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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
1989-01-18 to 1989-12-01
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline OECD 417; but as read-across from supporting substance maximum reliability is 2. Read-across hypothesis: for details please see read-across report in IUCLID section 13.
Justification for type of information:
For details on endpoint specific justification please see read-across report in section 13 or find a link in cross-reference “assessment report”.
Cross-reference
Reason / purpose:
assessment report

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report Date:
1990

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
: minor deficiencies in data reporting
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Tri-n-butylamin (1-14C), which was transformed to the hydrochloride by addition of HCl
- Physical state: liquid
- Analytical purity: 1-14C-Tri-n-butylamine hydrochloride, radiochemical purity purity 98 %, non-radioactive portion: chemical purity 99 %
- Lot/batch No.: 18061 destilled: 18061 1
- Specific activity (if radiolabelling): 834.7 MBq/g - 833.8 MBq/g
- Locations of the label (if radiolabelling): 1-C14
- Expiration date of radiochemical substance (if radiolabelling):
Radiolabelling:
yes
Remarks:
1-14C

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hoechst AG
- Age at study initiation: 6-8 weeks
- Weight at study initiation: 118 +/- 11 g
- Housing: in metabolism cages
- Diet (ad libitum): Altromin 1321, Altromin GmbH, Lage/Lippe, Germany
- Water (ad libitum): tap water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23-27
- Humidity (%): 25-30

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The labelled test substance was diluted with non-labelled test item to obtain a specifiv activity of 115.4 MBq/g (determination of metabolites) or 80.94 MBq/g

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 9 mg/g
Duration and frequency of treatment / exposure:
single exposure
Doses / concentrations
Remarks:
Doses / Concentrations:
50 mg/kg bw
No. of animals per sex per dose:
3 males, 3 females
Control animals:
other: not required
Details on dosing and sampling:
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled : urine
- Time and frequency of sampling: 0-24 h, 24-48 h, 48-72 h, 72-96 h
- From how many animals: urine of the males and the females were each pooled
- Method type(s) for identification: HPLC-MS, NMR

TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): treatment with ß-glucuronidase and aryl sulfatase

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on excretion:
75.2 % (males) and 82 % (females) of the radioactivity  were found  in the urine within 4 d after application, approx. 94 - 95 % of the total urinary radiactivity appeared within 24 h. The faeces contained 3.7% (males) and 2.4 % (females) % of the dose applied.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Unchanged test substance: 6 % (males); 13 % (females), overall about 10 %
Three of the five excreted metabolites were identified, one monohydroxy derivative  (males: 19 %, females: 29 %), one dihydroxy derivative (males: 21 %,  females: 16 %) and one monohydroxydesbutyl derivative (males: 14 %,  females: 9 %). The identified metabolites and the unchanged test substance accounted for about 60 % of the  radioactivity in the urine of male animals (67 % in females).  Main reactions are therefore hydroxylation of the alkyl sidechains distal from N (gamma-position), and desalkylation associated with oxidation in  alpha-position. The other metabolites are possibly trihydroxylation and di-desbutyl derivatives.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Under the conditions of this study, the test substance was efficiently metabolised to 5 compounds. Three of them were identified as monohydroxy derivative  (males: 19 %, females: 29 %), a dihydroxy derivative (males: 21 %,  females: 16 %) and a monohydroxydesbutyl derivative (males: 14 %,  females: 9 %).
Executive summary:

Three male and three female wistar rats received single oral doses of 50 mg radiolabelled test substance per kg body weight. Excretion and metabolism of the test substance were investigated.

After dosing, radioactivity was mainly excreted in urine. The unchanged test substance and the identified urinary metabolites accounted for 60-67 % of the total excreted radioactivity in urine. The identified metabolites were the monohydroxy derivative  (males: 19 %, females: 29 %), one dihydroxy derivative (males: 21 %,  females: 16 %) and one monohydroxydesbutyl derivative (males: 14 %,  females: 9 %). The unidentified metabolites are possibly trihydroxylated and di-desbutylated metabolism products (Hoechst, 1990b).

This study was performed similar to OECD 417 and is judged to be of high reliability (RL 2).