Octanoic acid, 2-phenoxyethyl ester

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

25 Oct - 01 Dec 2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 428 (Skin Absorption: In Vitro Method)

Version / remarks:

adopted Apr 2004

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit, München, Germany

Radiolabelling:

yes

Details on in vitro test system (if applicable):

SKIN PREPARATION
- Source of skin: Skin membranes of female human abdominal origin sourced from cosmetic surgery were used. Due to inter-individual variability skin from 4 different donors was used.
- Skin samples are either purchased from Biopredic International, France or prepared at Eurofins Munich in house (skin obtained from Hepacult/HTCR).
- Type of skin: Human abdominal skin without stretch marks, hair, moles or birthmarks. The dermatomed skin discs (200 to 400/500 µm) comprising the stratum corneum, the epidermis and part of the dermis showed a diameter of 16 mm.
- Thickness of skin (in mm): undiluted test substance: 0.385 - 0.458; diluted test substance: 0.356 - 0.442
- Membrane integrity check: After visual check of the skin membrane, the skin in the assembled diffusion cells was checked for barrier integrity using tritiated water. Therefore, after equilibration of the skin membranes for approximately 15 min, 40 µL of tritiated water (1 kBq) were applied to the skin surface for 20 min. The receptor fluid flow was regulated to deliver about 0.2 mL/h. The unabsorbed material was then blotted with a cotton-tipped applicator and 40 µL PBS was applied to the skin surface. Effluent from the flow cell was collected for an additional 60 min. Skin was regarded as being undamaged if not more than 2% of the applied radioactivity was recovered from the receptor fluid.
- Storage conditions: ≤ -15 °C

PRINCIPLES OF ASSAY
- Diffusion cell: The diffusion cell is designed with a PTFE-donator and -acceptor part of the flow through diffusion cell for horizontal exposure of the skin surface.
- Receptor fluid: 50% ethanol
- Flow-through system: The diffusion cells were set in a microprocessor controlled thermostatisation block. A multi-channel peristaltic pump was connected with the receptor part of the diffusion cell and a programmable fraction collector was responsible for collecting the samples. The receptor fluid flow was regulated to deliver about 0.2 mL/h.
- Test temperature: undiluted test substance: 31.1 - 33.5 °C (8 h) and 31.4 - 33.1 °C (24 h); diluted test substance: 32.3 - 33.8 °C (8 h) and 31.9 - 33.6 °C (24 h)
- Other: 10 µL/cm² were applied onto the skin surface (0.78 mm²), depending on the physical state of the test formulation (solid/liquid). Two different concentrations of the test item were tested. For each concentration - undiluted and diluted concentration - of the formulation 10 replicates were set up. After an exposure period of 8 h the test item was washed off with a cleansing agent (1% aqueous soap solution, “Reine Pflanzenöl Kernseife”, Haslinger Seifen & Kosmetik GmbH, Charge: 2981). Residual test item was wiped from the donor side of the diffusion cell and the skin surface with a cotton bud. Additionally various rinsing steps with receptor fluid were performed to remove the remaining test item. The cotton buds and the rinsing liquid were stored at ≤ -15°C for further analysis of the remaining test item. After a 24 h period the experiment will be terminated. Sampling times of receptor fluid were 1, 2, 4, 8, 12, 16 and 24 h. The receptor fluid flow was regulated to deliver about 0.2 mL/h. The skin discs were removed from the chambers and stripping of the upper skin layers was performed. Skin was stripped with 15 pieces of adhesive tape, whereas groups of the sequential layers will be pooled. Tape stripping was terminated, if there was evidence that the stratum corneum had been completely removed. Up to 100 µL of each fraction of the receptor fluid were mixed with 2 mL scintillation cocktail (UltimaGoldTM, Perkin Elmer). The quantitatively collected residual test item (cotton buds) was supplemented with 10 mL scintillation cocktail and incubated in a water bath at 50 °C for about 60 minutes. The exposed skin discs and strips were incubated with 4 mL or 3 mL SolvableTM (Perkin Elmer), respectively over night at 50°C. After lysis of the skin and cooling down to room temperature, 100 µL of this extract were added to 2 mL of the scintillation cocktail.
The amount of test item in the receptor fluid, the quantitatively collected residual, non penetrated test item (skin wash), the skin and the strips were analyzed using a β-counter (Tricarb, Perkin Elmer).

