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Endpoint:
basic toxicokinetics, other
Remarks:
G.I. human passive absorption
Type of information:
calculation (if not (Q)SAR)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a (Q)SAR model, with limited documentation / justification, but validity of model and reliability of prediction considered adequate based on a generally acknowledged source
Objective of study:
absorption
Guideline:
other: REACH Guidance on QSARs R.6
Principles of method if other than guideline:
Model to predict either high or low fraction absorbed for an orally administered, passively transported substance on the basis of a new absorption parameter. The model includes only two inputs: the octanol-water partition coefficient (Kow) and the dimensionless oversaturation number (OLumen). The latter is the ratio of the concentration of drug delivered to the gastro-intestinal (GI) fluid to the solubility of the compound in that environment.
Specific details on test material used for the study:
SMILES (used for QSAR prediction):
C=CCCCCCCCCC(=O)O
Species:
other: Human
Route of administration:
oral: unspecified
Type:
absorption
Results:
Absorption from gastrointestinal tract for 1 mg dose: 100%
Type:
absorption
Results:
Absorption from gastrointestinal tract for 1000 mg dose: 95%
Endpoint:
basic toxicokinetics, other
Remarks:
in silico
Type of information:
(Q)SAR
Adequacy of study:
other information
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
See enclosed files
Objective of study:
absorption
distribution
excretion
metabolism
Qualifier:
according to guideline
Guideline:
other: REACH Guidance on QSARs R.6
Qualifier:
according to guideline
Guideline:
other: REACH Guidance on IR&CSA, Chapter R.14, Occupational exposure assessment Update to change the scope of the guidance from exposure estimation to exposure assessment
Version / remarks:
August 2016
Principles of method if other than guideline:
pkCSM uses graph-based signatures to develop predictive models of central ADME properties. pkCSM performs as well or better than current methods.
Specific details on test material used for the study:
SMILES:
C=CCCCCCCCCC(=O)O
Type:
absorption
Results:
Intestinal absorption (human): 94%
Type:
distribution
Results:
VDss (human) (log L/kg): 0.669
Type:
distribution
Results:
Fraction unbound (human) : 0.321
Type:
distribution
Results:
BBB permeability (log BB): 0.098
Type:
distribution
Results:
CNS permeability (log PS): -2,089
Type:
excretion
Results:
Total Clearance (log ml/min/kg): 1, 68
Type:
excretion
Results:
Renal OCT2 substrate: no
Details on absorption:
Intestinal absorption is estimated at 94%
Details on distribution in tissues:
According to the model "VDss (human)", the volume of distribution (VD, i.e. theoritical volume that the total dose of a drug would need to be uniformly distributed to give the same concentration as in blood plasma) is high (Log between > 0.45).
According to the model "Fraction unbound (human)", 32,1% of the absorbed dose is unbound in the plasma.
According to the model "BBB permeability", the substance is readily cross the blood-brain barrier (Log BB > 0.3).
According to the model "CNS permeability", it is not possible to predict if the substance is unable or not to penetrate the CNS (-3

Property       Model Name       Predicted Value       Unit

Absorption       Water solubility       -3.673       Numeric (log mol/L)

Absorption       Caco2 permeability       1.563       Numeric (log Papp in 10-6 cm/s)

Absorption       Intestinal absorption (human)       94.198       Numeric (% Absorbed)

Absorption       Skin Permeability       -2.688       Numeric (log Kp)

Absorption       P-glycoprotein substrate       No       Categorical (Yes/No)

Absorption       P-glycoprotein I inhibitor       No       Categorical (Yes/No)

Absorption       P-glycoprotein II inhibitor       No       Categorical (Yes/No)

Distribution       VDss (human)       -0.669       Numeric (log L/kg)

Distribution       Fraction unbound (human)       0.321       Numeric (Fu)

Distribution       BBB permeability       0.098       Numeric (log BB)

Distribution       CNS permeability       -2.089       Numeric (log PS)

Metabolism       CYP2D6 substrate       No       Categorical (Yes/No)

Metabolism       CYP3A4 substrate       No       Categorical (Yes/No)

Metabolism       CYP1A2 inhibitior       No       Categorical (Yes/No)

Metabolism       CYP2C19 inhibitior       No       Categorical (Yes/No)

Metabolism       CYP2C9 inhibitior       No       Categorical (Yes/No)

Metabolism       CYP2D6 inhibitior       No       Categorical (Yes/No)

Metabolism       CYP3A4 inhibitior       No       Categorical (Yes/No)

