2-phenoxyethanol

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
See toxicokinetics, metabolism and distribution.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

According to OECD 417, biokinetic data of 2-phenoxyethanol were studied in male and female rats after single oral administration (BASF AG, 2007).In rats exposed to¹⁴C-2-phenoxyethanol, the test substance was rapidly and almost completely absorbed from the gastrointestinal tract with the highest plasma concentrations present 1-2 hours post-dosing.

After absorption, the radioactive material was distributed in different organs and tissues (GI tract, kidney, liver, pancreas, brain, muscle, heart, uterus, skin, bone marrow, and bone), tissue radioactivity concentrations generally declined with time parallel to plasma concentrations. In exhaled air, no relevant amounts of the administered radioactivity were detected as CO₂. The excretory investigations indicated a rapid excretion and showed that recovered radioactivity was predominantly excreted via urine (urine: 92-94%; faeces: 1.9-2.9%). Furthermore the results demonstrated that there were no gender differences in the excretion pattern, irrespectively of the dose.

The bioavailability of the test substance was generally > 90% of the applied dose. The plasmakinetic data indicated that an increase of the dose resulted in a disproportional increase of the AUC-values, demonstrating a saturation of excretion with increasing dose.

 

In a second study according to OECD 417 (BASF AG, 2007),the investigation of the metabolism of 2-phenoxyethanol in excreta, bile and plasma samples of female rats after oral administration of¹⁴C-2-phenoxyethanol was carried out. The results of this study confirmed the biokinetic data of BASF AG(2007). Overall, the elimination of the test compound was fast with up to approximately 70% of the dose being excreted within the first 6 hours (urine and faeces).

The authors observed that 2-phenoxyethanol was nearly completely metabolised. In urine and bile, less than 0.7% of the dose had been assigned to the parent compound. The parent compound was mainly metabolised to phenoxyacetic acid (PAA) by oxidation of the terminal hydroxyl group to carboxylic acid(up to 64% of the dose). Seven further metabolites were identified with up to < 10% of the applied dose. The other metabolic changes of¹⁴C-phenoxyethanol were either ring sulfation after hydroxylation or conjugation with glucuronic acid at the side chain. In a further step, these metabolites were mainly hydroxylated at the ring and in one case the terminal hydroxyl group was oxidised to carboxylic acid. In another study, The Dow Chemical Company (1986) identified also only small amounts of the parent compound and increased amounts of the metabolite PAA in serum samples of rabbits. This finding is further supported by a publication of Lappin et al. (2002). In this study oral administration of 4-chloro-2-methylphenoxyacetic acid (MCPA), a phenoxy herbicide, to the dog resulted in a significantly different pharmacokinetic profile to that observed in the rat. Excretion was much less rapid and metabolism more extensive in the dog and faecal elimination was an important route, particularly at higher doses. For the same dose levels area under the plasma curve (AUC) in dogs was up to one order of magnitude higher than in rats. These differences reflect the well-established low renal clearance of certain organic acids by dogs. Metabolic profiles from human volunteer studies, and indirect evidence from poisoning cases, suggest that in the case of MCPA (and the phenoxy herbicides in general) the rat is the more relevant model for human exposure.

 

BASF AG (2007) evaluated the relative rates of 2-phenoxyethanol metabolism in different species in vitro using liver S9 fractions. Since the haemolytic effects of 2-phenoxyethanol have been shown to be due to the intact parent compound (see chapter 7.9.3: BASF AG, 2007), any species differences in the overall metabolic fate of this compound could be useful in estimating interspecies variations in sensitivity to haemolysis.
The results indicated that the in vitro metabolism of 2-phenoxyethanol was primarily NADPH dependent, producing PAA as the major metabolite. The following species differences in the rate of PAA formation were found (from the highest to the lowest rate): human > rat > mouse > rabbit. With the exception of the rabbit data, these results were consistent with the in vitro relative sensitivity of these species to the haemolytic effects of 2-phenoxyethanol (see section 7.9.3: BASF AG, 2007).

These data suggest that metabolism of 2-phenoxyethanol to PAA is likely a detoxification pathway that limits haemolysis. In conclusion, human blood cells appeared to be more resistant to 2-phenoxyethanol-induced haemolysis than rat or rabbit blood cells and human liver tissue appeared to more rapidly metabolise 2-phenoxyethanol than either rat or rabbit liver.

 

The dermal absorption of 2-phenoxyethanol through rat and human skin under static and flow-through conditions was investigated in in vitro studies by Roper et al. (1997). 2-Phenoxyethanol was rapidly absorbed through rat skin mounted in both the static and flow-through diffusion cell with either aqueous ethanol or modified Earle’s medium (MEM) as receptor fluid. The stratum corneum did not appear to be a good barrier to 2-phenoxyethanol penetration. Covering increased the permeability coefficient of 2-phenoxyethanol in the static cell. The permeability profile and amount absorbed were similar for human and rat skin in the flow-through system with tissue culture medium. The mass balance recovery of 2-phenoxyethanol in the uncovered studies was low; static diffusion 68% and flow-through diffusion cell 51% at 24 h, due to the high evaporation. Percutaneous absorption values were determined as follows:

Rat: static (uncovered skin, 24 h): 64 ± 4%; static (covered skin, 24 h): 98.8 ± 7.0%; flow-through (uncovered skin, 24 h): 43 ± 3.7%

Human: flow-through (uncovered skin, 6 h): 59.3 ± 7.0%

 

Taking into account all metabolism/biokinetic data, there is no potential for bioaccumulation of 2-phenoxyethanol.

The physiologically-based pharmacokinetic (PBPK) model of Troutman et al (2015) was developed in order to reduce uncertainty associated with interspecies extrapolation and to derive margins of safety that can be used for risk assessment of phenoxyethanol, particularly after oral and dermal exposure. The total uncertainty factor for extrapolation of animal data to humans could be reduced from 100 to 25, i.e. if the margin of exposure is >25 the use of phenoxyethanol can be considered as safe.

 

References:

Lappin, G. J. et al. (2002). Absorption, metabolism and excretion of 4-chloro-2-methylphenoxyacetic acid (MCPA) in rat and dog. Xenobitika, Vol.32, No2, 153-163