Absorption in different matrices:

- Receptor fluid (in vitro test system): In the receptor fluid mean values of 0.28% (SD: 0.31%) of the undiluted test item and 3.67% (SD: 3.52%) of the 10% test item formulation were detected.
- Skin preparation (in vitro test system): In the skin mean values of 3.06% (SD: 0.84%) of the undiluted test item and 9.78% (SD: 4.79%) of the 10% test item formulation were detected.

Total recovery:

- Total recovery: Mean recovery rates were 100.26% and 95.11% for the undiluted and the 10% formulation of the test item, respectively.

Key result

Time point:

24 h

Dose:

10 µL/cm²

Parameter:

amount

Remarks:

mean

Absorption:

6.78 %

Remarks on result:

other: undiluted test item

Key result

Time point:

24 h

Dose:

10 µL/cm²

Parameter:

amount

Remarks:

mean

Absorption:

18.85 %

Remarks on result:

other: 10% test item solution in (in Basic Formulation W/O Lotion mit Tegosoft XC+DEC)

Table 1: Results (undiluted)

	1	2	3	4^d	5	6^d	7	8	9^d	10	Mean^e	SD
Skin Wash 8h	77.38	81.63	85.27	77.52	79.87	78.10	77.40	87.77	64.87	82.00	81.62	3.88
Skin Wash 24 h	3.04	3.86	2.55	1.06	1.98	1.19	4.52	2.16	11.66	2.06	2.88	0.98
Chamber wash lid	0.23	0.70	0.54	0.43	0.13	0.29	0.66	0.30	0.71	0.36	0.42	0.22
Strips 1-2	8.18	4.68	5.89	7.41	4.98	4.05	8.68	3.69	14.94	7.27	6.20	1.89
Strips 3 - ∞	7.66	5.90	2.64	6.91	7.08	4.20	5.34	3.53	4.15	4.71	5.27	1.81
Skin	3.17	2.76	2.26	5.65	4.67	11.12	3.09	2.15	1.83	3.31	3.06	0.84
Receptor Fluid (RF)	0.08	0.22	0.43	0.67	0.90	0.29	0.15	0.07	1.71	0.08	0.28	0.31
Gauze	0.23	0.22	0.37	0.27	0.28	0.69	0.12	0.23	0.08	0.19	0.24	0.08
Chamber wash RF	0.04	0.03	0.05	0.07	0.09	0.07	0.03	0.10	0.06	0.03	0.05	0.03
Total	100.00	100.00	100.00	100.00	100.00	100.00	100.00	100.00	100.00	100.00	100.00	0.00
Absorption [%]^a	11.18^b	3.24	5.75^b	6.66	13.03^b	16.37	3.39	2.55	7.82	8.31^b	6.78^c	4.16
Recovery [%] normalized on applied dose	100.49	96.49	99.52	98.63	102.14	99.48	100.39	103.56	94.92	99.21	100.26	2.25
% of total absorption at 12h	70.64	85.15	59.55	96.49	8.98	5.56	92.31	77.83	45.64	69.30	66.25	27.46

In the total absorption (a) the amount of test item of skin, receptor fluid, gauze and chamber wash RF is included. In case of chamber 1, 3, 5 and 10 the strips 3 - ∞ were included in the calculation of the total absorption (b). The mean value for total absorption (c) is calculated of the total absorption values of the single replicates. Replicates 4, 6 and 9 were excluded for evaluation of results (d). Mean is calculated from skin replicates1, 2, 3, 5, 7, 8 and 10(e).

Replicates 4 and 6 were excluded for evaluation of results due to a lack of receptor fluid. Replicates 9 was excludedbecause the recovery rates was outside the range of 100% ± 10%.