Excretion       Total Clearance       1.68       Numeric (log ml/min/kg)

Excretion       Renal OCT2 substrate       No       Categorical (Yes/No)

Toxicity       AMES toxicity       No       Categorical (Yes/No)

Toxicity       Max. tolerated dose (human)       -0.214       Numeric (log mg/kg/day)

Toxicity       hERG I inhibitor       No       Categorical (Yes/No)

Toxicity       hERG II inhibitor       No       Categorical (Yes/No)

Toxicity       Oral Rat Acute Toxicity (LD50)       1.493       Numeric (mol/kg)

Toxicity       Oral Rat Chronic Toxicity (LOAEL)       2.776       Numeric (log mg/kg_bw/day)

Toxicity       Hepatotoxicity       No       Categorical (Yes/No)

Toxicity       Skin Sensitisation       Yes       Categorical (Yes/No)

Toxicity       T.Pyriformis toxicity       0.846       Numeric (log ug/L)

Toxicity       Minnow toxicity       0.271       Numeric (log mM)

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
The results of the risk evaluation (see section 9 and 10 of CSR) indicate the need for restrictive risk management measures to control the risk for the dermal route of exposures, therefore we suggest to perform an in vitro skin absorption study (OECD 428) in order to have a more precise indication on undecylenic acid skin absorption as we used a maximum skin absorption factor of 100% for DNEL derivation via the dermal route. The risk evaluation will be therefore fine tuned and more relevant.
Qualifier:
according to guideline
Guideline:
OECD Guideline 428 (Skin Absorption: In Vitro Method)
GLP compliance:
yes (incl. QA statement)
Radiolabelling:
yes
Species:
other: Human skin see below study design
Type of coverage:
other: topic
Vehicle:
other: see below study design
Duration of exposure:
8 hours
Doses:
see below study design
No. of animals per group:
see below study design
Control animals:
no
Remarks:
see below
Details on study design:
Integrity of skin membranes

After placing the skin membranes in the diffusion cells (see section 4.3.2), membrane integrity was assessed. To this purpose, the permeability coefficient (Kp) for tritiated water was determined as follows: 200 µL saline (supplemented with 0.01% sodium azide) containing [3H]H2O (16.9 kBq.mL-1) was applied in the donor compartment of the flow-through diffusion cells. The compartments were covered with a glass slide. The receptor fluid consisted of saline (0.9% sodium chloride (w/v)) containing 0.01% sodium azide (w/v). Samples of the receptor fluid (ca. 1.8 mL per hour) were collected every hour up to three hours after application. Tritiated water remaining at the application site was then removed and the skin was dried with cotton swabs. Membranes were kept overnight to allow wash-out of the tritiated water from the skin.

Experimental design
10-Undecenoic acid was topically applied to the skin membranes according to the design below. The exposure time was 8 h and receptor fluid samples were collected from 0-24 h.

Test group A
Group size 8 b
Species Human
Total concentration 10-Undecenoic acid = 989 g.L-1
Mean dose 10-Undecenoic acid applied a =9588 ± 127 µg.cm-2

a A net volume of ca. 6.4 µL of the dose preparations was applied on each skin membrane (0.64 cm2)
b Two membranes from four donors

Dose formulation preparation

The dose formulations was prepared the day prior to application as follows:

-Test group A
-Amount of [14C]10-Undecenoic acid (a) ~0.015 MBq
-10-Undecenoic acid added =0.1757 g (~176 µL)
-Radioactive concentration measured /0.09 MBq.mL-1


a Dissolved in HPLC mobile phase (after purification; see 4.5.2). During evaporation, unfortunately part of the original amount of tracer left after purification was lost. Consequently, the anticipated radioactive dose was lower than anticipated.

For dose formulation A, [14C]10-Undecenoic acid, dissolved in HPLC mobile phase (after purification), was added to a brown glass vial. The solvent was evaporated under N2 gas until dry. The non-radiolabelled test material 10-Undecenoic acid was liquefied in a water bath, set at a temperature of maximally 40oC. When liquefied, the test compound was kept in a water bath at ca. 37oC. A volume of ca. 176 µL (0.1757 g) of 10-Undecenoic acid was added to the dried radioactive residue. The dose formulation was kept at ca. 38oC while mixing, until application. After application, the dose formulation was stored at 2-10ºC.


