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Endpoint:
basic toxicokinetics in vivo
Type of information:
other: expert statement
Adequacy of study:
weight of evidence
Study period:
2018-04-12
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: An assessment of the toxicokinetic behaviour of hexanal was performed, taking into account the available physico-chemical data
Objective of study:
absorption
distribution
excretion
Guideline:
other: ECHA Guidance R.7c
Principles of method if other than guideline:
An assessment of toxicological behaviour of hexanal is based on its physico-chemical properties.
GLP compliance:
no
Type:
absorption
Results:
The absorption rate of hexanal is assumed to be 100 % via the oral, dermal and inhalation route.
Type:
distribution
Results:
The substance is expected to be distributed widely through the body via blood circulation.
Type:
excretion
Results:
Hexanal is likely to be excreted in exhaled air and in urine.
Details on absorption:
Oral absorption
Absorption by passive diffusion is favoured for substances with moderate log P values (between -1 and 4). With a log P of 1.78, hexanal is likely to follow this route of absorption. Additionally, based on the low molecular weight (< 200 g/mol) and due to the solubility in water, hexanal may also be absorbed by passing through aqueous pores or being carried through the epithelial barrier by the bulk passage of water.
Taken together, based on the physical-chemical properties an oral absorption rate of 100 % is assumed for hexanal.

Dermal absorption
Absorption in the stratum corneum is favoured for substances with a molecular weight below 100 g/mol and very unlikely for chemicals with a molecular weight above 500 g/mol. To cross the lipid-rich stratum corneum a certain degree of lipophilicity is required (Log P > 0). The registered substance has a molecular weight of 100 g/mol and a log P of 1.78. Based on the low molecular weight and the log P above 0, the registered substance might be able to be absorbed by the stratum corneum. To partition from the stratum corneum into the viable part of the epidermis, a substance must be sufficiently soluble in water (>1 mg/L). Hexanal has a water solubility of 5 g/L. Thus, penetration into the deeper, viable layers of the epidermis is very likely.
In toxicological studies hexanal was shown to be skin irritating effects (Andres 2018), which may additionally favour dermal absorption.
All in all, based on the physical-chemical properties and the toxicological profile of hexanal, a dermal absorption rate of 100 % is assumed.

Respiratory absorption
As the substance is a liquid, no inhalable particles occur. Due to the vapour pressure of 11.47 hPa at 25°C hexanal is available for inhalation as a vapour. Penetration to the lower respiratory tract is favoured for substances with low water solubility, which do not dissolve in the mucus lining the respiratory tract. The moderate water solubility indicates that hexanal may dissolve in the mucus to a certain degree. However, penetration of hexanal to the alveolar region of the lung cannot be ruled out. Having a log P value of 1.78, absorption directly across the respiratory tract epithelium by passive diffusion is favoured for hexanal. Furthermore, the water solubility also favours absorption by passing through aqueous pores or being carried through the epithelial barrier by the bulk passage of water.
Based on the available data, it can be concluded that inhalatory exposure is possible. If respiratory exposure takes place, a high systemic availability can be predicted. As worst case, 100 % inhalation absorption is assumed.
Details on distribution in tissues:
Due to the low molecular weight and high water solubility, hexanal is expected to be widely distributed in the body via blood circulation. Based on the low log P (< 3) no accumulation in fatty tissue or stratum corneum is expected.
Details on excretion:
The molecular weight and water solubility of hexanal favours urinary excretion. Furthermore, due to the high vapour pressure, excretion via exhaled air is also relevant.
Metabolites identified:
no
Conclusions:
The absorption rate of hexanal 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. The main excretion route is urinary excretion and exhalation.
Executive summary:

There are no ADME studies available for Hexanal (CAS 66-25-1). The toxicokinetic profile was not determined by actual absorption, distribution, metabolism or excretion measurements. Rather, toxicokinetics of hexanal was assessed based on the physical-chemical properties in combination with results of toxicity studies. The absorption rate of hexanal 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. The main excretion route is urinary excretion and exhalation.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
distribution
excretion
toxicokinetics
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Short description of test conditions:
n-Hexanal was dissolved in physiological saline containing 1 % bovine serum albumin and administered to mice at a dose of 6.8 µmol/10g body weight by i.v. injection into the tail vein. Mice administered the aldehyde were dissected under ether anesthesia at 0, 5, 10, 30, 60, and 120 min after the treatments. Blood was drawn from the heart and the plasma was prepared by centrifugation.