Table 2: Results (10% formulation)

	1^d	2^d	3	4^d	5^d	6	7	8	9	10	Mean^e	SD
Skin Wash 8h	64.59	77.43	75.66	56.44	46.66	64.74	61.14	58.50	63.09	70.28	65.57	6.33
Skin Wash 24 h	4.85	1.49	3.20	4.46	5.52	4.33	5.98	4.15	4.06	5.55	4.54	1.03
Chamber wash lid	0.48	0.24	0.27	0.72	0.18	0.27	0.28	0.21	0.25	0.20	0.25	0.04
Cotton	0.61	0.64	0.65	0.62	0.69	0.64	0.67	0.62	0.59	0.66	0.64	0.03
Strips 1-2	3.32	2.16	3.99	5.14	7.63	7.41	8.93	10.23	7.18	4.06	6.97	2.53
Strips 3 - ∞	10.08	4.30	4.57	9.73	14.92	8.15	6.82	9.32	9.76	5.31	7.32	2.12
Skin	5.87	12.58	3.27	12.43	9.58	12.98	14.41	12.87	10.83	4.30	9.78	4.79
Receptor Fluid (RF)	6.45	0.24	7.11	7.67	13.93	0.22	0.21	2.64	3.17	8.66	3.67	3.52
Gauze	3.63	0.88	1.24	2.38	0.80	1.16	1.26	1.37	1.01	0.85	1.15	0.19
Chamber wash RF	0.13	0.04	0.04	0.42	0.09	0.11	0.29	0.09	0.06	0.12	0.12	0.09
Total	100.00	100.00	100.00	100.00	100.00	100.00	100.00	100.00	100.00	100.00	100.00	0.00
Absorption [%]^a	26.15	18.04	16.24	32.63	39.32	22.61	23.00	16.97	15.07	19.24	18.85	3.35
Recovery [%] normalized on applied dose	87.99	96.59	97.30	87.19	89.62	94.81	94.95	94.79	94.33	94.51	95.11	1.09
% of total absorption at 12h	49.33	37.37	48.68	1.06	44.21	61.83	61.72	97.14	93.39	45.03	67.96	22.23

In the total absorption (a) the amount of test item of skin, receptor fluid, gauze and chamber wash RF is included. In case of chamber 3, 6, 7 and 10 the strips 3 - ∞ were additionally included (b). The mean value for total absorption (c) is calculated of the total absorption values of the single replicates. Replicates 1, 2, 4 and 5 were excluded for evaluation of results (d). Mean is calculated from skin replicates 3, 6, 7, 8, 9 and 10(e).

Replicates 2 and 5 were excluded for evaluation of results due to a lack of receptor fluid. Replicates 1 and 4 were excludedbecause the recovery rates was outside the range of 100% ± 10%.

Description of key information

Octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1) is expected to have a high absorption potential via the oral route, but low absorption potential via the dermal and the inhalation route. The ester will be probably hydrolysed to the respective fatty alcohol 2-phenoxyethanol and the respective fatty acid octanoic acid in the gastrointestinal tract and mucus membranes, which facilitates the absorption. The fatty acid octanoic acid may be re-esterified with glycerol into triacylglycerides (TAGs) and transported via chylomicrons or absorbed from the small intestine directly into the bloodstream and transported to the liver. Via chylomicrons, fatty acids are transported via the lymphatic system and the blood stream to the liver and to extrahepatic tissue for storage e.g. in adipose tissue (Stryer, 1994). The major metabolic pathway for linear and branched fatty acids is the beta-oxidation pathway for energy generation, while alternatives are the omega-pathway or direct conjugation to more polar products. The excretion of octanoic acid will mainly be as CO₂in expired air; with a smaller fraction excreted as conjugated molecules in the urine. The excretion of 2-phenoxyethanol will occur in form of its metabolite 2-phenoxyacetic acid and its conjugates via urine. Thus, due to the metabolism of the parent substance and of the hydrolysis products, a bioaccumulation potential of the parent substance is not assumed.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

There were no in vivo toxicokinetic studies available for octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1). In accordance with Annex VIII, Column 1, 8.8.1, of Regulation (EC) 1907/2006 and with ‘Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance’ (ECHA, 2017), an assessment of the toxicokinetic behaviour of the substance octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1) was conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance-specific data on physico-chemical and toxicological properties according to the Chapter R.7c Guidance document (ECHA, 2017) and the results of an in vitro human skin penetration study.

Octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1) is a clear, colourless liquid at 20 °C which has a molecular weight of 264.37 g/mol and a water solubility of < 1 mg/L (Evonik, 2009). The experimentally determined log Pow value is 4.9 at 25 °C (Evonik, 2009) and the vapour pressure is determined to be 3.89E-03 Pa at 20 °C (Evonik, 2009).

 

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful physico-chemical parameters providing information on this potential are the molecular weight, the water solubility and the octanol/water partition coefficient (log Pow) value. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2017).

 

Oral

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds may be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) as these would otherwise be poorly absorbed (Aungst and Shen, 1986; ECHA, 2017).

When assessing the potential of octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1) to be absorbed in the GI-tract, it has to be considered that fatty acid esters will undergo to a high extent hydrolysis by ubiquitous GI-enzymes (Long, 1958; Lehninger, 1970; Mattson and Volpenhein, 1972; National technical information service, 1973). The resulting hydrolysis products are predicted by QSAR analysis using the OECD QSAR Toolbox (v4.2, OECD, 2018), which is further described in the metabolism section below. Therefore the predictions based on the physico-chemical characteristics of the intact parent substance may no longer apply alone but also include the physico-chemical characteristics of the breakdown products of the ester; the alcohol 2-phenoxyethanol and the corresponding fatty acid, octanoic acid.

The low water solubility (< 1 mg/L) and the high log Pow value of 4.9 of the parent compound indicate that absorption may be limited by the inability to dissolve into GI fluids. However, micellular solubilisation by bile salts may enhance absorption, a mechanism which is especially of importance for highly lipophilic substances with log Pow > 4 and low water solubility (Aungst and Shen, 1986).

In an opinion on 2-phenoxyethanol from the Scientific Committee on Consumer Safety, it has been reported that 2-phenoxyethanol was completely absorbed and rapidly excreted in rats after oral administration with 2-phenoxy[1-14C]ethanol. > 90% of 14C was found in urine where only 2-phenoxyacetic acid and its derivatives, mainly conjugates, could be detected (include reference).

The absorption potential of the hydrolysis product octanoic acid (144.2 g/mol) is also likely to be increased by micellular solubilisation. Within the epithelial cells, fatty acids are (re)-esterified with glycerol to triglycerides.

A study on acute oral toxicity with octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1) showed no signs of systemic toxicity, resulting in a LD50 value greater than 2000 mg/kg bw (Evonik, 2009). This may, however, also indicate low toxicity rather than a low absorption potential. The results of a subacute oral toxicity performed with octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1) the rat showed no adverse systemic effects; resulting in a NOAEL of 1000 mg/kg bw/day (Evonik, 2012).

In conclusion, taking into account the physico-chemical and toxicological properties of octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1), the oral absorption potential of the test substance and its hydrolysis products (2-phenoxyethanol and octanoic acid) is considered high.

Dermal

The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. The dermal uptake is expected to be low if the water solubility is < 1 mg/L. Log Pow values in the range of 1 to 4 are favourable for dermal absorption (values between 2 and 3 are optimal), in particular if the water solubility is high. For substances with a log Pow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2017).

Octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1) has a molecular weight of 264.37 g/mol and a water solubility of < 1 mg/L; therefore a low dermal absorption potential is likely (ECHA, 2017). The log Pow is 4.9, which means that the uptake into the stratum corneum is predicted to be slow and the rate of transfer between the stratum corneum and the epidermis will be slow (ECHA, 2017).

An in vitro human skin penetration study was performed according to OECD guideline 428 and under GLP conditions with octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1) (Evonik, 2018). Under the conditions of the study, permeation of octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1) through human skin was low. The major part of the applied dose was found remaining on the skin surface (84.5% skin wash 8 h and 24 h). The mean total absorption, comprising the content of active ingredient of strips, skin and receptor fluid, was found to be 6.78% ± 4.16% in the undiluted concentration. In the skin mean values of 3.06% (SD 0.84%) and in the receptor fluid mean values of 0.28% (SD 0.31%) were detected. The in vitro dermal penetration potential was therefore considered to be very low.

