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Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Type of information:
other: Toxicokinetic asessment based on the physicochemical properties of the substance and on the results of various in vitro and in vivo study results, including an OECD422 repeat dose and reproductive toxicity screening study.
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Based on toxicological data of the substance itself and on the physicochemical characteristics determined for the substance.
Qualifier:
according to
Guideline:
other: Expert statement
Deviations:
no
GLP compliance:
no
Details on absorption:
Oral Route
The physical chemical properties described above indicate that the substance has a molecular size at the upper end of the range that may be expected to be easily absorbed within the mammalian gastrointestinal tract, should that material be ingested. Being a mix of components with both lipophilic and hydrophilic properties the substance may be expected to cross gastrointestinal epithelial barriers, and the evidence from the repeated dose toxicity study indicates that absorption did occur because there were dose-related increases in liver organ weights. 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 600 mg/kg bw/day, the upper dose level being limited by local irritation effects in the intestine. The absence of adverse findings following oral dosing is probably due to a low index of inherent toxicity for this substance, and/or its metabolite(s).

Dermal Route
Regarding the dermal absorption of the substance, 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 both the high MW, the log Pow, and its low water solubility. These assumptions were supported by the absence of observed systemic effects following dermal application of the substance in the acute dermal toxicity study at up to 2000 mg/kg bw. However, the substance causes irritant effects after dermal exposure (although not classified for skin irritation) and this may facilitate absorption through the skin after prolonged exposure.

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 (semi-solid) and low vapour pressure of the substance 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 substance can be predicted from the physical chemical properties of this substance. The relatively low LogPow and poor water solubility of the majority of the substance, suggests that this substance, upon systemic absorption, may be transported through the circulatory system both in the aqueous phase and in association with a carrier molecule such as a lipoprotein or other macromolecules. The major proportion of the substance will not readily traverse cellular barriers or distribute into fatty tissues. There is evidence of systemic exposure and histopathological changes in repeated dose studies, but not of cumulative toxicity, as would be manifested by an accumulation of the substance or metabolites in tissues.

The substance is a UVCB and 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 substance was metabolized into toxic metabolites. Data from bacterial mutagenicity and mammalian cell mutagenicity tests in mammalian cells, in which the substance 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 substance 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.
Details on excretion:
The structural characteristics of the substance 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.
Key result
Test no.:
#1
Toxicokinetic parameters:
other: Please see conclusion
Conclusions:

Toxicokinetic assessment of the test substance
 
The toxicokinetic profile of the substance 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 substance is a yellow, semi-solid UVCB and the molecular weight of the major components is in the range of 395.6 to 475.5 with the majority at the upper end of the range. The substance is water soluble but loading rate dependent, such that no single figure may be given. However, at a 10% loading rate the range for four of the major components is 4.14 x 10-2to 59.5 g/L, with an estimated octanol/water partition coefficient in the range of log Pow-9.88 x 10-2to 2.68, and a low vapour pressure (0.254 Pa @ 25oC). The surface tension of the substance was 40.0 mN/m at 21.8°C and the substance is considered to be surface active. The majority of the substance components are salts and considered to dissociate.
 
Absorption
 
Oral Route
The physical chemical properties described above indicate that the substance has a molecular size at the upper end of the range that may be expected to be easily absorbed within the mammalian gastrointestinal tract, should that material be ingested. Being a mix of components with both lipophilic and hydrophilic properties the substance may be expected to cross gastrointestinal epithelial barriers, and the evidence from the repeated dose toxicity study indicates that absorption did occur because there were dose-related increases in liver organ weights. 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 600 mg/kg bw/day, the upper dose level being limited by local irritation effects in the intestine. The absence of adverse findings following oral dosing is probably due to a low index of inherent toxicity for this substance, and/or its metabolite(s).
 
 
Dermal Route
Regarding the dermal absorption of the substance, 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 both the high MW, the log Pow, and its low water solubility. These assumptions were supported by the absence of observed systemic effects following dermal application of the substance in the acute dermal toxicity study at up to 2000 mg/kg bw. However, the substance causes irritant effects after dermal exposure (although not classified for skin irritation) and this may facilitate absorption through the skin after prolonged exposure.
 
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 (semi-solid) and low vapour pressure of the substance 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 substance can be predicted from the physical chemical properties of this substance. The relatively low LogPow and poor water solubility of the majority of the substance, suggests that this substance, upon systemic absorption, may be transported through the circulatory system both in the aqueous phase and in association with a carrier molecule such as a lipoprotein or other macromolecules. The major proportion of the substance will not readily traverse cellular barriers or distribute into fatty tissues. There is evidence of systemic exposure and histopathological changes in repeated dose studies, but not of cumulative toxicity, as would be manifested by an accumulation of the substance or metabolites in tissues.
 