- Parameters analysed / observed: The content of n-hexanal in the plasma and liver and lung homogenates was determined.
GLP compliance:
no
Radiolabelling:
no
Species:
mouse
Strain:
other: ddY
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Clea Japan Inc.
- Age at study initiation: 6 weeks
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
Route of administration:
intravenous
Vehicle:
physiological saline
Remarks:
containing 1 % bovine serum albumin
Details on exposure:
n-Hexanal was dissolved in physiological saline containing 1 % bovine serum albumin and administered to mice at a dose of 6.8 µmol/10g body weight by i.v. injection into the tail vein.
Duration and frequency of treatment / exposure:
once
Dose / conc.:
6.8 other: µmol/10 g bw
No. of animals per sex per dose:
not specified
Control animals:
yes
Positive control:
no
Details on study design:
no details given
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): blood, plasma, liver, lung
- Time and frequency of sampling: 0, 5, 10, 30, 60 and 120 min after treatment
Type:
distribution
Results:
After injection n-hexanal is transported to the lung and the liver.
Type:
excretion
Results:
It is thought that n-hexanal could be either metabolized by the enzymes and/or transferred into the lung as such and excreted into expired gas easily.
Details on absorption:
not examined
Details on distribution in tissues:
After the injection of n-hexanal, the plasma content reached to ca. 500 nmol/ml at 5 min and decreased to less than half at 10 min. In the lung, the content of n-hexanal increased immediately and reached ca. 150 nmol/g in 30 min. From the mean of lung weight being ca. 0.17 g, the amount of n-hexanal in whole lung was ca. 26 nmol. This value corresponded to ca. 0.080 % of the whole injected aldehyde. After 30 min, the content of n-hexanal decreased significantly. The amount of n-hexanal at 120 min was ca. 20 % of that seen at 30 min. In the liver, the content of n-hexanal increased slightly 10 min after the injection. The content at 30 min decreased to the level of the untreated group.
Details on excretion:
It is thought that n-hexanal could be either metabolized by the enzymes and/or transferred into the lung as such and excreted into expired gas easily.
Metabolites identified:
not measured

no effect on the activities of GSH-Px and GSSGR and the content of GSH was observed

Conclusions:
After the injection of n-hexanal, the plasma content reached to ca. 500 nmol/ml at 5 min and decreased to less than half at 10 min. In the lung, the content of n-hexanal increased immediately and reached ca. 150 nmol/g in 30 min. From the mean of lung weight being ca. 0.17 g, the amount of n-hexanal in whole lung was ca. 26 nmol. This value corresponded to ca. 0.080 % of the whole injected aldehyde. After 30 min, the content of n-hexanal decreased significantly. The amount of n-hexanal at 120 min was ca. 20 % of that seen at 30 min. In the liver, the content of n-hexanal increased slightly 10 min after the injection. The content at 30 min decreased to the level of the untreated group. It is thought that n-hexanal could be either metabolized by the enzymes and/or transferred into the lung as such and excreted into expired gas easily.
Executive summary:

n-Hexanal was dissolved in physiological saline containing 1 % bovine serum albumin and administered to mice at a dose of 6.8 µmol/10g body weight by i.v. injection into the tail vein. Mice administered the aldehyde were dissected under ether anesthesia at 0, 5, 10, 30, 60, and 120 min after the treatments. Blood was drawn from the heart and the plasma was prepared by centrifugation. The content of n-hexanal in the plasma and liver and lung homogenates was determined. After the injection of n-hexanal, the plasma content reached to ca. 500 nmol/ml at 5 min and decreased to less than half at 10 min. In the lung, the content of n-hexanal increased immediately and reached ca. 150 nmol/g in 30 min. From the mean of lung weight being ca. 0.17 g, the amount of n-hexanal in whole lung was ca. 26 nmol. This value corresponded to ca. 0.080 % of the whole injected aldehyde. After 30 min, the content of n-hexanal decreased significantly. The amount of n-hexanal at 120 min was ca. 20 % of that seen at 30 min. In the liver, the content of n-hexanal increased slightly 10 min after the injection. The content at 30 min decreased to the level of the untreated group. It is thought that n-hexanal could be either metabolized by the enzymes and/or transferred into the lung as such and excreted into expired gas easily.

