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Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, acceptable for assessment, draft report

Data source

Referenceopen allclose all

Reference Type:
study report
Reference Type:
secondary source

Materials and methods

Objective of study:
other: Adsorption, Disposition, Metabolism and Excretion
GLP compliance:
not specified

Test material

Constituent 1
Details on test material:
- Radiochemical purity (if radiolabelling): > 90%

Test animals

Fischer 344
Details on test animals or test system and environmental conditions:
- Source: Charles River Breeders (Kingston, NY)
- Weight at study initiation: 240 - 347 g
- Housing: individual
- Individual metabolism cages: yes
- Diet: Certified Purina Rat Chow
- Water: furnished water
- Acclimation period: at least 1 week

Administration / exposure

Route of administration:
oral: gavage
unchanged (no vehicle)
Doses / concentrations
Doses / Concentrations:
502, 979 and 1970 mg 14C-TS per kg b.w.
No. of animals per sex per dose / concentration:
Control animals:
Details on dosing and sampling:
- Tissues and body fluids sampled: urine, faeces, liver, blood, entire small tissues, and portions of muscle, skin and adipose tissues
-Time and frequency of sampling: 0-0.5, 0.5-2, 0-6, 6-12, 12-24, 24-36, 36-48, 48-72 h
- From how many animals: (samples not pooled) 4
- Method type(s) for identification: total radioactivity was analysed by scintillation spectrophotometer, TS by HPLC

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Oral absorption of DMDHEU, based on urinary excretion, increased with increasing dosed amounts. An average of 17% of the 502 mg/kg dose was absorbed, 28% of the 979 mg/kg dose and 38% of the 1970 mg/kg dose. The reason for this increase in oral absorption with increasing dose level is not clear (statement by the author) .
Details on distribution in tissues:
Concentrations of radiolabeled compounds in tissues, in general, reflect the increased systemic load of [14C]DMHEU as the dose increased from 502 mg/kg (85 mg/kg absorbed) to 979 mg/kg (274 mg/kg absorbed) to 1970 mg/kg (749 mg/kg absorbed).
Details on excretion:
Orally administered DMDHEU was excreted both in urine and in feces. More than 90% of the 14C that was excreted in urine was excreted within 24 h after dosing.
Distribution of the 14C in tissues following oral dosing was similar to that found after intravenous dosing, where one-half hour after an intravenous dose of 51 mg/kg of [14C]DMDHE , an average of 26 % of the dose was recovered from the bladder contents and tissues containing significant fractions of the dose were skin (13%), muscle (12%), blood (6 %), liver (6%) and kidney (5 % ). Two hours after i.v. administration the percent dose in these tissues had decreased by factors of 4-12. Two tissues had tissue-blood ratios significantly greater than 1 at this time point - prostate (TBR=11) and seminal vesicle (TBR=5). By 72 h after i.v. dosing, less than 0 .5% of the dose remained in the tissues. Most of this (0 .3%) was found in muscle. Approximately 6 times as much 14C was present in blood at 72 h as was in plasma alone. A number of other tissues showed tissue-blood ratios greater than 1. This suggests that a very small portion of the DMDHEU may be metabolized to a relatively long lasting metabolite which may be covalently linked to biomolecules. (Tissue data for oral application not readable).

Applicant's summary and conclusion