Ditolyl ether

Basic toxicokinetics

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

Reference

Reference 1

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 2

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 3

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 4

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 5

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

Test material information

Constituent 1

Reference substance name:

Diphenyl ether

EC Number:

202-981-2

EC Name:

Diphenyl ether

Cas Number:

101-84-8

Molecular formula:

C12H10O

IUPAC Name:

1,1'-oxydibenzene

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 / concentration:

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.