Test concentration and homogeneity check, and application :

The concentration and homogeneity of [14C]10-Undecenoic acid in the dose formulations was checked by taking random aliquots in triplicate before dosing. For homogeneity, a coefficient of variation lower than 10% was considered sufficient. Random aliquots, in triplicate, were taken again after dose application. Prior to dose application, the skin surface was dried. The dose preparations were applied with a pipette and subsequently spread evenly on the skin surface within the donor compartment using a glass rod (dose volume ca. 10 µL.cm-2). A slightly higher volume than 6.4 µL (i.e. 6.7 µL)1 was applied to account for the expected loss of material during the distribution over the skin surface. Thus, a net volume of approximately 6.4 µL was applied.

Collection of mass balance samples :

Twenty-four hours after application, the mass balance of the test substance was determined from the following samples: receptor fluid samples, skin wash, receptor compartment wash, donor compartment wash, tape strips, and digested skin.

¿ Receptor fluid samples were collected during the following intervals: 0-1 h, 1-2 h, followed by 2-h intervals until 24 hours after application.
¿ Skin wash: After an exposure period of 8 h, the unabsorbed test substance was removed from the application site using a mild soap solution (i.e. 3% Dove in water, warmed up to ca. 45oC; six rinses) followed by two rinses with water. The skin was dried with cotton swabs between each rinse and finally dried with two cotton swabs (i.e. in total ten cotton swabs were collected).
¿ 24 h after application, the diffusion cell was dismantled. Receptor compartments were washed with ethanol. Donor compartments were extracted with ethanol.
¿ Each skin membrane was tape stripped 15 times using D-Squame® Skin Sampling Discs (CuDerm Corporation) and a D-Squame pressure device. Tape strips were collected individually for further analysis. Tape stripping was discontinued in case the epidermis was ruptured.
¿ Skin membranes were digested in a 1.5 M KOH solution with 20% aqueous ethanol for at least 24 h.

Analysis:

Determination of radioactivity

The radioactivity in the study samples was determined by liquid scintillation counting (LSC) using a Canberra Packard Tricarb 3100TR or Tricarb 3110TR scintillation counter as follows:

Dose formulations Ultima Gold™ (Packard) scintillation liquid was added to aliquots of the dose formulation taken just before and directly after dosing, to the glass rods that were used as spreading aid and to pipette tips used for application. Samples were measured by LSC.

Receptor fluid Ultima Gold™ scintillation liquid was added directly to the collected receptor fluid and samples were measured by LSC.

Skin wash The cotton swabs were pooled per skin membrane and extracted with ethanol for at least 24 h at ambient temperature. An ultra-sonication step was used to facilitate the extraction. Ultima Gold™ scintillation liquid was added to weighed aliquots of the extracted cotton swabs and samples were measured by LSC.

Donor compartment The samples were extracted for at least overnight at ambient temperature and sonicated. Subsequently, the samples were mixed with Ultima Gold™ scintillation liquid and measured by LSC.

Receptor compartment Ultima Gold™ scintillation liquid was added directly to the receptor compartment wash and samples were measured by LSC.

Tape stripping Ultima Gold™ scintillation liquid was added directly to individual tape strips for at least overnight extraction and samples were measured by LSC.

Skin membranes Hionic Fluor™ (Packard) scintillation liquid was directly added to the digested skin membranes and samples were measured by LSC.

Blank samples The appropriate scintillation liquid was added to blank receptor fluid samples, blank solution used for digestion of the skin membranes, blank skin wash samples and blank tape strips.

Radio-HPLC analysis of [14C]10-Undecenoic acid

The radiochemical purity of [14C]10-Undecenoic acid in the dose formulation was determined by radio-HPLC analysis according to the following method:

Column Inertsil ODS-2, 250 ¿ 4.6 mm, 5 µm
Mobile phase A: demineralised water + 0.01% formic acid (FA) B: acetonitrile + 0.01% FA
Gradient Time (min) 0 15 30 35 40

Column temperature B (%)
ambient 40 55 55 95 95
Flow rate 1.0 mL.min-1
Detection online radioactivity (¿-ram)
UV detection ¿ = 210 nm

Calculation and interpretation of the results

¿ The cumulative absorption of test substance equivalents was calculated from the receptor fluid samples by the following equation:
¿ Cumulative DPMT = DPMT + ¿(DPMT-1 ... DPM1)
¿ DPMT : radioactivity at sampling time T
¿ DPMT-1 : radioactivity at the sampling time preceding T
¿ DPM1 : radioactivity at the first sampling time
For each receptor fluid sample, background values were subtracted.

