Tall oil, reaction products with ethanolamine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Toxicokinetic assessment using physico-chemical properties and toxicological study data.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Toxicokinetic assessment using reliable physico-chemical properties and toxicological study data.

Materials and methods

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

The toxicokinetic profile of the test item was predicted using the physical chemical properties of the substance, the data obtained from acute and repeated-dose toxicity studies, as well as information gained from genotoxicity assays.

Test material

Test material information

Constituent 1

Reference substance name:

Tall oil, reaction products with ethanolamine

IUPAC Name:

Tall oil, reaction products with ethanolamine

Test material form:

semi-solid (amorphous): gel

Details on test material:

- Purity: 100%
- Physical state/Appearance: Brown gel
- Storage Conditions: Room temperature in the dark

Specific details on test material used for the study:

The test item is a UVCB with an average molecular weight of approximately 475. The substance is poorly water soluble at 5.2 x 10-5g/L, with a very high estimated octanol/water partition coefficient, log Pow 6.02 to >10.0 (which is >4, the bioaccumulation limit), and a low vapour pressure (1.69 x 10-2Pa @ 25oC). The surface tension of the substance has not been determined because of the low water solubility and the substance is considered not to dissociate at environmental pH.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

- Oral Route: The physical chemical properties described indicate that test item in an organic UVCB with an average molecular size of approximately ~475, however the molecular weight is expected to range from 302 to >600. Although a significant amount of the substance is expected have a molecular weight above the limit for exclusion, it may be expected that some will be within the range for passive absorption based on molecular weight alone. However, being highly lipophilic but with a Log Pow of 6.02 to >10, the test item may be expected not to easily cross gastrointestinal epithelial barriers. It may participate in micellar transport into the hepatic portal system along with other lipophilic substances (e.g., dietary fats), although this is considered unlikely because of the absence of ionic and surfactant properties. An acute oral gavage toxicity study identified no evidence of toxicity (LD50 >2000 mg/kg bw). The repeat dose and reproductive screening toxicology study using the oral route gave a NOAEL of 1000 mg/kg bw/day. The absence of adverse findings following oral dosing may be due to limited gastrointestinal absorption of the test material after dosing, or a very low index of inherent toxicity for this substance, and/or its metabolite(s). However, the absence of systemic effects indicates the likely absence of, or very low, potential for absorption of Tall-oil, reaction products with ethanolamine, or its metabolites, or at least some components of this UVCB substance.
- Dermal route: Regarding the dermal absorption of the test item, its rate of uptake into the stratum corneum and its rate of transfer between the stratum corneum and the epidermis are likely to be slow considering the high log Pow 6.02 to >10. Moreover, it is assumed that the dermal uptake of the test item is also limited based on its low water solubility (5.2-5g/L)1,2. These assumptions were supported by the absence of observed systemic effects following dermal application of the test item in the acute dermal toxicity study at up to 2000 mg/kg bw.
- Inhalation route: The potential for inhalation toxicity was not studied directly in a toxicology study using the inhalation route. However, the physical nature of the substance (a gel) low vapour pressure of the test item (1.69 x 10-2Pa) indicate a very low propensity to enter atmospheric air in a respirable form. Thus, respiratory absorption under normal use and based on the life-cycle information of this substance, is expected to be inconsequential.

Details on distribution in tissues:

Systemic distribution of the test item can be predicted from the physical chemical properties of this substance. The relatively high log Pow and poor water solubility suggests that this substance, upon systemic absorption, may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or other macromolecule. The lipophilic character but low water solubility and MW of the test item suggests that a major proportion of the substance will not readily traverse cellular barriers or distribute into fatty tissues. There is no evidence of systemic toxicity and/or histopathological changes or increasing severity of clinical observations from repeated dose studies, nor of cumulative toxicity, as would be manifested by an accumulation of the test item or metabolites in tissues.

Details on excretion:

The structural characteristics of the test item suggest that this molecule may undergo phase I and phase II metabolic transformation. The resulting metabolic by-products are expected to undergo routine renal and or biliary excretion.