Metabolism
 
The substance is a UVCB and 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 substance was metabolized into toxic metabolites. Data from bacterial mutagenicity and mammalian cell mutagenicity tests in mammalian cells, in which the substance 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 substance 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 substance 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:

Toxicokinetic assessment of the test substance

The toxicokinetic profile of the substance 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 substance is a yellow, semi-solid UVCB and the molecular weight of the major components is in the range of 395.6 to 475.5 with the majority at the upper end of the range. The substance is water soluble but loading rate dependent, such that no single figure may be given. However, at a 10% loading rate the range for four of the major components is 4.14 x 10E-2 to 59.5 g/L, with an estimated octanol/water partition coefficient in the range of log Pow-9.88 x 10E-2 to 2.68, and a low vapour pressure (0.254 Pa @ 25oC). The surface tension of the substance was 40.0 mN/m at 21.8°C and the substance is considered to be surface active. The majority of the substance components are salts and considered to dissociate.

 

Absorption

Oral Route

The physical chemical properties described above indicate that the substance has a molecular size at the upper end of the range that may be expected to be easily absorbed within the mammalian gastrointestinal tract, should that material be ingested. Being a mix of components with both lipophilic and hydrophilic properties the substance may be expected to cross gastrointestinal epithelial barriers, and the evidence from the repeated dose toxicity study indicates that absorption did occur because there were dose-related increases in liver organ weights. 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 600 mg/kg bw/day, the upper dose level being limited by local irritation effects in the intestine. The absence of adverse findings following oral dosing is probably due to a low index of inherent toxicity for this substance, and/or its metabolite(s).

 

Dermal Route

Regarding the dermal absorption of the substance, 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 both the high MW, the log Pow, and its low water solubility. These assumptions were supported by the absence of observed systemic effects following dermal application of the substance in the acute dermal toxicity study at up to 2000 mg/kg bw. However, the substance causes irritant effects after dermal exposure (although not classified for skin irritation) and this may facilitate absorption through the skin after prolonged exposure.

 

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 (semi-solid) and low vapour pressure of the substance 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 substance can be predicted from the physical chemical properties of this substance. The relatively low LogPow and poor water solubility of the majority of the substance, suggests that this substance, upon systemic absorption, may be transported through the circulatory system both in the aqueous phase and in association with a carrier molecule such as a lipoprotein or other macromolecules. The major proportion of the substance will not readily traverse cellular barriers or distribute into fatty tissues. There is evidence of systemic exposure and histopathological changes in repeated dose studies, but not of cumulative toxicity, as would be manifested by an accumulation of the substance or metabolites in tissues.

 

Metabolism

The substance is a UVCB and 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 substance was metabolized into toxic metabolites. Data from bacterial mutagenicity and mammalian cell mutagenicity tests in mammalian cells, in which the substance 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 substance 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 substance 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.

Description of key information

Toxicokinetic assessment of the test substance

 

The toxicokinetic profile of the substance 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 substance is a yellow, semi-solid UVCB and the molecular weight of the major components is in the range of 395.6 to 475.5 with the majority at the upper end of the range. The substance is water soluble but loading rate dependent, such that no single figure may be given. However, at a 10% loading rate the range for four of the major components is 4.14 x 10-2to 59.5 g/L, with an estimated octanol/water partition coefficient in the range of log Pow-9.88 x 10-2to 2.68, and a low vapour pressure (0.254 Pa @ 25oC). The surface tension of the substance was 40.0 mN/m at 21.8°C and the substance is considered to be surface active. The majority of the substance components are salts and considered to dissociate.

 

Absorption

 

Oral Route

The physical chemical properties described above indicate that the substance has a molecular size at the upper end of the range that may be expected to be easily absorbed within the mammalian gastrointestinal tract, should that material be ingested. Being a mix of components with both lipophilic and hydrophilic properties the substance may be expected to cross gastrointestinal epithelial barriers, and the evidence from the repeated dose toxicity study indicates that absorption did occur because there were dose-related increases in liver organ weights. 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 600 mg/kg bw/day, the upper dose level being limited by local irritation effects in the intestine. The absence of adverse findings following oral dosing is probably due to a low index of inherent toxicity for this substance, and/or its metabolite(s).

 

 

Dermal Route

Regarding the dermal absorption of the substance, 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 both the high MW, the log Pow, and its low water solubility. These assumptions were supported by the absence of observed systemic effects following dermal application of the substance in the acute dermal toxicity study at up to 2000 mg/kg bw. However, the substance causes irritant effects after dermal exposure (although not classified for skin irritation) and this may facilitate absorption through the skin after prolonged exposure.

 

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 (semi-solid) and low vapour pressure of the substance 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 substance can be predicted from the physical chemical properties of this substance. The relatively low LogPow and poor water solubility of the majority of the substance, suggests that this substance, upon systemic absorption, may be transported through the circulatory system both in the aqueous phase and in association with a carrier molecule such as a lipoprotein or other macromolecules. The major proportion of the substance will not readily traverse cellular barriers or distribute into fatty tissues. There is evidence of systemic exposure and histopathological changes in repeated dose studies, but not of cumulative toxicity, as would be manifested by an accumulation of the substance or metabolites in tissues.

 

Metabolism

 

The substance is a UVCB and 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 substance was metabolized into toxic metabolites. Data from bacterial mutagenicity and mammalian cell mutagenicity tests in mammalian cells, in which the substance 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 substance 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 substance 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.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information