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Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
no data
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference Type:
In vivo and in vitro metabolism of di-(2-ethylhexyl) adipate a peroxisome proliferator, in the rat
Cornu MC et al
Bibliographic source:
Arch Toxicol Suppl 12: 265-268.

Materials and methods

Objective of study:
Principles of method if other than guideline:
In Vivo Studies: Different doses of DEHA were administered by gavage to Wistar male rats for 5 days. Urine was collected each morning and metabolites were extracted.
In Vitro Studies: Hepatocytes were isolated by a two step in situ perfusion technique. The test substance dissolved in dimethyl formamide was added to the cultivated monolayers 24 h after seeding and added at each 24 h medium change. Medium metabolites were extracted.
Methods of Analysis of Biological Extracts: Glucuronides as their methyl and trimethylsilyl derivatives were identified by gas chromatography/mass spectrometry.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Bis(2-ethylhexyl) adipate
EC Number:
EC Name:
Bis(2-ethylhexyl) adipate
Cas Number:
Molecular formula:
bis(2-ethylhexyl) adipate
Details on test material:
- Name of test material (as cited in study report): Di(2-ethylhexyl)adipate (DEHA)
No further data

Test animals

Details on test animals or test system and environmental conditions:
no data

Administration / exposure

Route of administration:
oral: gavage
corn oil
Duration and frequency of treatment / exposure:
single dose
Doses / concentrationsopen allclose all
Dose / conc.:
665 mg/kg bw (total dose)
Dose / conc.:
1 500 mg/kg bw (total dose)
Details on dosing and sampling:
Different doses of DEHA were administered by gavage to Wistar male rats for 5 days. Control animals received the vehicle alone (0.5 ml corn oil). Urine was collected each morning and extracted.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on excretion:
After 24 h, no DEHA is recovered in rat urine.

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
Adipic acid is the main metabolite of DEHA. Only the EH metabolic pathway shows further metabolites, mainly EHA, which is either conjugated or submitted to omega and omega-1 pathways, giving respectively 2-ethyl hexanedioic acid and 2-ethyl-5-hydroxyhexanoic acid. The identification of all metabolites was in agreement with those in previous EH metabolism study. According to the authors, it appears that EHA glucuronidation is dose and time dependent but that EH glucuronidation is more stable.
See also attached file.

Applicant's summary and conclusion

Executive summary:

After oral administration of 665 or 1500 mg di(2-ethylhexyl) adipate/kg  bw to male rats up to 95 % of the theoretical amount from Di(2 -ethylhexyl)adipate (DEHA) was found  as adipic acid in urine on day 1 after dosing. The urinary recovery was  about 50%. Carbon dioxide (CO2) exhalation was not studied. Other metabolites were oxidized and conjugated forms of 2-ethyl hexanoic acid.