Statistics:
The Fixed Dose Procedure does not require any statistical analyses of the data.
Preliminary study:
In the preliminary study in one animal at 2000 mg/kg bw no mortality occurred. Hunched posture, piloerection and ptosis were noted between Days 1 and 12. The animal showed body weight loss between Days 1 and 8 and showed body weight gain again between Days 8 and 15. No findings were noted during macroscopic post mortem examination.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 mg/kg bw
Based on:
test mat.
Mortality:
At 2000 mg/kg, two animals were found dead, on Day 4 and 5 of the study.
At 300 mg/kg, no mortality occurred.
Clinical signs:
At 2000 mg/kg, hunched posture, piloerection and/or chromodacryorrhoea (snout) were noted for the animals between Days 1 and 4.
At 300 mg/kg, no clinical signs were noted for any of the animals.
Body weight:
At 2000 mg/kg, one of the surviving animals (pilot animal) showed bodyweight loss between Days 1 and 8 and showed body weight gain again between Days 8 and 15. The other surviving animal showed a normal body weight gain during the study period.
At 300 mg/kg, the mean body weight gain shown by the animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain.
Gross pathology:
At 2000 mg/kg, abnormalities of the stomach (glandular mucosa: focus/foci, several, black-brown) were found in one of the animals found dead. Macroscopic post mortem examination of the other animal that died during the study and of the surviving animals at termination did not reveal any abnormalities. Autolysis was noted for both animals found dead. This was considered not toxicologically relevant.
At 300 mg/kg, no abnormalities were found at macroscopic post mortem examination of the animals.
Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The highest dose level of Dilithium azelate that did not produce mortality in Wistar rats was established as 300 mg/kg body weight and the estimated minimum lethal dose level was 2000 mg/kg body weight. Based on the mortality rate at 2000 mg/kg body weight, it was concluded that the oral LD50 value of Dilithium azelate was within the range of 300-2000 mg/kg body weight. Based on these results Dilithium azelate should be classified as Category 4.
Executive summary:

The acute oral toxicity of Dilithium azelate to female Wistar rats was determined in a GLP-compliant, fixed-dose method study following OECD guideline 420 (Latour 2015). A preliminary study indicated no mortality of a single rat at 2000 mg/kg bw Dilithium azelate, therefore 2000 mg/kg bw was selected for the main study which was conducted in a stepwise approach on three further animals. Dilithium azelate was dosed by oral gavage and the rats were observed for mortality, systemic toxicity and bodyweight gain.When two animals were found dead at 2000 mg/kg bw, five animals were treated at a lower dose level of 300 mg/kg bw for 15 days. No deaths or significant signs of toxicity were observed at 300 mg/kg bw Dilithium azelate. The oral LD50 value is within the range 300 mg/kg bw - 2000 mg/kg bw Dilthium azelate. Based on these results Dilithium azelate should be classified as Category 4. The study is considered to be relevant and reliable for use for this endpoint.

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
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Further information is included under 'Attached justification' in IUCLID section 13 and 'Cross-reference'.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
according to guideline
Guideline:
other: 96/54 EC, B.1tris (Acute Toxic Class Method)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Wistar Hsd Brl: WH
Vehicle:
other: Carboxymethylcellulose (1 % in aqua dest.)
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
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:
Signs of toxicity related to dose levels: None
Gross pathology:
Effects on organs: None
Interpretation of results:
GHS criteria not met
Conclusions:
Interpretation of results: not classified.
Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Further information is included under 'Attached justification' in IUCLID section 13 and 'Cross-reference'.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
other: 96/54 EC, B.1tris (Acute Toxic Class Method)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Wistar Hsd Brl: WH
Vehicle:
other: carboxymethylcellulose (1% in aqua dest.)
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
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:
Signs of toxicity related to dose levels: None
Gross pathology:
Effects on organs: None
Interpretation of results:
GHS criteria not met
Conclusions:
Interpretation of results: not classified.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
High, the studies are GLP-compliant, guideline studies, and therefore are considered reliable.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No data on acute toxicity by oral route is available for the substance reaction mass of amines, hydrogenated tallow alkyl and azelaic acid and lithium hydroxide. Read across from dilithium azelate and reaction mixture of hydrogenated tallow alkyl amines with sebacic acid and lithium hydroxide is used to complete this endpoint. 

