Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Expert Statement
Adequacy of study:
key study
Study period:
2013
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: All available information was evaluated, though no explicit studies on toxikokinetics (ADME) were available

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2013
Report Date:
2013

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
All available physical, chemical and toxicological information was evaluated, though no explicit studies on toxikokinetics (ADME) were available
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Evaluation and Assessment of the Basic Toxicokinetic Properties of
Fatty acids, C16-18, reaction products with di-ethanolamine


Introduction:

Toxicokinetic parameters such as uptake, distribution, metabolism and excretion form part of the essential toxicological profile of a substance. Although the toxicokinetic behaviour of substances does not describe a toxicological endpoint itself, an approximate indication of the individual toxicokinetic parameters absorption, distribution, metabolism and excretion (ADME) can be gained from the results of basic toxicity testing. In this respect the following evaluation discusses results and observations from basic toxicity studies which can be used as approximate indications for the description of every individual toxicokinetic parameter. Such an approach is also justified by animal welfare considerations because additional animal testing can be avoided. The assessment of the toxicokinetic properties of Fatty acids, C16-18, reaction products with di-ethanolamine given below is based on the results obtained for the following toxicological endpoints:


• Acute oral toxicity
• Acute dermal toxicity
• Skin irritation
• Eye Irritation
• Skin sensitisation
• In vitro mutagenicity assays
• Subacute (OECD 422) oral toxicity


All of these studies were carried out according to the principles of Good Laboratory Practice and met the requirements of the OECD and EU-Guidelines for the Testing of Chemicals.


Simultaneously reference to physico-chemical data such as solubility, log Pow and hydrolytic stability are included in the evaluation. This information gives additional indications regarding special toxicokinetic parameters, e.g. distribution, metabolism and excretion.




Substance Identity:

Fatty acids, C16-18, reaction products with di-ethanolamine is produced by condensing 1 molecule of di-ethanolamine with 2 molecules of fatty acid. The result is a mixture (UVCB) of several ester-amides (main constituents) and di-ester-amides (main side-products) of the fatty acids. The molecular weights vary between about 600 and 900 Dalton. The material is available as a yellow solid.

Toxicological Profile:

Fatty acids, C16-18, reaction products with di-ethanolamine was tested for acute oral and dermal toxicity in male and female rats. After application of 2000 mg/kg body weight by gavage no dose-related lethality or clinical symptoms were observed. Body weight development was not influenced. Macroscopically visible changes were not observed. Based on these results the median lethal doses (dermal & oral, LD50) of the test material in the rat are greater than 2000 mg/kg body weight.

The test material is not irritating to the skin and is only slightly irritating to mucous membranes (no classified).

Testing for sensitizing properties in mice using the LLNA test revealed that Fatty acids, C16-18, reaction products with di-ethanolamine is not a skin sensitizer.

Fatty acids, C16-18, reaction products with di-ethanolamine gave negative results in Ames tests with S. typhimurium with and without metabolic activation and it did not induce mutations at the HGPRT locus in V 79 cells of the Chinese hamster in vitro with and without S9-mix. It was also not clastogenic in an in vitro test in human lymphocytes.

Based on the results of a subacute (>/=28-day) oral and reproductive toxicity study with Fatty acids, C16-18, reaction products with di-ethanolamine, daily administration of doses of 0, 100, 300 and 1000 mg/kg body weight to rats has not caused compound-related toxicity. The general health status of the animals was not altered. A `No Observed Adverse Effect Level` (NOAEL) of 1000 mg test material per kg body weight per day was established.


Evaluation and Assessment of the Toxicokinetic Profile:

Taking all available toxicological tests into account, qualitative estimates for ADME-parameters are possible.

