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Toxicological information

Basic toxicokinetics

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Administrative data

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

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1996

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
A study was conducted to evaluate the in vitro metabolism of LDEA in liver or kidney microsomes from rats; to determine the extent of its hydroxylation; to identify the products formed; and to examine whether treatment with an agent that induces P4504A forms would affect hydroxylation rates. DEHP and control treated liver and kidney microsomes were incubated with 100 µM LDEA for 30 min at 37 °C in a shaking water bath. The metabolites were separated and analysed by GC/MS. 
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Lauramide diethanolamine (LDEA)
- Lot/batch No.: Ch1E952
- Locations of the label (if radiolabelling): On the DEA moiety
- Other: Identification by mass spectrometry and proton NMR
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
Not applicable

Administration / exposure

Route of administration:
other: Not applicable
Vehicle:
other: Not applicable
Details on exposure:
- Diethyl hexyl pthalate (DEHP) and control treated liver and kidney microsomes were incubated with 100 µM of LDEA for 30 min at 37°C in a shaking water bath according to the method of Okita et al, 1990 .
Duration and frequency of treatment / exposure:
30 min
Doses / concentrations
Remarks:
Doses / Concentrations:
100 µM
No. of animals per sex per dose:
Not applicable
Control animals:
other: Not applicable
Positive control:
Not reported
Details on study design:
Not reported
Details on dosing and sampling:
METABOLITE CHARACTERISATION STUDIES:
- Method of identification: Mass spectral identification (GC/MS).
- Because LDEA contains a 12-carbon side chain, LDEA hydroxylation rates were compared with the hydroxylation rates for lauric acid.




Statistics:
Not reported

Results and discussion

Preliminary studies:
Not reported

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Not applicable
Details on distribution in tissues:
Not applicable
Details on excretion:
Not applicable
Toxicokinetic parameters
Toxicokinetic parameters:
other: Not applicable

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
- LDEA was metabolised by rat liver microsomes to two major products that were identified by GC/MS to be the 11- hydroxyl and 12-hydroxy derivatives of LDEA. The specific activities for LDEA 11- and 12-hydroxylation in microsomes prepared from control rats were 2.23±0.40 and 0.71±0.17 nmol/min/mg protein, respectively (See Table 1 in the attached document).
- Treatment of rats with the cytochrome P4504A inducer and peroxisome proliferator, diethyihexyl phthalate (DEHP) increased the LDEA 12-hydroxylation rate to 3.50 ± 0.48 nmol/mm/mg protein, a 5-fold increase in specific activity, whereas the LDEA 11-hydroxylase activity remained unchanged.
- The specific activities of lauric acid 11- and 12-hydroxylation reactions in DEHP treated rats were 1.7-fold and 3.2-fold greater than the LDEA 11- and 12-hydroxylation rates, respectively.
- Incubating liver microsomes from DEHP-treated rats with a polyclonal anti-rat 4A inhibited the formation of 12-OH-LDEA by 80% (3.98±0.10 vs. 0.80±0.08 nmol/min/mg protein), compared with the preimmune serum, but had no inhibitory effect on the rate of 1 1-OH-LDEA formation (1.93±0.09 vs. 2.20± 0.11 nmol/min/mg protein).
- Rat kidney microsomes also resulted in hydroxylation of LDEA at its 11- and 12-carbon atoms, with specific activities of 0.05±0.01 and 0.28±0.02 nmol/min/mg protein, respectively.

- The specific activities for LDEA and lauric acid 11- and 12-hydroxylation in control and DEHP-treated rats are given in table 1.
- A 5.1-fold increase in specific activity was observed for the LDEA l2-hydroxylation reaction after DEHP treatment, whereas the rate for LDEA 11-hydroxylation was similar in microsomes from control and DEHP-treated rats.

Any other information on results incl. tables

Other studies: Human liver microsome results: LDEA was also metabolised to 11- and 12-hydroxy derivatives by human liver microsomes at specific activities of 0.22±0.06 and 0.84±0.26 nmol/min/mg protein, respectively.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
Under the test conditions, lauramide diethanolamine in the presence of rat liver and kidney microsomes, is rapdily converted into 11 and 12 hydroxylated derivatives.

Executive summary:

A study was conducted to evaluate the in vitro metabolism of lauramide diethanolamine (LDEA) in liver or kidney microsomes from rat to determine the extent of its hydroxylation, to identify the products formed and to examine whether treatment with an agent that induces P450 enzymes would affect hydroxylation rates. DEHP and control treated liver and kidney microsomes were incubated with 100 µM LDEA for 30 min at 37 °C in a shaking water bath. The metabolites were then separated and analysed by GC/MS.  97% of the hydroxylated products were identified as two major products, 11- hydroxyl and 12-hydroxy derivatives of LDEA. The specific activities for LDEA 11- and 12-hydroxylation in microsomes prepared from control rats were 2.23±0.40 and 0.71±0.17 nmol/min/mg protein, respectively. Treatment of rats with the cytochrome P4504A inducer and peroxisome proliferator, diethyihexyl phthalate (DEHP) increased the LDEA 12-hydroxylation rate to 3.50 ± 0.48 nmol/mm/mg protein, a 5-fold increase in specific activity, whereas the LDEA 11-hydroxylase activity remained unchanged. Incubating liver microsomes from DEHP-treated rats with a polyclonal anti-rat 4A inhibited the formation of 12-OH-LDEA by 80% (3.98±0.10 vs. 0.80±0.08 nmol/min/mg protein), compared with the preimmune serum, but had no inhibitory effect on the rate of 1 1-OH-LDEA formation (1.93±0.09 vs. 2.20± 0.11 nmol/min/mg protein). Rat kidney microsomes also resulted in hydroxylation of LDEA at its 11- and 12-carbon atoms, with specific activities of 0.05±0.01 and 0.28±0.02 nmol/min/mg protein, respectively. Based on the results it can be concluded that lauramide diethanolamine in the presence of rat liver and kidney microsomes, is rapidly converted into 11 and 12 hydroxy derivatives.