Urea, reaction products with formaldehyde and glyoxal

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, acceptable for assessment, draft report

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1985

Reference 2

Reference Type:

secondary source

Title:

Unnamed

Year:

1985

Materials and methods

Objective of study:

other: Adsorption, Disposition, Metabolism and Excretion

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Details on test material:

- Radiochemical purity (if radiolabelling): > 90%

Radiolabelling:

yes

Remarks:

14C

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- 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

Vehicle:

unchanged (no vehicle)

Doses / concentrations

Remarks:

Doses / Concentrations:
502, 979 and 1970 mg 14C-TS per kg b.w.

No. of animals per sex per dose / concentration:

4

Control animals:

no

Details on dosing and sampling:

METABOLITE CHARACTERISATION STUDIES
- 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).