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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
calculation (if not (Q)SAR)
Remarks:
Migrated phrase: estimated by calculation
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Assessment is based upon evaluation of the chemistry and physiochemical properties of test substance, as well as experience for ADME as it relates to similar molecules. The assessment is not based upon experimental data.

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2008

Materials and methods

GLP compliance:
not specified

Test material

Constituent 1
Details on test material:
- Name of test material (as cited in study report): Methyl Polyhydroxymethyl Stearate
- Molecular formula (if other than submission substance): not specified in the report
- Molecular weight (if other than submission substance): not specified in the report
- Smiles notation (if other than submission substance): not specified in the report
- InChl (if other than submission substance): not specified in the report
- Structural formula attached as image file (if other than submission substance): not specified in the report
- Substance type: Mixture of functionalized fatty acid methyl esters (FAMEs), which may be derived from a variety of natural seed oils.
- Physical state: Waxy solid at room temperature
- Analytical purity: > 95.2 %
- Impurities (identity and concentrations): not specified in the report
- Composition of test material, percentage of components:
Methyl Palmitate: 9.68 %
Methyl Stearate: 17.8 %
Methyl Hydroxymethyl Stearate: 38.6 %
Methyl Dihydroxymethyl Stearate: 26.7 %
Methyl Trihydroxymethyl Stearate: 2.37 %
- Isomers composition: not specified in the report
- Purity test date: not specified in the report
- Lot/batch No.: (lot # 200500200-25-4)
- Expiration date of the lot/batch: not specified in the report
- Radiochemical purity (if radiolabelling): not applicable
- Specific activity (if radiolabelling): not applicable
- Locations of the label (if radiolabelling): not applicable
- Expiration date of radiochemical substance (if radiolabelling): not applicable
- Stability under test conditions: not specified in the report
- Storage condition of test material: not specified in the report

Results and discussion

Preliminary studies:
Natural oil monomer consists of esters of the fatty acids palmitic acid (C16), margaric acid (C17) and stearic acid (C18), and C16-C18 fatty acids with one or more methanol side groups on the chain. The methyl groups are likely to hydrolyse readily. Palmitic and stearic acid are endogenous compounds and are present in abundance in our food. Margaric acid is a naturally occurring dietary fat present in our food, but this fatty acid is not synthesized by the human body. The anticipated toxicokinetic behaviour of NOM is consistent with the (low) toxicity of the substance.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Absorption

An almost complete absorption (97.3 and 94.1%, respectively) of palmitic and stearic acid is known to occur after oral administration of these compounds to man (Baer et al, 2003). For margaric acid, absorption after oral administration has been demonstrated, but not quantified (Wolk et al, 2001). It is to be expected that the bioavailability of margaric acid and of the fatty acids with methanol side groups will be high as well.

Based on the vapour pressure of NOM, (< 0.004 Pa), uptake via inhalation is not anticipated. Conversely, fatty acids and fatty acid methyl esters are used as penetration enhancers for drug delivery (Chukwumerije et al., 1989; Kogan and Garti, 2006) and thus, it is expected that the fatty acid properties of NOM would allow for dermal penetration. Consistent with the uses for drug delivery, dermal absorption of fatty acids are generally regarded as safe, and the toxicity profile of MPS following dermal testing is consistent with this as well . The dermal absorption of MPS has not been studied to date. However, the permeability of this compound through skin can be estimated with QSAR programs, such as the DermWin model from the US EPA. Using this application, the steady-state flux of a 1% solution of NOM through skin is estimated to be 0.65-240 mg/cm2 surface area of skin, for the various components (Text Table 1). The calculated Kp, or rate of penetration via the DermWin model, is calculated to be 1.28-24.4 cm/hr.


Text Table 1. Measured and Predicted Physicochemical Values for NOM components

Details on distribution in tissues:
Distribution
The fatty acids will be incorporated in the cell’s metabolism and processes. They will be incorporated in adipose tissue and serum lipids (Wolk et al, 2001). Significant accumulation in fatty tissue is not anticipated for this compound. Consistent with this, the predicted volume of distribution (Vd) for the NOM components ranges from 2.3-5.1 L/kg, via the ADME Boxes QSAR application (v4.03, Pharma Algorithms Inc., Toronto, Ontario, CA)(Text Table 1).
Details on excretion:
Metabolism and excretion
Fatty acids will be metabolized and excreted via the normal biotransformation routes for endogenous fatty acids.
Fatty acids with a methanol side group may be sulfated or glucuronidated on the side group in the liver (Parkinson, 2001). An alternative metabolism pathway may be oxidation of the methanol group to the corresponding aldehyde and carboxylic acid, after which conjugation to the acid group may take place. The sulfate and glucuronide conjugates are likely to be excreted via bile and/or urine.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Conclusion
Uptake via inhalation is not anticipated for NOM, while dermal absorption is feasible.
The fatty acids are anticipated to be distributed, metabolized and excreted in the same way as naturally occurring fatty acids. Fatty acids with an additional methanol side group are expected to follow these same pathways, with the additional potential for Phase II conjugation of the methanol moieties of these components. Significant accumulation in fatty tissue is highly unlikely. The anticipated toxicokinetic behaviour of NOM is consistent with the low toxicity of the substance.
Executive summary:

Natural Oil Monomer (NOM) consists of esters of the fatty acids palmitic acid (C16), margaric acid (C17) and stearic acid (C18), and C16-C18 fatty acids with one or more methanol side groups on the chain. The methyl groups are likely to hydrolyse readily. Palmitic and stearic acid are endogenous compounds and are present in abundance in our food.  Margaric acid is a naturally occurring dietary fat present in our food, but this fatty acid is not synthesized by the human body.

Uptake via inhalation is not anticipated for NOM, while dermal absorption is feasible.

The fatty acids are anticipated to be distributed, metabolized and excreted in the same way as naturally occurring fatty acids.  Fatty acids with an additional methanol side group are expected to follow these same pathways, with the additional potential for Phase II conjugation of the methanol moieties of these components.   Significant accumulation in fatty tissue is highly unlikely. The anticipated toxicokinetic behaviour of NOM is consistent with the low toxicity of the substance.

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