Metabolite characterisation studies

Details on metabolites:

The test item is a UVCB. Like most xenobiotics, it may be expected to undergo phase I oxidation/reduction, esterase-catalyzed hydrolysis and subsequent Phase II conjugation. Acute and repeated-dose toxicity testing provided no evidence that the test item was metabolized into toxic metabolites. Data from bacteria mutagenicity and chromosomal aberration in mammalian cells, in which the test item was subjected to rat hepatic microsomal enzyme systems did not show any evidence of genotoxic activity from the substance or its metabolites. Furthermore, the in vitro toxicity of the test item was slightly reduced in the presence of metabolic enzymes. This may indicate that the metabolites may be less toxic than the substance itself but more likely that the presence of protein may bind the substance, or protect the cells, such that the toxicity is reduced.

Applicant's summary and conclusion

Conclusions:

The toxicokinetic profile of the test item was predicted using the physical chemical properties of the substance, the data obtained from acute and repeated-dose toxicity studies, as well as information gained from genotoxicity assays.

Physico-chemical properties
The test item is a UVCB with an average molecular weight of approximately 475. The substance is poorly water soluble at 5.2 x 10-5g/L, with a very high estimated octanol/water partition coefficient, log Pow6.02 to >10.0 (which is >4, the bioaccumulation limit), and a low vapour pressure (1.69 x 10-2Pa @ 25oC). The surface tension of the substance has not been determined because of the low water solubility and the substance is considered not to dissociate at environmental pH.

- Oral Route: The physical chemical properties described indicate that test item in an organic UVCB with an average molecular size of approximately ~475, however the molecular weight is expected to range from 302 to >600. Although a significant amount of the substance is expected have a molecular weight above the limit for exclusion, it may be expected that some will be within the range for passive absorption based on molecular weight alone. However, being highly lipophilic but with a Log Pow of 6.02 to >10, the test item may be expected not to easily cross gastrointestinal epithelial barriers. It may participate in micellar transport into the hepatic portal system along with other lipophilic substances (e.g., dietary fats), although this is considered unlikely because of the absence of ionic and surfactant properties. An acute oral gavage toxicity study identified no evidence of toxicity (LD50 >2000 mg/kg bw). The repeat dose and reproductive screening toxicology study using the oral route gave a NOAEL of 1000 mg/kg bw/day. The absence of adverse findings following oral dosing may be due to limited gastrointestinal absorption of the test material after dosing, or a very low index of inherent toxicity for this substance, and/or its metabolite(s). However, the absence of systemic effects indicates the likely absence of, or very low, potential for absorption of Tall-oil, reaction products with ethanolamine, or its metabolites, or at least some components of this UVCB substance.
- Dermal route: Regarding the dermal absorption of the test item, its rate of uptake into the stratum corneum and its rate of transfer between the stratum corneum and the epidermis are likely to be slow considering the high log Pow 6.02 to >10. Moreover, it is assumed that the dermal uptake of the test item is also limited based on its low water solubility (5.2-5g/L)1,2. These assumptions were supported by the absence of observed systemic effects following dermal application of the test item in the acute dermal toxicity study at up to 2000 mg/kg bw.
- Inhalation route: The potential for inhalation toxicity was not studied directly in a toxicology study using the inhalation route. However, the physical nature of the substance (a gel) low vapour pressure of the test item (1.69 x 10-2Pa) indicate a very low propensity to enter atmospheric air in a respirable form. Thus, respiratory absorption under normal use and based on the life-cycle information of this substance, is expected to be inconsequential.

Distribution
Systemic distribution of the test item can be predicted from the physical chemical properties of this substance. The relatively high log Pow and poor water solubility suggests that this substance, upon systemic absorption, may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or other macromolecule. The lipophilic character but low water solubility and MW of the test item suggests that a major proportion of the substance will not readily traverse cellular barriers or distribute into fatty tissues. There is no evidence of systemic toxicity and/or histopathological changes or increasing severity of clinical observations from repeated dose studies, nor of cumulative toxicity, as would be manifested by an accumulation of the test item or metabolites in tissues.

Metabolism
The test item is a UVCB. Like most xenobiotics, it may be expected to undergo phase I oxidation/reduction, esterase-catalyzed hydrolysis and subsequent Phase II conjugation. Acute and repeated-dose toxicity testing provided no evidence that the test item was metabolized into toxic metabolites. Data from bacteria mutagenicity and chromosomal aberration in mammalian cells, in which the test item was subjected to rat hepatic microsomal enzyme systems did not show any evidence of genotoxic activity from the substance or its metabolites. Furthermore, the in vitro toxicity of the test item was slightly reduced in the presence of metabolic enzymes. This may indicate that the metabolites may be less toxic than the substance itself but more likely that the presence of protein may bind the substance, or protect the cells, such that the toxicity is reduced.

