Ethoxyquin

Basic toxicokinetics

Administrative data

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)

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2007

Report date:

2007

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

toxicokinetics

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

Ethoxyquin

EC Number:

202-075-7

EC Name:

Ethoxyquin

Cas Number:

91-53-2

Molecular formula:

C14H19NO

IUPAC Name:

ethoxyquin

Details on test material:

Chemical name
IUPAC: 6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline
CAS: 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline

Radiolabelling:

other: partially in reference toxicokinetic study

Test animals

Species:

other: not applicable

Strain:

other: not applicable

Details on test animals or test system and environmental conditions:

not applicable

Administration / exposure

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

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Oral absorption of 25 mg/kg bw was >90%, absorption of 250 mg/kg bw was 70%.

Main ADME results 2

Type:

distribution

Results:

Ethoxyquin was rapidly partitioned from the blood into the major tissues of both rats and mice.

Main ADME results 3

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.

Toxicokinetic / pharmacokinetic studies

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.

Transfer into organs

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

Toxicokinetic parameters:

Tmax:

Remarks:

levels of ethoxyquin in rat blood increased again from 12 hours to 24 hours post dosing.

Metabolite characterisation studies

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.

Applicant's summary and conclusion

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.