The acute oral study with reaction mixture of hydrogenated tallow alkyl amines with sebacic acid and lithium hydroxide was conducted to EU guideline (98/54 EC. B. tris Acute Toxic Class method) and is GLP compliant. Three male and three female Wistar rats were orally administered 2000 mg/kg bw of the test substance in carboxymethylcellulose (1 % in aqua dest.). The LD50 value was >2000 mg/kg bw. Based on the study results no classification was required. The study has been used as key study in the NONS dossier for the source substance and has been used to conclude on the hazard assessment and classification of the substance. Therefore, the data are considered to be reliable and adequate for assessment of the hazards of the substance. No Klimisch scores have been assigned by the original registrants and little detail is included in the robust study summary provided for the source substance but the study is GLP-compliant, guideline study, and therefore is considered reliable.

 

The acute oral toxicity of dilithium azelate to female Wistar rats was determined in a GLP-compliant, fixed-dose method study following OECD guideline 420. The oral LD50 value is within the range 300 mg/kg bw - 2000 mg/kg bw. Based on these results it was concluded that the substance Dilithium azelate should be classified as Category 4. The study is considered to be relevant and reliable for use for this endpoint.

Reaction mass of amines, hydrogenated tallow alkyl and azelaic acid and lithium hydroxideis exclusively manufactured in situ in base oil and not in isolated form. The melting point is greater than 300°C, so the potential for the generation of inhalable forms is low, also the use of the grease forms will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur. In accordance with REACH Regulation, Annex VIII, 8.6.1, column 2 as well as Annex XI, 1, the performance of acute inhalation toxicity studies is not justified due to exposure as well as toxicological considerations.

The acute dermal toxicity testing is waived on the basis that the lithium-azelate-amine reaction mass is expected, based on read across, not to meet the criteria for classification for acute toxicity or STOT SE by the oral route and no systemic effects after dermal exposure is expected.

Justification for classification or non-classification

As the reaction mass of lithium hydroxide, sebacic acid and hydrogenated tallow alkyl amines is not classified, it is considered that the organic components of the reaction mass of amines, hydrogenated tallow alkyl and azelaic acid and lithium hydroxide would not contribute to the acute toxicity of the substance. Dilithium azelate is classified, however, this is expected to relate to the concentration of lithium ions present in the substance. On this basis, the reaction mass of amines, hydrogenated tallow alkyl and azelaic acid and lithium hydroxide is not expected to be classified for acute oral toxicity.

As the organic component is not an important factor for acute oral toxicity, the focus for acute oral toxicity resides with the lithium ion. Regarding the lithium ion, the lowest of several oral LD50 values for partially soluble lithium carbonate quoted in the ECHA Dissemination Portal file is 525 mg/kg based on a report in RTECS (and a very similar value of 526 mg/kg was also reported for lithium chloride). On the basis of atomic and molecular weight considerations (atomic weight of lithium being 6.94 g/mol, the molecular weight of Li2CO3 is 73.89 g/mol), 525 mg of Li2CO3 is equivalent to 98.63 mg lithium. Extrapolating this to dilithium azelate (MW 200.1 g/mol), 98.63 mg lithium is equivalent to 1421.2 mg/kg of the salt. The value is within the upper classification limit of acute toxicity (2000 mg/kg), supporting the lithium content being the driver for classification of the salt as acute toxicity category 4.

Applying the same logic to reaction mass of amines, hydrogenated tallow alkyl and azelaic acid and lithium hydroxide, which has a typical lithium content of around 4.15%, 98.63 mg/L is equivalent to 2376.6 mg/kg, which is above the criteria for classification as acute oral toxicity (2000 mg/kg). Therefore, reaction mass of amines, hydrogenated tallow alkyl and azelaic acid and lithium hydroxide would not meet the criteria for classification for acute oral toxicity.