¿ The permeability coefficient or Kp value for tritiated water [cm.h-1] was calculated as follows:
¿ Kp = flux constant [µg.cm-2.h-1] / applied concentration [µg.cm-3]
¿ Using the program Microsoft Excel, the ‘slope’ and ‘intercept’ of the virtual line through the linear portion of the absorption curve was calculated. A straight line was mathematically represented by the formula “y = slope × x + intercept”, in which y represents the cumulative absorption and x represents time. This formula was used to calculate the maximal flux and the lag time from the mean values of the skin preparations:
¿ Maximal flux = slope
¿ Lag time = - intercept / slope
¿ For each test group, the following data was calculated:
¿ Percentage of the applied dose reaching the receptor fluid
¿ Amount of the test substance reaching the receptor fluid
¿ RATA: the amount in the receptor fluid at each time point, relative to the total cumulative amount reaching the receptor fluid over 24 h
¿ Recovery of the test substance (% of applied dose) in each compartment
¿ Mass balance of the test substance
¿ The total absorption (absorbed dose): the amount of compound-related radioactivity present in the receptor fluid, the receptor compartment wash, and the skin (excluding tape strips)
¿ The potentially absorbed dose: the amount of compound-related radioactivity present in the receptor fluid, the receptor compartment wash, the skin, and the stratum corneum (except for the first 2 tape strips)

¿ Limits of detection (LoD) for radioactivity in receptor fluid and tape strip samples were used if the radioactivity in the measured sample was below LoD. The LoD was calculated according to the following formula: (v(counting efficiency × average background × counting time)/counting time)/counting efficiency × 3 + average background, where the counting efficiency was 90% (0.9) and the counting time was at least 2 min.
¿ If more than 50% of the amount of test substance in the receptor fluid and/or tape strips samples of a replicate was below the LoD, the cumulative absorption and/or total (cumulative) value for this replicate was presented as ‘< calculated value’.
¿ If more than 50% of the amount of test substance in the samples contributing to the (potentially) absorbed dose was below the LoD, the (potentially) absorbed dose was presented as ‘< calculated value’.
¿ If more than 50% of the replicates showed values below the LoD, the mean value was presented as ‘< calculated value’.




Details on in vitro test system (if applicable):
4.3.1 Preparation of skin membranes

Human skin membranes were prepared from frozen skin samples, present at Triskelion. Human skin, derived from the breast and abdomen, was obtained from four female donors after surgery.

In agreement with the hospital, only skin tissue for which informed consent was given by the donor, was provided to Triskelion. The transportation of the skin to the laboratory was carried out on ice. Subcutaneous fat was removed and the skin was stored at <-18 °C until use.

Upon thawing, the skin was cut to a target thickness of ca. 0.2-0.4 mm (i.e. split-thickness skin membranes) using a Dermatome (25 mm, Nouvag GmbH, Germany). The thickness of all skin preparations was measured with a digimatic micrometer (Mitutoyo Corporation, Japan) and is presented in Appendix 1.

Flow-through diffusion cells and receptor fluid

Approximately 20 h before the start of exposure to the test preparation, the split-thickness skin membranes were placed in 9 mm flow-through automated diffusion cells (PermeGear Inc.,
Riegelsville, PA, USA) to hydrate the skin. The actual mean skin surface temperature was 32 ± 1ºC and exposure was at ambient humidity. Following application of the test preparations, the actual temperature was recorded at 15-minute intervals during the study in one diffusion cell containing a non-exposed skin membrane.



The receptor fluid was pumped at a flow rate of ca. 1.8 mL.h-1 and consisted of phosphate buffered saline (PBS) containing 0.01% sodium azide, (w/v)) supplemented with 6% PEG (polyoxyethylene-20-oleyl ether, v/v), pH ca. 7.2.
Signs and symptoms of toxicity:
not examined
Dermal irritation:
not examined
Absorption in different matrices:
Integrity of skin membranes

Prior to the determination of the percutaneous absorption of 10-Undecenoic acid, the permeation coefficient (Kp) for tritiated water was determined in human skin membranes.

Skin membranes with a Kp value below the cut-off value of 2.5×10-3 cm.h-1 were selected for the study. The individual data of the absorption of tritiated water through the skin preparations are given in Appendix 1.

Receptor fluid solubility

The solubility of 10-Undecenoic acid in water is reported to be 73.7 µg.mL-1 (at 30oC, see section
4.2.1 for reference). PBS containing 0.01% sodium azide (w/v), was supplemented with 6% PEG (w/v) to further improve the solubility of the test substance in the receptor fluid. In the present study, the maximum absorption of 10-Undecenoic acid into the receptor fluid was 375 µg (i.e. 587 µg.cm-2, replicate A-2) in ca. 40 mL over 24 h, i.e. 9.4 µg.mL-1. Therefore, the solubility in the receptor fluid was considered sufficient.

