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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: read -across with diphenyl ether as surrogate

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Disposition and metabolism of diphenylether in rats
Author:
Law FCP, Song YY, Chakrabarti S
Year:
1983
Bibliographic source:
Xenobiotica 13, 627-633
Reference Type:
publication
Title:
Metabolism of the parent compounds of some of the simpler synthetic estrogenic hydrocarbons
Author:
Stroud SW
Year:
1940
Bibliographic source:
J Endocrinol 2, 55-62
Reference Type:
publication
Title:
The metabolism of ethers in the rabbit. I. Anisole and diphenyl ether
Author:
Bray HG, James SP, Thorpe WV, Wasdell MR
Year:
1953
Bibliographic source:
Biochem J 54, 547-551
Reference Type:
publication
Title:
Biotransformation of diphenyl ether by trout and guinea-pigs after intraperitoneal administration
Author:
Poon G, Chui YC, Law FCP
Year:
1986
Bibliographic source:
Xenobiotica 16, 795-800
Reference Type:
publication
Title:
Irreversible binding of 14C-diphenyl ether-derived radioactivity to liver microsomes in vitro and tissue proteins in vivo
Author:
Law FCP
Year:
1983
Bibliographic source:
Drug Chem Toxicol 6, 285-294

Materials and methods

Objective of study:
metabolism
Principles of method if other than guideline:
metabolism of diphenyl ether was examined in rats, rabbits, and guinea pigs
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
diphenyl ether was used as surrogate
Radiolabelling:
other: radiolabelled and not radiolabelled

Test animals

Species:
other: rat, rabbit, and guinea pig
Strain:
not specified
Sex:
not specified

Administration / exposure

Route of administration:
other: intragastric (i.g.) or i.p. administration
Vehicle:
other: undiluted, with sesame oil or water
Duration and frequency of treatment / exposure:
single treatment or repeated dose for metabolism studies
Doses / concentrations
Remarks:
Doses / Concentrations:
variable doses from 5 mg/kg up to 500 mg/kg
No. of animals per sex per dose:
no. of animals not specified
Control animals:
not specified

Results and discussion

Preliminary studies:
no data

Toxicokinetic / pharmacokinetic studies

Details on absorption:
diphenyl ether is absorbed readily by various rat tissues after i.p. or i.g. administration. The absorption rate constant following a single oral dose of diphenyl ether is about 0.024/h (Law, 1983)
Details on distribution in tissues:
after i.p. administration of [14C]diphenyl ether (5 mg/kg) to rats, radioactivity was detected in all organs and tissues (Law, 1983)
Details on excretion:
more than 90% of the intragastrically administered dose was excreted in urine and faeces within 3 days; > 80 % dose was in the urine (Law, 1983)
Toxicokinetic parameters
Toxicokinetic parameters:
half-life 1st: ca. 1.5 hours after i.g. application

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
in the urine of all animals 4-hydroxydiphenyl ether was found as main metabolite and in smaller amounts 4,4'-dihydroxydiphenyl ether , both metabolites as free metabolites and as conjugated substances. As additional metabolites 2-hydroxydiphenyl ether, 4-methoxymonohydroxydiphenyl ether and 4-methoxydihydroxydiphenyl ether were found in the urine of rats and rabbits

Any other information on results incl. tables

no evidence was seen for a species difference in animals in the metabolism of diphenyl ether

Applicant's summary and conclusion

Conclusions:
Interpretation of results: bioaccumulation potential cannot be judged based on study results as intermediates for the hydroxylation step the formation of arene oxides are presumed.
Executive summary:

Metabolism of diphenyl ether was examined in rats, rabbits, and guinea pigs. In the urine of these animals 4-hydroxydiphenyl ether was found as main metabolite and in smaller amounts 4,4'-dihydroxydiphenyl ether, both metabolites as free as well as conjugated substances. As additional metabolites 2-hydroxydiphenyl ether, 4-methoxymonohydroxydiphenyl ether and 4-methoxydihydroxydiphenyl ether was found in the urine of rats and rabbits. Investigations with radiolabelled [14C]diphenyl ether indicated a biological half-life of about 1.5 hours after i.g. application.