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Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
Not reported
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented study, meets generally accepted scientific principles, acceptable for assessment.
Justification for data waiving:
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference Type:

Materials and methods

Objective of study:
Test guideline
no guideline followed
Principles of method if other than guideline:
A toxicokinetic study was conducted to evaluate the disposition of 1000 mg/kg bw orally administered radiolabelled (14C) lauramide diethanolamine (LDEA) in three male Fischer rats.
GLP compliance:
not specified

Test material

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

Test animals

Fischer 344
Details on test animals and environmental conditions:
- 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
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
Doses / Concentrations:
1000 mg/kg bw (5 mL/kg bw )
No. of animals per sex per dose:
Control animals:
not specified
Positive control:
Not applicable

Details on study design:
- 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).

- 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, 1990).
Values for test groups were compared by ANOVA followed by Dunnett’s test.

Results and discussion

Preliminary studies:
Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:
LDEA was readily absorbed (for details see Table 1 in the attached document).
Details on distribution in tissues:
Tissue to blood ratio (TBR) was highest in adipose tissue and liver, which had TBRs of about 50. (See Table 1 in the attached document).

Transfer into organs
Transfer type:
other: not determined
Details on excretion:
The radiolabelled test material was excreted mostly in urine as two polar metabolites. Approximately 60 and 80 % of the dose was recovered in the urine 24 and 72 h respectively and 9 % of the dose was recovered in feces after 72 h. (For details see Table 1 in the attached document).
Toxicokinetic parameters
Toxicokinetic parameters:
other: Not determined

Metabolite characterisation studies

Metabolites identified:
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

Interpretation of results (migrated information): low bioaccumulation potential based on study results
Lauramide diethanolamine is 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 the radiolabelled (14C) lauramide diethanolamine (LDEA) in the Fischer 344 rats. Three male F344 rats were administered a single dose of radiolabelled LDEA at 1000 mg/kg bw by oral gavage. The urine was collected 6 to 24 h post-dosing to isolate any metabolites present. Tissue blood ratio (TBR) was also determined, by collecting adipose tissue, blood, kidney and liver from these animals 72 h post-dosing. The results of the investigation showed that LDEA was well absorbed and mostly excreted in the urine as two polar metabolites. Approximately 60 and 80 % of the dose was recovered in the urine 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, which had TBRs of approximately 50. Therefore it can be concluded that lauramide diethanolamine is well absorbed and mostly excreted in the urine as two polar metabolites.