Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
from 1988-02-01 to 1988-06-30
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: 2e: Study well performed even if did not follow any guideline nor GLP procedures. The developed method for screening metabolic product gave satisfactory results.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988
Report Date:
1988

Materials and methods

Objective of study:
excretion
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
The purpose was to determine whether 11-aminoundecanoic acid is excreted in major amounts in unmetabolized form by rats.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- supplier: DuPont/NEN Dreieich, FRG
- Purity test date: 1986-11-18
- Lot/batch No.: 2376-050
- Radiochemical purity (if radiolabelling): 97.1%
- Specific activity (if radiolabelling): 14.22 mCi/mmol
- Locations of the label (if radiolabelling): Carbon-11
no more data
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hannoversche Versuchstierzucht, Hannover, FRG
- Age at study initiation: no data
- Weight at study initiation: females 186/188/193/188/192 g and male 263/233/225/233/234 g
- Fasting period before study: no data
- Housing: no data
- Individual metabolism cages: yes in all-glass metabolic cages
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): continuous airstream sucked through the cages and drawn through a soda lime (14CO2 trapping)
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: data not avaiable

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 5% aqueous acetic acid
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
test compound dissolved in 1mL of 5% aqueous acetic acid solution (warmed to 35°C to get a clear solution)

ADMINISTRATION: 1 mL administered with a stomach tube

VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: 5%
- Amount of vehicle (if gavage): 0.05mL (1mL administrated in total)

no more data
Duration and frequency of treatment / exposure:
single application
Doses / concentrations
Remarks:
Doses / Concentrations:
Males: 1 mCi of 11-14C-aminoundecanoic acid
Females: 1 mCi of 11-14C-aminoundecanoic acid except for one animal at 0.5mCi
No. of animals per sex per dose:
5 males and 5 females per dose
Control animals:
not specified
Details on dosing and sampling:
PHARMACOKINETIC STUDY
- body fluids sampled : during a DNA binding study 24H-urine of each animal following oral administration of labelled substance was collected, filtered (O.45µm Millipore) and deep-frozen at -80°C
- Total radioactivity in urine and feces collected during 24 h was determined by liquid scintillation counting of aliquots

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine (same sample)
- From how many animals: not pooled, individual characterisation
- Method type(s) for identification: Gas liquid chromatography coupled with mass spectrometry
- Limits of detection and quantification: no data
- Identification by GC/MS: calibration with unlabelled 11 aminoundecanoic acid. The pattern obtained allowed to describe a fragmentation pattern with the 3 main peaks corresponding to 3 impurities : silylated 11 aminoundecanoic acid (main peak), mono and triple silylated 11-aminoundecanoic acid. Further peaks were negligible.
Statistics:
none

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on excretion:
Less than 20% of the administered radioactively labelled 11-aminoundecanoic acid was excreted unchanged.
An identification of the substance was possible because the retention time and fragmentation pattern were known from studying authentic compound. Through selective staining of the substance with nihydrine, approximately 80% of radioactivity derived from 14C-11-aminoundecanoic acid is excreted in form of metabolites in rat urine.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
Major excretory product is still unidentified.
The only indice is that it is metabolically changed at the N-terminal end.

Any other information on results incl. tables

- About 10% of the applied radioactivity was recovered within 24h in the urine of treated animals.

- Some radioactivity (not quantitated) was found in the soda lime, indicating that minor amounts of 14CO2 had been produced by metabolism of

14C-11 -aminoundecanoic acid

- Thin layer chromatography pattern were different within male and female. Both sex of F-344 rats metabolised differently the 11 -aminoundecanoic

acid.

Radioactivity distribution
The excretion of radioactivity derived from 11aminoundecanoic acid is slow; only some 10% of the dose was excreted in urine and feces during the
first 24 h after dosing (Tab. 1).In addition, minor amounts of radioactivity (not quantitated) were excreted in breath, apparently as 14C02 (in the CO2
soda lime trapping). Table 1: Total radioactivity (dpm) in urine and feces after 24 hours of a single oral dose of 11-aminoundecanoic acid as 
determined by liquid scintillation counting of aliquots (0.1 ml urine/50 µg feces
F-344 rats, female
F-344 rats, male
urine
feces
urine
feces
1
4.92 x10e7
3.93 x10e5
1
2.01 x10e8
1.01 x10e8 (+)
2 (++)
1.29 x10e8
3.15 x10e7 (+)
2
2.55 x10e8
7.61 x10e7
3
2.20 x10e8
1.65 x10e8 (+)
3
1.32 x10e8
1.38 x10e6
4
4.93 x10e7
1.43 x10e6
4
2.90 x10e8
2.78 x10e7
5
1.64 x10e8
1.64 x10e8 (+)
5
1.89 x10e 8
5.23 x10e5
(+)  feces contaminated with urine(++) female No. 2 received only 1/2 doseTable 2: Percent of radioactivity dose excreted within 24 h (x+S.D.):
F-344 rats, female
F-344 rats, male
urine
6.7 ± 4.3
9.6 ± 2.8
feces
3.3 ± 3.8
1.9 ± 2.0
urine + feces
9.9 ± 7.2
11.5 ± 4.0

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Under the conditions of this test, 11-aminoundecanoic was mainly excreted in urine in form of metabolites (80 %). Moreover, results showed that the substance is metabolised differently by both sexes of F-344 rats.
Executive summary:

The purpose of the study was to determine whether AA is excreted in major amounts in unmetabolized form by this species.

During a DNA binding study (Bolt H.M., 1987), 24h-urine samples were collected and deep-frozen for further analyses. Then, these urine samples were used for investigating the metabolism of 11 -aminoundecanoic acid excretion products. After one single oral administration (gavage) of 1mCi of labelled 11-aminoundecanoic acid in 5 male and 5 female F-344 rats, it was shown that the substance is excreted in urine.

According the the results, less than 20% of the administered radiocatively labelled AA was excreted unchanged in the urine by rats. It was also demonstrated that 80% of the urinary excretion products were metabolites.

Excretion patterns are different between male and female.

However, the main product seems to be identical for both males and females.

Metabolites were not identified. The metabolic conversion which resulted in the main excretory product must have taken place in the N-terminal part of the substance. Possible metabolic reactions are : oxidative deamination, acetylation and conjugation with glucuronic acid / glutathione.