Furthermore, in the flow-through cells used, the volume of the receptor fluid in the receptor chamber beneath the skin was ca. 0.2 mL, which at a flow rate of ca. 1.8 mL.h-1, was replenished continuously (9 times per hour). Thus, it was assured that the rate of diffusion into the receptor fluid did not become a rate-limiting step (i.e. sink conditions were maintained).



Total recovery:
The mean absorption of 10-Undecenoic acid, applied as neat compound, into the receptor fluid over the 24 h study duration was 412 µg.cm-2, representing 4.31% of the applied dose. The mean maximal flux for the absorption of 10-Undecenoic acid through human skin was
34.7 µg.cm-2.h-1 and the lag time was 4.0 h.

The mean total absorption, defined as the compound-related radioactivity present in the receptor fluid, the receptor compartment wash and the skin membranes (excluding tape strips) was 5.52 ± 1.12% of the applied dose. The mean potentially absorbed dose, which is defined as the compound-related radioactivity present in the receptor fluid, the receptor compartment wash, the skin membranes and the stratum corneum (except for the first 2 tape strips) was 6.12 ± 1.19% of the applied dose.

The mean recovery of 10-Undecenoic acid in human skin was 99.3 ¿ 1.5% of the applied dose.

Less than 75% of the absorption of 10-Undecenoic acid in the receptor fluid over 24 hours occurred within half of the study duration (i.e. 12 hours). For risk assessment, in agreement with the EFSA Scientific Opinion behind the revision of the Guidance Document on Dermal Absorption (2012), it is considered appropriate to include the tape strips (except the first 2 tape strips) in the calculations of the total absorption values (i.e. use the potentially absorbed dose).

Based on the new EFSA guidance on dermal absorption (2017), the mean potentially absorbed should be corrected to account for variability. Based on the number of replicates (i.e. n=8), a multiple (i.e. 0.84) of the standard deviation is added to the mean value. The mean potentially absorbed dose is thus calculated as 7.1%.
Time point:
24 h
Dose:
9588 ± 127
Parameter:
other: [µg.cm-2]
Absorption:
7.1 %
Remarks on result:
other: In vitro Human skin absorption
Conclusions:
The mean potentially absorbed dose of Undecylenic acid though in vitro Human skin is thus calculated as 6.1%.
Executive summary:

The study was designed to examine the invitro percutaneous absorption of 10-Undecenoicacid (or Undecylenic acid) through human skin membranes. The test substance was tested as neat compound, which represents the maximal concentration possible when handling the neat compound. Under realistic in-use conditions the test item is handled at high temperatures; therefore, the test substance was applied in its liquid form,i.e.at a temperature ofca.37oC. The objective of the study was to elucidate the extent of percutaneous absorption of the compound-related radioactivity. The contact time was 8 hours,i.e.a normal working day and the post exposure time was 16 hours. In addition to the amount of radioactivity in the receptor fluid, the residues remaining in/on the skin membranes and in the stratum corneum(16 h post exposure) were determined. The study was performed in flow-through diffusion cells.

The mean absorption of 10-Undecenoic acid, applied as neat compound, into the receptor fluid over the 24 h study duration was 412 µg.cm-2, representing 4.31% of the applied dose. The mean maximal flux for the absorption of 10-Undecenoic acid through human skin was 34.7 µg.cm-2.h-1and the lag time was 4.0 h.

 The mean total absorption, defined as the compound-related radioactivity present in the receptor fluid,the receptor compartment was hand the skin membranes(excludingtapestrips) was 5.52 ± 1.12% of the applied dose. The mean potentially absorbed dose, which is defined as the compound-related radioactivity present in the receptor fluid, the receptor compartment wash,the skin membranes and the stratumcorneum(except for the first 2 tape strips) was 6.12 ± 1.19% of the applied dose.

 The mean recovery of 10-Undecenoic acid in human skin was 99.3±1.5% of the applied dose.

 Less than 75% of the absorption of 10-Undecenoic acid in the receptor fluid over 24 hours occurred within half of the study duration (i.e. 12 hours). For risk assessment, in agreement with the EFSA Scientific Opinion behind the revision of the Guidance Document on Dermal Absorption(2012),it is consideredappropriate to include the tape strips(except the first 2 tape strips) in the calculations of the total absorption values (i.e.use the potentially absorbed dose).

