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Reference
Endpoint:
basic toxicokinetics, other
Remarks:
expert statement
Type of information:
other: expert statement
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The toxicokinetic profile of the test substance was assessed based on existing toxicity studies and the physical-chemical properties of the substance.
Objective of study:
absorption
distribution
excretion
toxicokinetics
Qualifier:
no guideline available
Principles of method if other than guideline:
The toxicokinetic profile of the test substance was assessed based on existing toxicity studies and the physical-chemical properties of the substance.
Type:
absorption
Results:
An absorption of 100% is assumed for the oral, dermal and inhalation route.
Type:
distribution
Results:
The test substance is expected to be distributed widely through the body via blood circulation. No accumulation is expected.
Type:
metabolism
Results:
There are no evidence of the importance of the metabolism.
Type:
excretion
Results:
The main excretion route is urinary excretion.
Details on absorption:
Absorption
A substance can enter the body via the gastrointestinal tract, the lungs, or the skin, depending on the route of exposure.

Oral absorption
After oral administration, in general, a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract. So, the water solubility of a substance is a crucial parameter. With an estimated water solubility of >1003 g/L at 20 °C, the test substance is considered to highly soluble in water (>10,000 mg/L). It is therefore to be expected that the test substance will readily dissolve into the gastrointestinal fluid.
Generally, the smaller the molecule the more easily it may be absorbed. The substance has molecular weight of 118 g/mol and thus below the guidance value of 500, below which absorption is favorable. Absorption from the gastro-intestinal lumen can occur by passive diffusion but also by specialized transport system. Asorption by passive diffusion is favoured for substances with moderate log P values (between -1 and 4). The test substance has a log P of 1.67, thus ready absorption by passive diffusion is expected.
In sum, based on the physicochemical properties of the test substance (i.e. moderate to high solubility in water and its ability to penetrate biomembranes related to its size and moderate log P value), high oral absorption is expected. This assumption is also supported by available toxicological studies. Absorption of the test substance in the gastrointestinal tract and distribution in the body was demonstrated in an oral Combined Repeated Dose / Reproduction /Developmental Toxicity Screening Study according to OECD TG 422. Indications for systemic effects were also seen after single oral administration (acute oral toxicity according to OECD TG 423).
Therefore, for risk assessment purposes oral absorption is set at 100%.

Dermal absorption
Generally, absorption in the stratum corneum is favoured for substances with a molecular weight below 100 g/mol, but it is also possible for substances with a molecular weight of below 500 g/mol. To cross the lipid-rich stratum corneum a certain degree of lipophilicity is required; Log P values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal, particularly if water solubility is high). To partition from the stratum corneum into the epidermis the substance must be sufficiently soluble in water e.g. at values between 100-10,000 mg/L, moderate to high absorption is expected. Generally it is assumed that substances with vapour pressures above 100-10,000 Pa at 25 ° C can be too volatile to penetrate further skin layers, below 100 Pa substances are likely to be well absorbed.
As a water-soluble liquid, which is nevertheless sufficient lipophilic to cross the stratum corneum, the test substance possesses properties favourable for skin absorption. The molecular weight of 118 and the log P of 1.67 generally indicates that the test substance is able to be taken up by the stratum corneum. Furthermore, due to the substance’s high water-solubility (>10,000 mg/L) partition form the stratum corneum to deeper layer of the epidermis is considered possible.
However, the substance’s vapour pressure of 1,125 Pa might limit the rate of absorption, as it is generally assumed that with vapour pressures between 100-10,000 Pa a substance may be too volatile to penetrate deeper beyond the stratum corneum.
Available toxicological data give no indication that skin absorption occur. In an acute dermal toxicity study based on OECD TG 402 no local or systemic test substance related effects were noted from clinical observations or post-mortem examinations. Furthermore the substance is neither irritative/corrosive nor skin sensitising, so no enhanced penetration is to be expected.
Even though there are indications that absorption via skin is limited, a standard absorption of 100% is assumed as a worst-case consideration, in line with ECHA Guidance. According to the criteria given in the ECHA Guidance R.7c, 100 % absorption is generally used unless molecular mass is > 500 and log P is outside the range <-1 or >4 in which case a value of 10% skin absorption is chosen (de Heer et al., 1999).