Absorption:
Based on the subacute (28-day) oral toxicity study only absorption of toxicologically not significant amounts of Fatty acids, C16-18, reaction products with di-ethanolamine via the gastrointestinal tract has to be assumed since no obvious signs of toxicity were observed throughout the study.
The skin irritation and sensitisation studies indicate very little, if any, dermal bioavailability. Systemic availability via skin seems to be negligible since no systemic signs of intoxication were seen after occlusive administration of 2000 mg of Fatty acids, C16-18, reaction products with di-ethanolamine per kg body weight in rats in the acute dermal toxicity study. Indications of a significant dermal absorptive potential were also not revealed by testing for primary irritation in vitro.

Distribution:
Based on the results of the subacute oral toxicity study no substance related findings were observed in any of the examined tissues. Thus it can be concluded, that either Fatty acids, C16-18, reaction products with di-ethanolamine is absorbed only very slightly through the gastrointestinal tract and is expected to be systemically available within the organism only at very low concentrations or degradation into innocuous metabolites is sufficient to protect the organism form damage. Histopathological findings do not indicate a deposition/accumulation of the material in specific tissues, although the physical-chemical properties (solubility in water) and the molecular structure clearly indicate lipophilicity.

Metabolism:
Fatty acids, C16-18, reaction products with di-ethanolamine proved to be inactive in almost all toxicological experiments performed. No effects were seen in the subacute study. No functional or structural impairments were detected. Therefore, Fatty acids, C16-18, reaction products with di-ethanolamine is considered to mostly just pass through the intestine without quantitatively significant bioavailability and, hence, metabolism.
Metabolites, if any are formed, appear less toxic than the parent compound. It is considered likely that the fraction of the material becoming bio-available in the organism is small and undergoes relatively easy hydrolysis to produce small amounts of fatty acids and di-ethanolamine. The fatty acids are likely to be channelled into the normal fatty acid metabolism to produce carbon dioxide and water, while di-ethanolamine as an easily water soluble molecule is excreted directly, metabolised to conjugates or degraded. Accumulation in membrane lipids is not likely due to the low internal exposure concentrations.
At extremely high, unrealistic doses the capacity of the excretion mechanisms for di-ethanolamine might become exhausted leading to deposition of the di-ethanolamine derivatives in tissue membranes.

Excretion:
Taking into account the physico-chemical properties and the molecular structure of the material it can be assumed that only very little of the absorbed dose will be excreted. The small fraction absorbed is assumed to be metabolised completely.


Conclusion:

Based on all available data, Fatty acids, C16-18, reaction products with di-ethanolamine does not exhibit conspicuous toxicokinetic behaviour in the sense of accumulative and/or delayed effects with regard to the individual parameters absorption, distribution, metabolism and excretion.
The results from studies with dermal exposure indicate that Fatty acids, C16-18, reaction products with di-ethanolamine has a very small dermal absorptive potential. Fatty acids, C16-18, reaction products with di-ethanolamine is unlikely to be absorbed from the gastrointestinal tract in significant amounts. The small fraction absorbed is assumed to be distributed throughout the body. Metabolism most likely occurs in the liver in analogy to normal fat metabolism. Indications of a bio-accumulative potential do not exist as no delayed toxicity occurred.

Summary:

Based on the available data base on Fatty acids, C16-18, reaction products with di-ethanolamine relevant information exists to make a qualitative evaluation of the toxicokinetic profile of this compound. This is in line with animal welfare considerations because additional animal tests can be avoided by such an evaluation.

