Panthenol , DL-form

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: statement

Adequacy of study:

key study

Study period:

2012

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Principles of method if other than guideline:

Expert statement, no guideline required.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Panthenol , DL-form

EC Number:

240-540-6

EC Name:

Panthenol , DL-form

Cas Number:

16485-10-2

Molecular formula:

C9H19NO4

IUPAC Name:

2,4-dihydroxy-N-(3-hydroxypropyl)-3,3-dimethylbutanamide

Test material form:

liquid: viscous

Radiolabelling:

other: not applicable

Test animals

Species:

other: no measurement (expert statement)

Strain:

other: no measurement (expert statement)

Administration / exposure

Route of administration:

other: no measurement (expert statement)

Results and discussion

Preliminary studies:

no measurement (expert statement)

Toxicokinetic / pharmacokinetic studies

Details on absorption:

With a molecular weight of 205.25 g/mol, a logKow value of -1.02 and a water solubility of 562.3 g/L DL Panthenol is likely to be absorbed in the GI tract. Due to the high water solubility the substance may not diffuse across plasma membranes. More likely gastro-intestinal absorption of DL- Panthenol is triggered by passage through aqueous pores or carriage with the bulk passage of water which is favoured for small (molecular weight around 200 g/mol), water soluble substances. Since there is an active transport mechanism for Pantothenic acid, active transport may also be likely for DL- Panthenol. It remains unclear if the active transport is enantiomer- specific as only the D- form of Pantothenic acid is transported. Nevertheless, extensive gastrointestinal absorption is expected for DL Panthenol based on physical chemical properties.
Based on the low vapour pressure of 0.0036 Pa DL Panthenol does not vaporise in a sufficient manner to become available for inhalation exposure. Exposure to aerosols may occur. However, due to the high water solubility the substance is likely to solve in the mucus lining of the respiratory tract but subsequent systemic absorption is not likely.
The substance characteristics and physical-chemical properties indicate that dermal absorption is likely. The physical state favours quick dermal absorption with liquids taken up more readily than dry particulates. Data available for D- Panthenol show that dermal absorption occurred following topical administration to rats, which was proven by the higher urinary excretion of Pantothenic acid, the oxidation product of D- Panthenol, in comparison to controls (Erlemann et al, 1962). In vitro dermal penetration studies with D- Panthenol using rat and pig skin also showed that dermal penetration occurred (unpublished DSM Nutritional Products Reports Klecak, 1985). In conclusion, the available data suggest that DL- Panthenol will be systemically absorbed after skin exposure.

Details on distribution in tissues:

Following oral and dermal absorption DL- Panthenol is likely to systemically distribute through extracellular compartments. Data obtained from oral subchronic repeated dose toxicity testing give not rise to any target organ specificity. As D- Panthenol was shown to be rapidly metabolised to Pantothenic acid it may be concluded that DL- Panthenol undergoes a first pass effect in liver after oral application, indicating that distribution of the parent compound is limited through oral routes. Furthermore, oral absorption may be limited by microbiological degradation in the intestine. However, systemic distribution following dermal exposure is expected for DL- Panthenol, based on the toxicokinetic behaviour of the pure D enantiomer of Panthenol (Erlemann et al, 1962). The low half life, based on the presumed rapid metabolic degradation and subsequent quick urinary excretion, indicate a low potential for bioaccumulation. In addition, the low logKow of -1.02 also indicates a very low bioaccumulation potential.

Details on excretion:

Data obtained from testing with D- Panthenol in rats indicate, that topical administered substance is quickly metabolised to Pantothenic acid, which is rapidly excreted via the urine. Similar is expected for DL- Panthenol, as metabolism of the parent compound will result into Pantothenic acid as well, triggered by the same enzymatic pathways. If administered orally, excretion may also occur via faeces as metabolic degradation via the intestinal microflora is expected.

Metabolite characterisation studies

Details on metabolites:

Based on the chemical structure, the substance may be metabolised by phase I and II enzymes, mainly in the liver. Initial alcohol oxidation by cytochrome P450 monooxygenases (CYP) or alcohol and aldehyde dehydrogenases (ADH/ AlDH) will result in the generation of Pantothenic acid (vitamin B5). Results obtained from D- Panthenol indicate quick oxidation to Pantothenic acid and it is expected that DL- Panthenol is metabolised through the same enzymatic pathways. Further, a hydrolysis of the amide- bond is proposed resulting in 2,4 Dihydroxy-3,3-dimethyl-butyric acid and 3- Hydroxypropylamine. The parent compound as well as Pantothenic acid and the hydrolysis products may be readily conjugated by phase II metabolising enzymes like Glucuronosyltransferases and Sulfotransferases. No conversion into a toxic metabolite is expected as indicated by in vitro genetic toxicity tests performed with DL Panthenol and DL- Ethyl Panthenol.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: no bioaccumulation based on expert statement
DL- Panthenol is expected to be systemically absorbed after oral and dermal exposure. Based on its physical chemical properties, the substance is not expected to diffuse into intracellular compartments. Moreover distribution through extracellular body fluids is likely. It is expected, that DL- Panthenol undergoes a first- pass effect in the liver after oral application. Metabolism will most likely include phase I enzymes and will result in the quick formation of Pantothenic acid. Excretion of the breakdown products will most likely occur via the urine. No bioaccumulation is expected.