Description of key information

Hexanal was shown to be transported to the lung and the liver after iv injection in mice (Yoshino 1993).

The absorption rate of hexanal 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. The main excretion route is urinary excretion and exhalation.

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

Toxicokinetic Statement for Hexanal (CAS 66-25-1)

General

There are no ADMEstudies available for hexanal (CAS 66-25-1). The toxicokinetic profile was not determined by actual absorption, distribution, metabolism or excretion measurements. Rather, toxicokinetics of hexanal was assessed based on the physical-chemical properties in combination with results of toxicity studies.

Substance identity

Table 1: Physical-chemical properties of hexanal

 

 

Hexanal (CAS 66-25-1)

Structural formula

C5H12O3

Structure

Molecular Weight [g/mol]

100

Physical state

liquid

Water Solubility (20°C)

5 g/L  

Log P

1.78

Vapour Pressure (25°C)

11.47 hPa

 

 

Oral absorption

Absorption by passive diffusion is favoured for substances with moderate log P values (between -1 and 4). With a log P of 1.78, hexanal is likely to follow this route of absorption. Additionally, based on the low molecular weight (< 200 g/mol) and due to the solubility in water, hexanal may also be absorbed by passing through aqueous pores or being carried through the epithelial barrier by the bulk passage of water.

Taken together, based on the physical-chemical properties an oral absorption rate of 100 % is assumed for hexanal. 

 

Dermal absorption

Absorption in the stratum corneum is favoured for substances with a molecular weight below 100 g/mol and very unlikely for chemicals with a molecular weight above 500 g/mol. To cross the lipid-rich stratum corneum a certain degree of lipophilicity is required (Log P > 0). Hexanal has a molecular weight of 100 g/mol and a log P of 1.78. Based on the low molecular weight and the log P above 0, the hexanal might be able to be absorbed by the stratum corneum. To partition from the stratum corneum into the viable part of the epidermis, a substance must be sufficiently soluble in water (>1 mg/L). Hexanal has a water solubility of 5 g/L. Thus, penetration into the deeper, viable layers of the epidermis is very likely. In toxicological studies hexanal was shown to be skin irritating effects (Andres 2018), which may additionally favour dermal absorption. 

All in all, based on the physical-chemical properties and the toxicological profile of hexanal, a dermal absorption rate of 100 % is assumed.

 

Respiratory absorption

As the substance is a liquid, no inhalable particles occur. Due to the vapour pressure of 11.47 hPa at 25°C, hexanal is available for inhalation as a vapour. Penetration to the lower respiratory tract is favoured for substances with low water solubility, which do not dissolve in the mucus lining the respiratory tract. The moderate water solubility indicates that hexanal may dissolve in the mucus to a certain degree. However, penetration of hexanal to the alveolar region of the lung cannot be ruled out. Having a log P value of 1.78, absorption directly across the respiratory tract epithelium by passive diffusion is favoured for hexanal. Furthermore, the water solubility also favours absorption by passing through aqueous pores or being carried through the epithelial barrier by the bulk passage of water.

Based on the available data, it can be concluded that inhalatory exposure is possible. If respiratory exposure takes place, a high systemic availability can be predicted. As worst case, 100 % inhalation absorption is assumed.

 

Distribution and Accumulation

Due to the low molecular weight and high water solubility, hexanal is expected to be widely distributed in the body via blood circulation. Based on the low log P (< 3) and the high water solubility of 5 g/L no accumulation in fatty tissue or stratum corneum is expected.

 

Elimination

The molecular weight and water solubility of hexanal favours urinary excretion. Furthermore, due to the high vapour pressure, excretion via exhaled air is also relevant.

References

ECHA (2017): Guidance on Information Requirements and Chemical Safety Assessment; Chapter R.7c: Endpoint specific guidance, version 3, ISBN 978-92-9495-838-9