Excretion
The structural characteristics of the test item suggest that this molecule may undergo phase I and phase II metabolic transformation. The resulting metabolic by-products are expected to undergo routine renal and or biliary excretion.

Executive summary:

The toxicokinetic profile of the test item was predicted using the physical chemical properties of the substance, the data obtained from acute and repeated-dose toxicity studies, as well as information gained from genotoxicity assays.

Physico-chemical properties

The test item is a UVCB with an average molecular weight of approximately 475. The substance is poorly water soluble at 5.2 x 10-5g/L, with a very high estimated octanol/water partition coefficient, log Pow6.02 to > 10.0 (which is >4, the bioaccumulation limit), and a low vapour pressure (1.69 x 10-2Pa @ 25 °C). The surface tension of the substance has not been determined because of the low water solubility and the substance is considered not to dissociate at environmental pH.

Absorption

- Oral Route: The physical chemical properties described indicate that test item in an organic UVCB with an average molecular size of approximately ~475, however the molecular weight is expected to range from 302 to >600. Although a significant amount of the substance is expected have a molecular weight above the limit for exclusion, it may be expected that some will be within the range for passive absorption based on molecular weight alone. However, being highly lipophilic but with a Log Pow of 6.02 to >10, the test item may be expected not to easily cross gastrointestinal epithelial barriers. It may participate in micellar transport into the hepatic portal system along with other lipophilic substances (e.g., dietary fats), although this is considered unlikely because of the absence of ionic and surfactant properties. An acute oral gavage toxicity study identified no evidence of toxicity (LD50 >2000 mg/kg bw). The repeat dose and reproductive screening toxicology study using the oral route gave a NOAEL of 1000 mg/kg bw/day. The absence of adverse findings following oral dosing may be due to limited gastrointestinal absorption of the test material after dosing, or a very low index of inherent toxicity for this substance, and/or its metabolite(s). However, the absence of systemic effects indicates the likely absence of, or very low, potential for absorption of Tall-oil, reaction products with ethanolamine, or its metabolites, or at least some components of this UVCB substance.

- Dermal route: Regarding the dermal absorption of the test item, its rate of uptake into the stratum corneum and its rate of transfer between the stratum corneum and the epidermis are likely to be slow considering the high log Pow 6.02 to >10. Moreover, it is assumed that the dermal uptake of the test item is also limited based on its low water solubility (5.2-5g/L)1,2. These assumptions were supported by the absence of observed systemic effects following dermal application of the test item in the acute dermal toxicity study at up to 2000 mg/kg bw.

- Inhalation route: The potential for inhalation toxicity was not studied directly in a toxicology study using the inhalation route. However, the physical nature of the substance (a gel) low vapour pressure of the test item (1.69 x 10-2Pa) indicate a very low propensity to enter atmospheric air in a respirable form. Thus, respiratory absorption under normal use and based on the life-cycle information of this substance, is expected to be inconsequential.

Distribution

Systemic distribution of the test item can be predicted from the physical chemical properties of this substance. The relatively high log Pow and poor water solubility suggests that this substance, upon systemic absorption, may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or other macromolecule. The lipophilic character but low water solubility and MW of the test item suggests that a major proportion of the substance will not readily traverse cellular barriers or distribute into fatty tissues. There is no evidence of systemic toxicity and/or histopathological changes or increasing severity of clinical observations from repeated dose studies, nor of cumulative toxicity, as would be manifested by an accumulation of the test item or metabolites in tissues.

Metabolism

The test item is a UVCB. Like most xenobiotics, it may be expected to undergo phase I oxidation/reduction, esterase-catalyzed hydrolysis and subsequent Phase II conjugation. Acute and repeated-dose toxicity testing provided no evidence that the test item was metabolized into toxic metabolites. Data from bacteria mutagenicity and chromosomal aberration in mammalian cells, in which the test item was subjected to rat hepatic microsomal enzyme systems did not show any evidence of genotoxic activity from the substance or its metabolites. Furthermore, the in vitro toxicity of the test item was slightly reduced in the presence of metabolic enzymes. This may indicate that the metabolites may be less toxic than the substance itself but more likely that the presence of protein may bind the substance, or protect the cells, such that the toxicity is reduced.

Excretion

The structural characteristics of the test item suggest that this molecule may undergo phase I and phase II metabolic transformation. The resulting metabolic by-products are expected to undergo routine renal and or biliary excretion.