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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Type of information:
other: Expert Assessment
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Peer-reviewed assessment report (attached in section 13)
Objective of study:
absorption
distribution
excretion
metabolism
toxicokinetics
Qualifier:
no guideline required
Principles of method if other than guideline:
The toxicokinetic behaviour of ethoxyquin was assessed and summarized by expert judgement within a peer-reviewed assessment report, taking into account the available toxicokinetics and phys.-chem. data.
GLP compliance:
no
Radiolabelling:
other: partially in reference toxicokinetic study
Species:
other: not applicable
Strain:
other: not applicable
Details on test animals or test system and environmental conditions:
not applicable
Route of administration:
other: not applicable
Details on exposure:
see results
Duration and frequency of treatment / exposure:
see results
Details on study design:
see results
Details on dosing and sampling:
see results
Type:
absorption
Results:
Oral absorption of 25 mg/kg bw was >90%, absorption of 250 mg/kg bw was 70%.
Type:
distribution
Results:
Ethoxyquin was rapidly partitioned from the blood into the major tissues of both rats and mice.
Type:
excretion
Results:
About 90 % of 25 mg/kg bw (given by oral or by iv route) was excreted in urine and faeces within 24 hours post-dosing. No more than 60 % of the higher dose of 250 mg/kg bw was excreted within 24 hours following oral (gavage) administration.
Details on absorption:
Oral absorption:
Ethoxyquin was rapidly and nearly quantitatively (> 90 %) absorbed from the GI tract of rats following single oral (gavage) administration of 25 mg/kg bw. The assumption of this high oral absorption rate is based on urinary excretion and the comparison of the elimination pattern in the experiments with oral and iv exposure. Peak blood concentrations were observed 0.75 hour after dosing. In contrast, single oral administration of a tenfold higher dose of 250 mg/kg bw resulted in only 70 % absorption within 24 h following dosing.

Dermal absorption:
No experimental dermal absorption data is available for ethoxyquin. Thus, the assessment has to be based on physico-chemical endpoints. The values for the molecular mass and the octanol/water partition coefficient support the assumption of 100 % dermal absorption for ethoxyquin as a small lipophilic molecule. Toxicokinetic studies show virtually complete absorption at low doses if administered as a single oral dose. The actual amount of absorbed compound will depend on the type of emulsion in the preparation that is handled but for exposure calculation, 100 % should be used as a worst-case assumption.
Details on distribution in tissues:
Ethoxyquin was rapidly partitioned from the blood into the major tissues of both rats and mice receiving 25 mg/kg bw by iv injection. The disposition of single doses up to 25 mg/kg bw was similar in the rat and mouse. Liver, kidney, and adipose tissue consistently contained the highest concentrations of ethoxyquin-derived radioactivity. The content of [14C]-ethoxyquin in the brain, however, was not analysed. At least in rats, a portion of 8 % of blood content of [14C]-ethoxyquin appeared to have been covalently bound to plasma proteins. Interestingly, levels of ethoxyquin in rat blood increased again from 12 hours to 24 hours post dosing. This might be indicative of a redistribution from a deep compartment such as adipose tissue back into blood.
Key result
Transfer type:
other: Transfer into organs
Observation:
distinct transfer
Remarks:
Liver, kidney, and adipose tissue consistently contained the highest concentrations of ethoxyquin-derived radioactivity.
Details on excretion:
About 90 % of a total low dose (25 mg/kg bw given either by the oral or by the iv route) was excreted in urine and faeces within 24 hours post-dosing. In contrast, no more than 60 % of the higher dose of 250 mg/kg bw was excreted within 24 hours following oral (gavage) administration.
Urinary excretion only slightly predominated over faecal excretion (60 % / 40 %) suggesting that a remarkable amount must have been eliminated via bile. The occurence of enterohepatic circulation was confirmed in another study where approximately 16 % of the dose was reabsorbed from the intestines following biliary excretion.
Total recovery of radioactivity accounted for more than 90 % but the fate of about 7 % remains unknown.
Toxicokinetic parameters:
Tmax:
Remarks:
levels of ethoxyquin in rat blood increased again from 12 hours to 24 hours post dosing.
Metabolites identified:
yes
Details on metabolites:
Metabolism of ethoxyquin was rapid in both the rat and the mouse following either oral or iv administration. Little or no parent compound was detected in cumulative 24-hour urine.
Ethoxyquin has been shown to induce a wide range of enzymes, including cytochrome P450, epoxide hydrolase, and glucuronosyl and GSH transferases. All of these enzyme systems appear to be involved in ethoxyquin metabolism and induction of any or all of these systems should result in more rapid clearance of the compound and, thus, ethoxyquin might induce its own metabolism. Ethoxyquin was primarily metabolised to easily excretable conjugation products whereby certain species differences in conjugation pathways were detected. Mice produced primarily glucuronide metabolites whereas in rats sulphate conjugates were predominant. This difference might be due to higher sulphotransferase activity in the rat.
The major pathways of ethoxyquin metabolism in both species were O-deethylation and conjugation to endogenous substrates.
The two major ethoxyquin metabolites excreted in rat urine were in the form of sulphate conjugates: 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline sulphate (metabolite G), and 1,2,3,4-tetrahydro-3,6-dihydroxy-4-methylene-2,2-dimethylquinoline sulphate (metabolite E). The latter might have arised from an intramolecular rearrangement of the 3,4-epoxide of ethoxyquin. A third peak was identified as a hydroxylated conjugate: 1,2-dihydro-6-ethoxy-8-hydroxy-2,2,4-trimethylquinoline glucuronide (metabolite H), but levels of glucuronides in rat urine were lower than those of sulphates.
In rat bile, ethoxyquin-derived radioactivity was excreted mainly as GSH conjugates. Two of these biliary metabolites were glutathione conjugates of ethoxyquin 3,4-epoxide. The third seemed to be a conjugate of either ethoxyquin 7,8-epoxide or 2,2,4-trimethylquinol-6-one. However, between 75 and 85 % of total radioactivity excreted in the bile within 12 h of oral dosing was reported to be unchanged ethoxyquin.
In contrast to the rat, mouse urine contained one major glucuronide, 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline glucuronide (metabolite F), as well as one major sulphate conjugate, 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline sulphate (metabolite G).
In rats, sulphation appears to become saturated in rats following repeated exposure to 250 mg/kg bw, as evidenced by the large decrease in metabolites E and G, whereas glucuronide metabolites F and H dramatically increased. This may be explained by the fact that hepatic sulphation (but not glucuronidation) has been shown to be capacity-limited at high xenobiotic doses.
Conclusions:
As information was provided via a peer-reviewed assessment report, it can be considered as sufficiently reliable to describe sufficiently the toxicokinetic behaviour of ethoxyquin, and to predict relevant absorption rates and the potential for bioaccumulation. Based on the rapid distribution and general excretion, no high potential for bioaccumulation can be detected, bioaccumulation in the central nervous system however cannot absolutely be excluded. Oral absorption rates vary dose-dependently between 70% and >90%, and as the probability for humans to ingest higher dosages accidently is very low, an oral absorption rate of >90% should be most reasonably assumed.
Executive summary:

In a peer-reviewed assessment report, the toxicokinetic behaviour of ethoxyquin was assessed and summarized by expert judgement, taking into account the available toxicokinetics and phys.-chem. data, providing information on absorption, distribution, metabolism and excretion. Ethoxyquin is well absorbed (70% - >90%) after oral gavage, dermal absorption was estimated (worst case) to 100 %. Ethoxyquin was rapidly partitioned from the blood into the major tissues of both rats and mice, and levels of ethoxyquin in rat blood increased again from 12 hours to 24 hours post dosing. About 90 % of a total low dose was excreted in urine and faeces within 24 hours post-dosing. In contrast, no more than 60 % of a higher dose was excreted within 24 hours following oral (gavage) administration. U

rinary excretion only slightly predominated over faecal excretion (60 % / 40 %). The two major ethoxyquin metabolites excreted in rat urine were in the form of sulphate conjugates: 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline sulphate, and 1,2,3,4-tetrahydro-3,6-dihydroxy-4-methylene-2,2-dimethylquinoline sulphate. A third peak was identified as a hydroxylated conjugate: 1,2-dihydro-6-ethoxy-8-hydroxy-2,2,4-trimethylquinoline glucuronide.

In rat bile, ethoxyquin-derived radioactivity was excreted mainly as GSH conjugates. Two of these biliary metabolites were glutathione conjugates of ethoxyquin 3,4-epoxide. The third seemed to be a conjugate of either ethoxyquin 7,8-epoxide or 2,2,4-trimethylquinol-6-one. However, between 75 and 85 % of total radioactivity excreted in the bile within 12 h of oral dosing was reported to be unchanged ethoxyquin. M

ouse urine contained one major glucuronide, 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline glucuronide, as well as one major sulphate conjugate, 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline sulphate. Repeated administration of ethoxyquin resulted in a moderate increase in [14C] in particular in adipose tissues suggesting a possibility of at least some accumulation of this lipophilic substance or its metabolites.

Description of key information

Basic Toxicokinetics: Ethoxyquin is well absorbed (70% - >90%) after oral gavage, dermal absorption was estimated (worst case) to 100 %, low potential for bioacumulation was concluded (

peer-reviewed report, expert assessment)

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

From the peer-reviewed report it can be concluded that the oral absorption rate is also > 90%, so in a WoE approach it was concluded that the absorption rate for further assessment should be set as 100%.

No experimental dermal absorption data is available for ethoxyquin. Thus, the assessment has to be based on physico-chemical endpoints. The values for the molecular mass and the octanol/water partition coefficient support the assumption of 100 % dermal absorption for ethoxyquin as a small lipophilic molecule. Toxicokinetic studies show virtually complete absorption at low doses if administered as a single oral dose. The actual amount of absorbed compound will depend on the type of emulsion in the preparation that is handled but for exposure calculation, 100 % should be used as a worst-case assumption.

A similar approach must be used for inhalative absorption, as no test data is available. The measured vapour pressure of ethoxyquin is 3.46 x 10-2 Pa at 25 °C, Ethoxyquin has a solidification point of < -20°C and decomposes before boiling, but is not marketed in a solid form, indicating a certain potential for aerosol formation. The measured log Pow of ethoxyquin is 3.18, 3.39 and 3.19, respectively at pH 5, 7 and 9, and the measured water solubility (at 20°C) of ethoxyquin is 101 mg/L, 60 mg/L and 70 mg/L, respectively at pH 5, 7 and 9. According to ECHA's Guidance document, moderate log P values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. Low water solubility, like small particle size enhances penetration to the lower respiratory tract.

Generally the smaller the molecule the more easily it may be taken up. Molecular weights below 500 are favourable for absorption, which is the case for ethoxyquin with a MW of 217.3 g/mol, too. S

o, due to the lack of further data, the inhalative absorption rate should be set precautionarily to 100%, too.