The results of basic toxicity testing give no reason to anticipate unusual characteristics with regard to the toxico-kinetics of Fatty acids, C16-18, reaction products with di-ethanolamine. The data indicate that there is little systemic availability via skin or the gastro-intestinal tract. Fatty acids, C16-18, reaction products with di-ethanolamine may be absorbed from the gastro-intestinal tract in small amounts. Indications of a bio-accumulative potential do not exist. Metabolism of systemically available Fatty acids, C16-18, reaction products with di-ethanolamine is likely to occur mainly in the liver and metabolites are expected to be excreted via the kidney or completely degraded to carbon dioxide and water.
Executive summary:

Evaluation and Assessment of the Basic Toxicokinetic Properties of Fatty acids, C16-18, reaction products with di-ethanolamine

 

Introduction:

 

Toxicokinetic parameters such as uptake, distribution, metabolism and excretion form part of the essential toxicological profile of a substance. Although the toxicokinetic behaviour of substances does not describe a toxicological endpoint itself, an approximate indication of the individual toxicokinetic parameters absorption, distribution, metabolism and excretion (ADME) can be gained from the results of basic toxicity testing. In this respect the following evaluation discusses results and observations from basic toxicity studies which can be used as approximate indications for the description of every individual toxicokinetic parameter. Such an approach is also justified by animal welfare considerations because additional animal testing can be avoided. The assessment of the toxicokinetic properties ofFatty acids, C16-18, reaction products with di-ethanolaminegiven below is based on the results obtained for the following toxicological endpoints:

 

 

·               Acute oral toxicity

·               Acute dermal toxicity

·               Skin irritation

·               Eye Irritation

·               Skin sensitisation

·               In vitro mutagenicity assays

·               Subacute (OECD 422) oral toxicity

 

 

All of these studies were carried out according to the principles of Good Laboratory Practice and met the requirements of the OECD and EU-Guidelines for the Testing of Chemicals.

 

 

Simultaneously reference to physico-chemical data such as solubility, log Powand hydrolytic stability are included in the evaluation. This information gives additional indications regarding special toxicokinetic parameters, e.g. distribution, metabolism and excretion.

 


 

 

Substance Identity:

 

Fatty acids, C16-18, reaction products with di-ethanolamine is produced by condensing 1 molecule of di-ethanolamine with 2 molecules of fatty acid. The result is a mixture (UVCB) of several ester-amides (main constituents) and di-ester-amides (main side-products) of the fatty acids. The molecular weights vary between about 600 and 900 Dalton. The material is available as a yellow solid.

 

Toxicological Profile:

 

Fatty acids, C16-18, reaction products with di-ethanolamine was tested for acute oral and dermal toxicity in male and female rats. After application of 2000 mg/kg body weight by gavage no dose-related lethality or clinical symptoms were observed. Body weight development was not influenced. Macroscopically visible changes were not observed. Based on these results the median lethal doses (dermal & oral, LD50) of the test material in the rat are greater than2000 mg/kg body weight.

 

The test material is not irritating to the skin and is only slightly irritating to mucous membranes (no classified).

 

Testing for sensitizing properties in mice using the LLNA test revealed that Fatty acids, C16-18, reaction products with di-ethanolamine is not a skin sensitizer.

 

Fatty acids, C16-18, reaction products with di-ethanolamine gave negative results in Ames tests with S. typhimurium with and without metabolic activation and it did not induce mutations at the HGPRT locus in V 79 cells of the Chinese hamster in vitro with and without S9-mix. It was also not clastogenic in an in vitro test in human lymphocytes.

 

Based on the results of a subacute (>/=28-day) oral and reproductive toxicity study with Fatty acids, C16-18, reaction products with di-ethanolamine, daily administration of doses of 0, 100, 300 and 1000 mg/kg body weight to rats has not caused compound-related toxicity. The general health status of the animals was not altered. A `No Observed Adverse Effect Level` (NOAEL) of 1000 mg test material per kg body weight per day was established.


 

Evaluation and Assessment of the Toxicokinetic Profile:

 

Taking all available toxicological tests into account, qualitative estimates for ADME-parameters are possible.

 

Absorption:

Based on the subacute (28-day) oral toxicity study only absorption of toxicologically not significant amounts of Fatty acids, C16-18, reaction products with di-ethanolamine via the gastrointestinal tract has to be assumed since no obvious signs of toxicity were observed throughout the study.

