Registration Dossier

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.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid: viscous

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 -1.06 and a water solubility of >509 g/L D 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 D- 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 D- Panthenol. Nevertheless, extensive gastrointestinal absorption is expected for D Panthenol based on physical chemical properties.
Based on the low vapour pressure of 0.000056 Pa D 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 D- Panthenol will be systemically absorbed after skin exposure.
Details on distribution in tissues:
Following oral and dermal absorption D- 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 it 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, based on the toxicokinetic behaviour of D 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 1.06 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. If administered orally, excretion may also occur via faeces as metabolic degradation via the intestinal microflora is expected.

Metabolite characterisation studies

Metabolites identified:
not specified
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. 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 D and DL Panthenol.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: no bioaccumulation based on expert statement
D- 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 D- 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 -1.06 and a water solubility of >509 g/L D‑ 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 D- 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 D- Panthenol. Nevertheless, extensive gastrointestinal absorption is expected for D‑ Panthenol based on physical chemical properties.

Based on the low vapour pressure of 0.000056 Pa D‑ 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 D- Panthenol will be systemically absorbed after skin exposure.

 

Distribution:

Following oral and dermal absorption D- 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 it 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, based on the toxicokinetic behaviour of D‑ 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 ‑ 1.06 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. 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 D‑ and DL‑ 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. If administered orally, excretion may also occur via faeces as metabolic degradation via the intestinal microflora is expected.

In conclusion, D- 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 D- 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.