Executive summary:

Absorption:

With a molecular weight of 205.25 g/mol, a logKow value of -1.02 and a water solubility of 562.3 g/L DL‑ Panthenol is likely to be absorbed in the GI tract. Due to the high water solubility the substance may not diffuse across plasma membranes. More likely gastro-intestinal absorption of DL- Panthenol is triggered by passage through aqueous pores or carriage with the bulk passage of water which is favoured for small (molecular weight around 200 g/mol), water soluble substances. Since there is an active transport mechanism for Pantothenic acid, active transport may also be likely for DL- Panthenol. It remains unclear if the active transport is enantiomer- specific as only the D- form of Pantothenic acid is transported. Nevertheless, extensive gastrointestinal absorption is expected for DL‑ Panthenol based on physical chemical properties.

Based on the low vapour pressure of 0.0036 Pa DL‑ Panthenol does not vaporise in a sufficient manner to become available for inhalation exposure. Exposure to aerosols may occur. However, due to the high water solubility the substance is likely to solve in the mucus lining of the respiratory tract but subsequent systemic absorption is not likely.

The substance characteristics and physical-chemical properties indicate that dermal absorption is likely. The physical state favours quick dermal absorption with liquids taken up more readily than dry particulates. Data available for D- Panthenol show that dermal absorption occurred following topical administration to rats, which was proven by the higher urinary excretion of Pantothenic acid, the oxidation product of D- Panthenol, in comparison to controls (Erlemannet al, 1962).In vitrodermal penetration studies with D- Panthenol using rat and pig skin also showed that dermal penetration occurred (unpublished DSM Nutritional Products Reports Klecak, 1985). In conclusion, the available data suggest that DL- Panthenol will be systemically absorbed after skin exposure.

 

Distribution:

Following oral and dermal absorption DL- Panthenol is likely to systemically distribute through extracellular compartments. Data obtained from oral subchronic repeated dose toxicity testing give not rise to any target organ specificity. As D- Panthenol was shown to be rapidly metabolised to Pantothenic acid it may be concluded that DL- Panthenol undergoes a first pass effect in liver after oral application, indicating that distribution of the parent compound is limited through oral routes. Furthermore, oral absorption may be limited by microbiological degradation in the intestine. However, systemic distribution following dermal exposure is expected for DL- Panthenol, based on the toxicokinetic behaviour of the pure D‑ enantiomer of Panthenol (Erlemannet al, 1962). The low half life, based on the presumed rapid metabolic degradation and subsequent quick urinary excretion, indicate a low potential for bioaccumulation. In addition, the low logKow of -1.02 also indicates a very low bioaccumulation potential.

 

Metabolism:

Based on the chemical structure, the substance may be metabolised by phase I and II enzymes, mainly in the liver. Initial alcohol oxidation by cytochrome P450 monooxygenases (CYP) or alcohol and aldehyde dehydrogenases (ADH/ AlDH) will result in the generation of Pantothenic acid (vitamin B5). Results obtained from D- Panthenol indicate quick oxidation to Pantothenic acid and it is expected that DL- Panthenol is metabolised through the same enzymatic pathways. Further, a hydrolysis of the amide- bond is proposed resulting in 2,4‑ Dihydroxy-3,3-dimethyl-butyric acid and 3- Hydroxypropylamine. The parent compound as well as Pantothenic acid and the hydrolysis products may be readily conjugated by phase II metabolising enzymes like Glucuronosyltransferases and Sulfotransferases. No conversion into a toxic metabolite is expected as indicated by in vitro genetic toxicity tests performed with DL‑ Panthenol and DL- Ethyl Panthenol.

 

Excretion

Data obtained from testing with D- Panthenol in rats indicate, that topical administered substance is quickly metabolised to Pantothenic acid, which is rapidly excreted via the urine. Similar is expected for DL- Panthenol, as metabolism of the parent compound will result into Pantothenic acid as well, triggered by the same enzymatic pathways. If administered orally, excretion may also occur via faeces as metabolic degradation via the intestinal microflora is expected.

In conclusion, DL- Panthenol is expected to be systemically absorbed after oral and dermal exposure. Based on its physical chemical properties, the substance is not expected to diffuse into intracellular compartments. Moreover distribution through extracellular body fluids is likely. It is expected, that DL- Panthenol undergoes a first- pass effect in the liver after oral application. Metabolism will most likely include phase I enzymes and will result in the quick formation of Pantothenic acid. Excretion of the breakdown products will most likely occur via the urine. No bioaccumulation is expected.