The skin irritation and sensitisation studies indicate very little, if any, dermal bioavailability.Systemic availability via skin seems to be negligible since no systemic signs of intoxication were seen after occlusive administration of 2000 mg of Fatty acids, C16-18, reaction products with di-ethanolamine per kg body weight in rats in the acute dermal toxicity study. Indications of a significant dermal absorptive potential were also not revealed by testing for primary irritation in vitro.

 

Distribution:

Based on the results of the subacute oral toxicity study no substance related findings were observed in any of the examined tissues. Thus it can be concluded, that either Fatty acids, C16-18, reaction products with di-ethanolamine is absorbed only very slightly through the gastrointestinal tract and is expected to be systemically available within the organism only at very low concentrations or degradation into innocuous metabolites is sufficient to protect the organism form damage. Histopathological findings do not indicate a deposition/accumulation of the material in specific tissues, although the physical-chemical properties (solubility in water) and the molecular structure clearly indicate lipophilicity.

 

Metabolism:

Fatty acids, C16-18, reaction products with di-ethanolamine proved to be inactive in almost all toxicological experiments performed. No effects were seen in the subacute study. No functional or structural impairments were detected. Therefore, Fatty acids, C16-18, reaction products with di-ethanolamine is considered to mostly just pass through the intestine without quantitatively significant bioavailability and, hence, metabolism.

Metabolites, if any are formed, appear less toxic than the parent compound. It is considered likely that the fraction of the material becoming bio-available in the organism is small and undergoes relatively easy hydrolysis to produce small amounts of fatty acids and di-ethanolamine. The fatty acids are likely to be channelled into the normal fatty acid metabolism to produce carbon dioxide and water, while di-ethanolamine as an easily water soluble molecule is excreted directly, metabolised to conjugates or degraded. Accumulation in membrane lipids is not likely due to the low internal exposure concentrations.

At extremely high, unrealistic doses the capacity of the excretion mechanisms for di-ethanolamine might become exhausted leading to deposition of the di-ethanolamine derivatives in tissue membranes.

 

Excretion:

Taking into account the physico-chemical properties and the molecular structure of the material it can be assumed that only very little of the absorbed dose will be excreted. The small fraction absorbed is assumed to be metabolised completely.


 

Conclusion:

 

Based on all available data, Fatty acids, C16-18, reaction products with di-ethanolamine does not exhibit conspicuous toxicokinetic behaviour in the sense of accumulative and/or delayed effects with regard to the individual parameters absorption, distribution, metabolism and excretion.

The results from studies with dermal exposure indicate that Fatty acids, C16-18, reaction products with di-ethanolamine has a very small dermal absorptive potential. Fatty acids, C16-18, reaction products with di-ethanolamine is unlikely to be absorbed from the gastrointestinal tract in significant amounts. The small fraction absorbed is assumed to be distributed throughout the body. Metabolism most likely occurs in the liver in analogy to normal fat metabolism. Indications of a bio-accumulative potential do not exist as no delayed toxicity occurred.

 

Summary:

 

Based on the available data base on Fatty acids, C16-18, reaction products with di-ethanolamine relevant information exists to make a qualitative evaluation of the toxicokinetic profile of this compound. This is in line with animal welfare considerations because additional animal tests can be avoided by such an evaluation.

 

The results of basic toxicity testing give no reason to anticipate unusual characteristics with regard to the toxico-kinetics of Fatty acids, C16-18, reaction products with di-ethanolamine. The data indicate that there is little systemic availability via skin or the gastro-intestinal tract. Fatty acids, C16-18, reaction products with di-ethanolamine may be absorbed from the gastro-intestinal tract in small amounts. Indications of a bio-accumulative potential do not exist. Metabolism of systemically available Fatty acids, C16-18, reaction products with di-ethanolamine is likely to occur mainly in the liver and metabolites are expected to be excreted via the kidney or completely degraded to carbon dioxide and water.