Damage to the skin surface may enhance penetration of the test substance (ECHA, 2017). However, available in vitro corrosion and irritation studies with octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1) revealed neither skin corrosive nor skin irritant properties of the test substance (Evonik, 2009). Moreover, a local lymph node assay performed with octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1) did not show a potential for skin sensitisation (Evonik, 2009).

Overall, taking into account the physico-chemical properties and toxicological properties of octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1), the dermal absorption potential of the substance is expected to be low.

Inhalation

The Inhalation potential of octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1) is considered as negligible as the test substance has a very low vapour pressure of 3.89E-03 Pa (Evonik, 2009) and a very high boiling point of 342 °C (Evonik, 2009). This indicates the substance has a low volatility. Moreover, the use of the substance will not result in spray applications and the possibility of exposure to aerosols, particles or droplets of an inhalable size. Thus, exposure to humans via the inhalation route will be unlikely to occur.

Based on the physico-chemical properties and uses of octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1), absorption via the respiratory tract and lungs is negligible.

Distribution and accumulation

Distribution of a compound within the body depends on the physico-chemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. Small water-soluble molecules and ions will diffuse through aqueous channels and pores. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2017).

As the parent compound octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1) will largely be hydrolysed prior to absorption (as discussed above); the distribution of the intact substance is less relevant than the distribution of the hydrolysis products, 2-phenoxyethanol and octanoic acid.

Like all medium and long chain fatty acids, the fatty acid octanoic acid may be re-esterified with glycerol into triacylglycerides (TAGs) and transported via chylomicrons or absorbed from the small intestine directly into the bloodstream and transported to the liver. Via chylomicrons, fatty acids are transported via the lymphatic system and the blood stream to the liver and to extrahepatic tissue for storage e.g. in adipose tissue (Stryer, 1994).

After a single oral dose of 14C-2-phenoxyethanol, no relevant amount of the administered radioactivity was detected as CO2 in exhaled air for either dose. At 168 hours after dosing, the total amount of radioactivity excreted in urine and in faeces was ≥ 90% and approximately 2%, respectively. The time course for appearance of radioactivity in urine and faeces indicated rapid excretion after administration (SCCS, 2016). Therefore accumulation is not expected for the alcohol.

The intact parent compound is not expected to bioaccumulate as hydrolysis mainly takes place before absorption and distribution. Accumulation of the fatty acids in triglycerides in adipose tissue or the incorporation into cell membranes is possible as further described in the metabolism section below. However, at the same time, fatty acids will be used for energy generation. There is a continuous turnover of fatty acids as they are permanently metabolised and excreted. Bioaccumulation of fatty acids only takes place, if their intake exceeds the caloric requirements of the organism.

In summary, the available information on octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1) and its breakdown products indicate that no significant bioaccumulation of the parent substance for its hydrolysis products in adipose tissue is expected.

Metabolism

Fatty acid esters like octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1) will undergo enzymatic hydrolysis in the GI-tract to the respective fatty acids and fatty alcohol (Long, 1958; Lehninger, 1970; Mattson and Volpenhein, 1972; National technical information service, 1973). The esterases catalysing the reaction are present in most tissues and organs, with particularly high concentrations in the GI-tract and the liver (Fukami and Yokoi, 2012).

An important metabolic pathway for linear fatty acids is the beta-oxidation for energy generation. In this multi-step process, the fatty acids are at first esterificated into acyl-CoA derivatives and subsequently transported into cells and mitochondria by specific transport systems. In the next step, the acyl-CoA derivatives are broken down into acetyl-CoA molecules by sequential removal of 2-carbon units from the aliphatic acyl-CoA molecule. Further oxidation via the citric acid cycle leads to the formation of H2O and CO2 (Lehninger, 1970; Stryer, 1994).

According SCCS (2016), the main biotransformation step of 2-phenoxyethanol in rats is oxidation of the terminal hydroxyl group to a carboxylic acid. This yields the dominant metabolite phenoxyacetic acid. In this SCCS opinion, it is further reported from an adult male volunteer who ingested a dose of 10.3 mg non-labelled 2-phenoxyethanol. Urine was collected 24 h before dosing and for 72 h thereafter. 2-Phenoxyethanol was rapidly and completely absorbed and excreted in urine. Free 2-phenoxyethanol and 2-phenoxyacetic acid was extracted from urinary samples: the remaining aqueous phase was acidified and hydrolysed. Only free 2-phenoxyacetic acid (85%) and its conjugates (15%) were found by use of gas/liquid chromatography. No free 2-phenoxyethanol or its conjugates could be detected.