Respiratory absorption
The test substance is a viscous liquid. Its vapour pressure indicates whether it is available as vapour for inhalation. As general guide a substance with a vapour pressure of >25 KkPa (25,000 Pa) is considered highly volatile, with a vapour pressure of <500 Pa low volatile. Since the test substance has a vapour pressure of 1,125 Pa at 20°C, low to moderate volatility can be assumed, so inhalation exposure is likely to be low, but cannot be excluded. Generally, higher exposure needs to be considered if the substance is used in situations in which liquid aerosols may be generated (e.g. by spraying). However, no spray applications are intended for the substance.
In the case of inhalation exposure, the absorption is potentially high. Based on the physico-chemical properties (i.e. moderate to high solubility in water and its ability to penetrate biomembranes related to its size and moderate log P value), the test substance would readily diffuse/dissolve into the mucus lining the respiratory tract and would then have the potential to be absorbed directly across the respiratory tract epithelium.
Based on these assumptions and since inhalation exposure cannot be fully excluded a default of 100% absorption via inhalative is set for the purpose of risk assessment.
Details on distribution in tissues:
Due to the low molecular weight (118 g/mol) and the high water solubility (>10,000 mg/L), the test substance is expected to be widely distributed in the body via blood circulation. This assumption is also supported by available toxicological studies, demonstrating distribution in the body in an oral Combined Repeated Dose / Reproduction /Developmental Toxicity Screening Study. Since the test substance has a log P value of 1.67 it is considered lipophilic (log P >0), and thus is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.
The potential for bioaccumulation is considered to be low, based on the low partition coefficient. In general, a potential to accumulate is expected for highly lipophilic substances with a log P > 4.
Conclusions:
The absorption rate of the registered substance is assumed to be 100 % via the oral, dermal and inhalation route. The substance is expected to be distributed widely through the body via blood circulation. No accumulation is expected. The main excretion route is urinary excretion.
Executive summary:

Toxicokinetic Statement for the test substance


General


No toxicokinetic experimental data (animal or human studies/information) are currently available on the UVCB substance . Therefore the toxicokinetic profile of the test substance was assessed based on existing toxicological studies and physical-chemical properties.


 


Substance identity


 


Table 1: Physical-chemical properties of the test substance


































Substance ID



Propionaldehyde, reaction products with formaldehyd



Molecular Weight [g/mol]



118 (average)



 Molecular formula



UVCB



Physical state



liquid: viscous



Water Solubility (20°C)



>1003 g/L



Log P (35°, pH 7)



1.67



Vapour Pressure (20°C)



1,125 Pa



 


Absorption


A substance can enter the body via the gastrointestinal tract, the lungs, or the skin, depending on the route of exposure.


 


Oral absorption


After oral administration, in general, a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract. So, the water solubility of a substance is a crucial parameter. With an estimated water solubility of >1003 g/Lat 20 °C, the test substance isconsidered to highly soluble in water (>10,000 mg/L). It is therefore to be expected that the test substance will readily dissolve into the gastrointestinal fluid.


Generally, the smaller the molecule the more easily it may be absorbed. The substance has molecular weight of 118 g/mol and thus below the guidance value of 500, below which absorption is favorable. Absorption from the gastro-intestinal lumen can occur by passive diffusion but also by specialized transport system. Asorption by passive diffusion is favoured for substances with moderate log P values (between -1 and 4). The test substance has alog P of 1.67, thus ready absorption by passive diffusion is expected.


In sum, based on the physicochemical properties of the test substance (i.e. moderate to high solubility in water and its ability to penetrate biomembranes related to its size andmoderate log P value), high oral absorption is expected.This assumption is also supported by available toxicological studies. Absorption of the test substance in the gastrointestinal tract and distribution in the body was demonstrated in an oral Combined Repeated Dose / Reproduction /Developmental Toxicity Screening Study according to OECD TG 422. Indications for systemic effects were also seen after single oral administration (acute oral toxicity according to OECD TG 423).


Therefore, for risk assessment purposes oral absorption is set at 100%.


