Registration Dossier

Diss Factsheets

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication which meets basic scientific principles

Data source

Reference Type:

Materials and methods

Objective of study:
Test guideline
no guideline followed
Principles of method if other than guideline:
Pre-guideline study; absorption, distribution, and excretion was examined after oral application of radiolabelled test substance. Urine, bile and faeces were collected and analysed for radioactivity. Body radioactivity and radioactivity in organs was determined after dissolution/digestion of the biomaterial. Radioactivity of expired air was examined with a radiorespirator.
GLP compliance:
pre- guideline study

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
- Name of test material (as cited in study report): 4-isopropylbiphenyl
- Substance type: organic
- Analytical purity: no data
- Radiochemical purity (if radiolabelling): radiolabelled test substance was chemically pure
- Specific activity (if radiolabelling): 6.3 µCi/mg
- Locations of the label (if radiolabelling): methyl group of the isopropyl side chain
- Stability under test conditions: no data, assumed to be stable

Test animals

other: Purdue-Wistar
Details on test animals or test system and environmental conditions:
- Source: Harlan Industries, Cumberland, In, USA
- Age at study initiation: adult
- Weight at study initiation: 200 - 250 g
- Fasting period before study: yes
- Housing: individually in metabolism cages, for biliary elimination studies in restraining cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitumm
- Water (e.g. ad libitum): ad libitum

Administration / exposure

Route of administration:
other: oral (gavage) and intraperitoneal
other: 1% aqueous methocel
Details on exposure:
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: 10 mg/mL
- Amount of vehicle (if gavage): 2.5 mL
Duration and frequency of treatment / exposure:
single doses
Doses / concentrations
Doses / Concentrations:
25 mg/kg
No. of animals per sex per dose / concentration:
Control animals:
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, bile, faeces, total body, and organs/tissues (liver, spleen, kidney, heart, lung, fat, brain, muscle)
- Time and frequency of sampling: urine bileand faeces were collected over a period of 48 h after dosing, animals were sacrificed 48 h after treatment and whole body and tissues/organs collected. In the respiratory experiment, expired air was collected for 24 h after dosing.

Results and discussion

Main ADME resultsopen allclose all
Isopropylbiphenyl was quantitatively absorbed from the intestinal tract after oral administration to rats.
48 h after administration of radiolabelled 4-isopropybiphenyl, 14C was detected in several organs/tissues. Tissues with 14C levels higher than found in blood were liver, kidney, and epididymal fat.
Ca. 85 % of radioactivity applied was excreted in urine and bile/faeces within 48 h. After oral administration, excretion in urine was ca. 40%, in bile/faeces ca. 45-48%. No radioactivity was found in air expired by rats within 48 h after administration.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
In bile, about the same amount of radioactivity was analysed as in faeces demonstrating that radioactivity in faeces is result of biliary excretion and not of intestinal passage. This is proof that Isopropylbiphenyl is quantitatively absorbed from the instestinal duct after oral administration.
Details on distribution in tissues:
48 h after application of 25 mg/kg radiolabelled 4-isopropybiphenyl, the following amounts of isopropylbiphenyl were found in tissues/organs

µg equiv. isopropylbiphenyl/g tissue
Tissue oral intraperitoneal
Blood 0.63 1.74
Liver 5.24 4.17
Spleen 0.16 0.33
Kidney 0.94 1.13
Heart 0.23 0.34
Lung 0.54 0.84
Fat 4.73 17.57
Brain 0.04 0.07
Muscle 0.15 0.18

After oral application, isopropyl concentrations are highest in liver and fat. After intraperitoneal application, sequence was reversed. Concentration in fat was much higher than in liver followed by other tissues. Higher 14C concentrations in fat than in organs responsible for metabolism and elimination indicate, that isopropybiphenyl or metabolites are sequestered in the fatty tissue of the body and then released at slower rates into the blood stream for ultimate metabolism and elimination.
Details on excretion:
After oral or intraperitoneal single dose application of 25 mg/kg 14C isopropylbiphenyl, most of the radioactivity (ca. 85%) was excreted into urine and faeces within 48h. The balance remained in the carcass. Measured values are reported below.

Elimination of applied radioactivity (%)
Application Urine Faeces Carcass
oral 40.0 47.9 12.1
intraperitoneal 29.8 53.6 16.6

Elimination in faeces is somewhat higher than in urine especially after intraperitoneal administration.

In a separate experiment, bile was collected and analysed for radioactivity after oral administration of labelled isopropylbiphenyl. 45% of radioactivity were recovered which is close to the amount found in faeces.

In the respirator experiment, no radioactivity was detected in the expired air of rats during the 48 h period after dosing. Results demonstrate that isopropylbiphenyl was not eliminated unaltered via the lung and that the primary carbon atom of the isopropyl side chain was not metabolically oxidised with final release of carbon dioxide.

Applicant's summary and conclusion

Interpretation of results (migrated information): low bioaccumulation potential based on study results
4-Isopropybiphenyl is quantitatively absorbed from the intestinal tract after oral administration to rats. It is distributed mostly to metabolising and excreting organs (liver, kidney) and to an equal or higher amount to fat tissue from which it can be released over time. Within 48 hours after application, ca. 85 % of the dose is excreted via urine and bile the remainder still present in the body. Excretion in urine is slightly lower than in bile (ca. 40% compared to 45-48%). No excretion was discovered in expired air of test animals monitored for 48 hours.