 Based on the new EFSA guidance on dermal absorption (2017), the mean potentially absorbed should be corrected to account for variability. Based on the number of replicates (i.e.n=8), a multiple (i.e.0.84) of the standard deviation is added to the mean value. The mean potentially absorbed dose is thus calculated as 7.1%.

Description of key information

No experimental toxicokinetic study is available on undecylenic acid.

However, as per REACH guidance document R7.C , information on absorption, distribution, metabolism and excretion may be deduced from the physical-chemical properties and QSAR predictions.

Based on the physical-chemical properties and QSAR predictions, the absorption of undecylenic acid is expected to be high by oral route and inhalation. By dermal route, an oecd 428 study (Maas, 2018) reported an percutaneous dermal absortion of 6%.

Key value for chemical safety assessment

Absorption rate - oral (%):
100
Absorption rate - dermal (%):
6
Absorption rate - inhalation (%):
100

Additional information

Available data on absorption, distribution, metabolism and excretion is very scarce, both for human and experimental animals.

Absorption

No oral or inhalation absorption study is available for undecylenic acid.

According to the model "Intestinal absorption (human)", 94.2% of the substance is absorbed (pkCSM).100% of oral absorption is taken into account for the risk assessment.

Based on the vapour pressure (1.92 x 10E-2 Pa), undecylenic acid is considered to be not volatile because lower than 100 Pa, however based on absence of data, 100% of absorption is taken for the risk assessment.

Data on dermal absorption (i.e. dermal penetration) are available in an OECD 428 in vitro skin penetration study (Maas, 2018), dermal penetration is estimated at 6% through Human skin.

Distribution

According to the model "VDss (human)", the volume of distribution (VD, i.e. theoritical volume that the total dose of a drug would need to be uniformly distributed to give the same concentration as in blood plasma) is high (Log between > 0.45).

Metabolism

No metabolism study is available.

Undecylenic acid should be degradable within the available fatty acid metabolism system. Initial metabolic activation of undecylenic acid may involve several enzymatic systems. First, the double bond at carbon 10 of undecylenic acid may undergo epoxidation followed by further oxidation to yield aldehyde and eventually carboxylic acid intermediates or by hydrolysis to yield diol intermediates. These enzymatic activations to the respective intermediates are expected to be very similar to those that result in the activation of eicosatetraenoic acid to intermediate precursors of leukotriene biosynthesis (Capdevila et al., 1982). Secondly, the cytochrome P450 gene 4 family (CYP4) consists of a group of over 63 members that omega-hydroxylate the terminal carbon of fatty acids (Hardwick, 2008). In mammals, six subfamilies have been identified and three of these subfamily members show a preference in the metabolism of short (C7-C10)-CYP4B, medium (C10-C16)-CYP4A, and long (C16-C26)-CYP4F, saturated, unsaturated and branched chain fatty acids. These omega-hydroxylated fatty acids are converted to dicarboxylic acids, which are preferentially metabolized by the peroxisome beta-oxidation system to shorter chain fatty acids that are transported to the mitochondria for complete oxidation. Third, undecylenic acid may undergo beta-oxidation, the first step of metabolic activation in the chain shortening and turn over process of all fatty acids in the fatty acid cycle (Katz and Guest, 1994).

Several metabolic intermediates of undecylenic acid may react with coenzyme A (CoA) and then enter as the coenzyme A ester the fatty acid pathway and the tricarboxylic acid cycle. To a minor extent, aldehyde intermediates also may be reduced to alcohols or conjugated with labile sulfhydryl-containing substances, such as glutathione (Brabec, 1993).

Elimination

The predicted total clearance (Pires, 2015) is estimated as high (1,68 mL/min/kg which is >= 1 mL/min/kg)

References

Brabec MJ. (1993)Patty’s Hygenie Toxicology, 4thEd.,, Vol. IIA, pages 283 – 327.

Capdevila J, Marnett LJ, Chacos N, Prough RA, Estabrook RW. (1982) Proc. Natl. Acad. Sci. USA.,79, 767-70.

Hardwick JP. (2008) Biochem Pharmacol. 75, 2263-2275.

Katz GV, and Guest D. (1994) Patty’s Hygenie Toxicology, 4thEd., Vol IID, Chapt. 36, pages 3523 – 3671.

Lington AW, and Bevan C. (1994) Patty’s Hygenie Toxicology, 4thEd., Vol. IID, Chapt. 30, pages 2585 – 2750.