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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Lauramide diethanolamine absorption, metabolism and disposition in rats and mice after oral, intravenous and dermal administration
Author:
Mathews JM, deCosta K and Thomas BF
Year:
1996
Bibliographic source:
Drug Metab. Dispos. 24(7):702-710

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
Three male rats were administered a single dose of (14C) test substance at 1000 mg/kg bw by oral gavage. Urine was collected 6 to 24 h post-dosing to isolate metabolites. Tissue to blood ratios (TBR) were determined by collecting adipose tissue, blood, kidney and liver 72 h post-dosing.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
N,N-bis(2-hydroxyethyl)dodecanamide
EC Number:
204-393-1
EC Name:
N,N-bis(2-hydroxyethyl)dodecanamide
Cas Number:
120-40-1
Molecular formula:
C16H33NO3
IUPAC Name:
N,N-bis(2-hydroxyethyl)dodecanamide
Details on test material:
- Name of test material (as cited in study report): Lauramide diethanolamine (LDEA)
- Radiochemical purity (if radiolabelling): 96 to 97%
- Specific activity (if radiolabelling): 841 µCi/mmol
- Locations of the label (if radiolabelling): On the DEA moiety
- Other: Identity confirmed by: Mass spectrometry and proton NMR
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc. (Raleigh, NC)
- Age at study initiation: 81 to 87 d
- Housing: Individual glass metabolism chambers, which allowed separate collection of carbon dioxide, urine, and feces.
- Individual metabolism cages: Yes
- Diet: Purina Rodent Chow (no. 5002), ad libitum
- Water: Ad libitum

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
ORAL DOSE FORMULATION: 16 to 18 µCi radiolabel per dose, an appropriate amount of unlabeled LDEA and water

DOSE VOLUME: 5 mL/kg bw
Duration and frequency of treatment / exposure:
Duration of treatment: 72 h
Frequency of treatment: Single dose
Doses / concentrations
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose / concentration:
Three
Control animals:
not specified
Details on study design:
ANESTHESIA
- Identity: Sacrificed by overdosing with sodium pentobarbital (300 mg/kg bw) through intracardiac route
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: Urine, faeces, blood, adipose tissue, liver and kidney
- Time and frequency of sampling: 72 h after dosing
- Method type(s) for identification: Radioactivity was determined using a Packard Tricarb 1500 Liquid Scintillation Analyzer (Packard Instrument Company, Downers Grove, IL).
- Brief description on method of analysis: Digested samples of tissues, feces, and blood in Soluene-350 (Packard Instrument Company, Meriden, CT) overnight, were bleached with perchloric acid/hydrogen peroxide before addition of scintillation cocktail (Ultima Gold).


METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: Urine
- Time and frequency of sampling: 6 to 24 h after dosing
- From how many animals: samples were pooled from 3 animals
- Method type(s) for identification: Lyophilised samples of urine were analysed for metabolites using HPLC reversed- phase, further purified using cation and anion-exchange chromatography and identification of metabolites were done using mass spectrophotometry; The trimethylsilyl derivative of LDEA were prepared and analyzed by GC/MS with chemical ionisation (Thomas et.al., 1990).
Statistics:
Values for test groups were compared by ANOVA followed by Dunnett’s test.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The test substance was readily absorbed
Details on distribution in tissues:
Tissue to blood ratio (TBR) was highest in adipose tissue and liver, which had TBRs of about 50.
Details on excretion:
The radiolabelled test substance was excreted mostly in urine as two polar metabolites. Approximately 60 and 80% of the dose was recovered in the urine after 24 and 72 h, respectively, and 9% of the dose was recovered in feces after 72 h.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Urine chromatographed on a reverse phase column resulted in 2 peaks. The mass spectrum of Peak 1 was assigned as the half-acid amide of succinate and DEA (loss of 8 carbons) and Peak 2 as the adipate (loss of 6 carbons) half-acid amide.

Any other information on results incl. tables

Other examinations: Metabolism in rat and human liver slices: LDEA partitioned well into liver slices, and about 70% of the radioactive LDEA was absorbed into the slices within 4h.The absorbed radioactivity was present mostly as parent compound. About 20 and 43% of the radioactivity present in media from the un-induced and DEHP-induced rats respectively were comprised of metabolites. About 30% of the radioactivity in the media of the human liver slice incubations was in the form of metabolites.

Analytes present in the incubation media from human and rat liver slices include the half-acid amides identified as metabolites in vivo, parent LDEA, and perhaps three other metabolites that have been identified as products of ω - and ω-1 to 4 hydroxylation (Merdink et al., 1996).

Applicant's summary and conclusion

Conclusions:
Under the study conditions, the substance was well absorbed and mostly excreted in urine as two polar metabolites.
Executive summary:

A study was conducted to evaluate the absorption, distribution, metabolism and excretion of radiolabelled N,N-bis(2-hydroxyethyl)dodecanamide (LDEA) in F344 rats. Three male rats were administered a single dose of (14C) LDEA at 1000 mg/kg bw by oral gavage. Urine was collected 6 to 24 h post-dosing to isolate metabolites. Tissue to blood ratios (TBR) was also determined by collecting adipose tissue, blood, kidney and liver 72 h post-dosing. The results of the investigation showed that LDEA was well absorbed and mostly excreted in urine as two polar metabolites. Approximately 60 and 80 % of the dose was recovered in urine after 24 and 72 h, respectively, and 9% of the dose was recovered in faeces after 72 h. The metabolites were isolated and characterized as the half-acid amides of succinic and of adipic acid. The TBRs were highest in the adipose and liver tissues, with values of approximately 50. Under the study conditions, the substance was well absorbed and mostly excreted in urine as two polar metabolites (Mathews, 1996).