 


Dermal absorption


Generally, absorption in the stratum corneum is favoured for substances with a molecular weight below 100 g/mol, but it is also possible for substances with a molecular weight of below 500 g/mol. To cross the lipid-rich stratum corneum a certain degree of lipophilicity is required; Log P values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal, particularly if water solubility is high). To partition from thestratum corneuminto the epidermis the substance must be sufficiently soluble in water e.g. at values between 100-10,000 mg/L, moderate to high absorption is expected. Generally it is assumed that substances with vapour pressures above 100-10,000 Pa at 25 ° C can be too volatile to penetrate further skin layers, below 100 Pa substances are likely to be well absorbed.


As a water-soluble liquid, which is nevertheless sufficient lipophilic to cross thestratum corneum, the test substance possesses properties favourable for skin absorption. The molecular weight of 118 and the log P of 1.67 generally indicates that thetest substanceis able to be taken up by the stratum corneum. Furthermore, due to the substance’s high water-solubility (>10,000 mg/L) partition form the stratum corneum to deeper layer of the epidermis is considered possible.


However, the substance’s vapour pressure of 1,125 Pa might limit the rate of absorption, as it is generally assumed that with vapour pressures between 100-10,000 Pa a substance may be too volatile to penetrate deeper beyond the stratum corneum.


Available toxicological data give no indication that skin absorption occur. In an acute dermal toxicity study based on OECD TG 402 no local or systemic test substance related effects were noted from clinical observations or post-mortem examinations. Furthermore the substance is neither irritative/corrosive nor skin sensitising, so no enhanced penetration is to be expected.


 


Even though there are indications that absorption via skin is limited, a standard absorption of 100% is assumed as a worst-case consideration, in line with ECHA Guidance. According to the criteria given in the ECHA Guidance R.7c, 100 % absorption is generally used unless molecular mass is > 500 and log P is outside the range<-1 or >4in which case a value of 10% skin absorption is chosen (de Heer et al., 1999).


 


Respiratory absorption


The test substance is a viscous liquid. Its vapour pressure indicates whether it is available as vapour for inhalation. As general guide a substance with a vapour pressure of >25 KkPa (25,000 Pa) is considered highly volatile, with a vapour pressure of <500 Pa low volatile. Since the test substance has a vapour pressure of 1,125 Pa at 20°C, low to moderate volatility can be assumed, so inhalation exposure is likely to be low, but cannot be excluded. Generally, higher exposure needs to be considered if the substance is used in situations in which liquid aerosols may be generated (e.g. by spraying). However, no spray applications are intended for the substance.


In the case of inhalation exposure, the absorption is potentially high. Based on the physico-chemical properties (i.e. moderate to high solubility in water and its ability to penetrate biomembranes related to its size andmoderate log P value), the test substance would readily diffuse/dissolve into the mucus lining the respiratory tract and would then have the potential to be absorbed directly across the respiratory tract epithelium.


 


Based on these assumptions and since inhalation exposure cannot be fully excluded a default of 100% absorption via inhalative is set for the purpose of risk assessment.


 


Distribution and Accumulation


Due to the low molecular weight (118 g/mol) and the high water solubility (>10,000 mg/L), the test substance is expected to be widely distributed in the body via blood circulation.This assumption is also supported by available toxicological studies, demonstrating distribution in the body in an oral Combined Repeated Dose / Reproduction /Developmental Toxicity Screening Study. Since the test substance has alog P value of 1.67it is considered lipophilic (log P >0), and thus is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.


The potential for bioaccumulation is considered to be low, based on the low partition coefficient. In general, a potential to accumulate is expected for highly lipophilic substances with a log P > 4.


 


Metabolism


Available hydrolysis data indicates that hydrolysis within the gastro-intestinal tract or respiratory tracts is not expected. No relevant differences occurred in the two mutagenicity studies with and without the addition of a metabolising system. Therefore no indication of the importance of the metabolism of the test item was obtained from these studies. Due to lack of data no further predictions can be made.


 


Elimination


The test substance is of low molecular weight and has high water solubility and is therefore likely to be subject to rapid urinary excretion. Therefore, urinary excretion is expected to be the major route of excretion.

Description of key information

The absorption rate of the registered substance is assumed to be 100 % via the oral, dermal and inhalation route. The substance is expected to be distributed widely through the body via blood circulation. No accumulation is expected. The main excretion route is urinary excretion.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information