In addition, the potential metabolites following enzymatic metabolism were predicted using the QSAR OECD toolbox (v4.2, OECD, 2018). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. 33 hepatic and 2 dermal metabolites were predicted for the test substance, respectively. In the skin and in the liver, hydrolysis of the parent substance to 2-phenoxyethanol and octanoic acid is predicted. In the liver, several other metabolites such as short chain aldehydes, alcohols or carboxylic acids were also predicted. These predicted metabolites can be regarded as phase I metabolites which are a common prerequisite for the phase II reactions or conjugation reactions, which transfer functional groups to the phase I metabolites to increase the water solubility and the excretion of the xenobiotic. Phase II metabolism by e.g. uridine 5′-diphospho(UDP)-glucuronosyltransferases (UGT) and sulfotransferases typically generate excretable hydrophilic metabolites by transferring activated glucuronic acid and sulfate-moiety to hydroxyl groups of the substrates, respectively (Aktories, 2005). Besides the skin and liver metabolites, up to 60 metabolites were predicted to result from all kinds of microbiological metabolism for the test substance. Most of the metabolites were found to be a consequence of the degradation of the molecule.

Available genotoxicity data from the test substance octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1) do not show any genotoxic properties. In particular, an Ames-tests (Evonik, 2009), an in vitro chromosomal aberration test and an in vitro mammalian gene mutation assay were consistently negative and therefore no indication of a genotoxic reactivity is indicated.

Excretion

Based on the metabolism described above, octadecanoic acid, 2-phenoxyethyl ester (CAS 23511-73-1) and its breakdown products are expected to be metabolised in the body to a high extent. The fatty acid component is not expected to be excreted to a significant degree via the urine or faeces but excreted via exhaled air as CO2 or stored as described above. The metabolite of the alcohol component 2-phenoxyacetic acid is excreted via urine unchanged or as conjugate (SCCS, 2016).

References

Aktories K., Förstermann U., Hofmann F. and Starke K. (2005): Allgemeine und spezielle Pharmakologie und Toxikologie. 9. Auflage, Urban & Fischer Verlag.

Aungst B. and Shen D.D. (1986). Gastrointestinal absorption of toxic agents. In Rozman K.K. and Hanninen O. Gastrointestinal Toxicology. Elsevier, New York, US.

ECHA (2017). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 2.0, June, 2017.

Fukami, T. and Yokoi, T. (2012). The Emerging Role of Human Esterases. Drug Metab Pharmacokinet 27(5): 466-477

Lehninger, A.L. (1970). Biochemistry. Worth Publishers, Inc.

Long, C.L. et al. (1958). Studies on absorption and metabolism of propylene glycol distearate. Arch Biochem Biophys, 77(2):428-439.

Mattson F.H. and Volpenhein R.A. (1968). Hydrolysis of primary and secondary esters of glycerol by pancreatic juice. J Lip Res 9, 79-84.

Mattson, F.H. and Volpenheim, R.A. (1972). Absorbability by rats of compounds containing from one to eight ester groups. J Nutrition, 102: 1171 -1176.

National technical information service (1973). Evaluation of the Health Aspects of Propylene Glycol and Propylene Glycole Monostearate as Food Ingredient. Fed of America Societies for Experimental Biology, Bethesda, MD. Contract No. FDA 72 – 85.

OECD, 2018: OECD QSAR Toolbox v4.2, Feb 2018, Laboratory of Mathematical Chemistry Oasis. Downloaded from https://qsartoolbox.org/ Prediction performed on 30 Apr 2018.

Scientific Committee on Consumer Safety (SCCS, 2016): Opinion on 2-phenoxyethanol. SCCS/1575/16, 06 October 2016.

Stryer, L. (1994): Biochemie. 2nd revised reprint, Heidelberg; Berlin; Oxford: Spektrum Akad. Verlag.