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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2001-Nov to 2002-Sept
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Similar to OECD 417 test guidelines for radiolabelled toxicokinetic studies but study was limited to evaluating oral bioavailability, radioactivity mass balance andidentifying metabolites in urine; study carried out under GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report Date:
2002

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
limited study to evaluate oral bioavailability and nature of metabolites in urine, one dose conc. only
Principles of method if other than guideline:
Study methodology followed general radioactivity toxicokinetic test guidelines for oral absorption, mass balance of radioactivity in urine, feces, cage washes, residual tissues over standard period of 96 hr. Collection of expired air to trap expired radiolabelled carbon dioxide was not carried out since radiolabel is positioned in naphthalene ring. Metabolite profiling of urine was carried out using standard enzymatic (glucuronidase/sulfatase) hydrolysis, extraction, HPLC-radiometric or TLC-radiometric analysis. LC-MS and GC-MS analyses were carried out on urine samples (hyrolyzed, unhydrolyzed and derivatized, i.e., acetylated). The primary purpose of this preliminary toxicokinetic experiment was to provide information on oral bioavailability/absorpiton and on the metabolic disposition of radiolabelled sec-hexadecylnaphthalene in the urine.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): MCP 917
- Physical state: liquid
- Radiochemical purity (if radiolabelling): greater than 97% HPLC; 99.8-100% by TLC
- Specific activity (if radiolabelling): 10 millicurie/mmole
- Locations of the label (if radiolabelling): C14-uniformly ring-labelled at 1,4,6,9-positions of naphthalene ring
Source: Moravek Biochemicals, Brea California USA
- Expiration date of radiochemical substance (if radiolabelling): Nov 2006
Radiolabelling:
yes
Remarks:
Uniformly ring-labelled C14-sec-hexadecylnaphthalene (MCP 917)

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Duration and frequency of treatment / exposure:
Male rats were individually dosed with single dose of 100 mg/kg of the unlabelled test material and the C14-radiolabelled test substance (ca. 7.5 microcurie per animal).
Doses / concentrations
Remarks:
Doses / Concentrations:
100 mg/kg unlabelled test material and C14-radiolabelled test material in corn oil
Total radiolabel dose was ca 7.5 microcurie per rat.
No. of animals per sex per dose:
3
Control animals:
no

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Based on mass balance analysis , it was estimated that about 10% of the radioactive dose was absorbed orally. The remaining unabsorbed radiolabelled material passed through the GI tract and was recovered in the feces (89% within 48 hr).
Details on distribution in tissues:
Only about 2.1% of the radioactivity was found in the residual carcass indicating a low degree of retention or distribution to the tissues at 96 hr. Distribution to individual tissues/organs could not be assessed due to the design of the study (i.e., whole body residual carcass digestion). Individual tissues were not collected and analyzed. Likely organs for distribution would be expected to be liver, kidney, adipose based on diisopropylnaphthalene analog (see Kojima et al. 1978).
Details on excretion:
The absorbed radioactivity is primarily excreted in the urine and as conjugated metabolites. Unchanged parent material was not excreted in the urine. HPLC and TLC-radiometric analyses indicated as many as 28 discrete urinary metabolites.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Metabolites have been identified primarily as glucuronide or sulfate conjugates in the urine. Extensive HPLC and TLC-radimetric analysis of urine samples (hydrolyzed and unhydrolyzed) indicate the presence of about 28 possible metabolites. However, these metabolites have not been fully characterized in spite of extensive LC-MS and GC-MS analyses. The identity of the metabolites have not been fully characterized owing to lack of available synthetic metabolite standards for comparison/confirmation. Metabolism of the hexadecyl group is expected to be major biotransformation pathway in the test substance.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: low oral bioavailability and low bioaccumulation potential based on study results
Oral absorption of radiolabelled sec-hexadecylnaphthalene was relatively low, occurring only to the extent of 10% after a single adminstration of 100 mg/kg oral dose in male rats. The test substance was extensively biotransformed to a large number of conjugated metabolites which were excreted in the urine. The metabolites have not been fully characterized but have been demonstrated to be glucuronide or sulfate conjugates, based on enzymatic hydrolysis experiments.
Executive summary:

Radiolabelled sec-hexadecylnaphthalene (MCP 917) (100 mg/kg and 7.5 microcurie per animal) was orally adminstered to male rats in a limited toxicokinetic study to evaluate the ADME of the test substance (i.e., primarily to assess oral absorption and metabolism). Oral absorption/ bioavailability was evaluated to be low (10%). Residue carass radioactivity (~2.1%) indicated a low bioaccumulation potential in the tissues. More importantly, the test substance was extensively metabolized to a large number of metabolites (28 discrete components) which were excreted in the urine. The metabolites have not been fully characterized in spite of extensive LC-MS and GC-MS analyses but preliminary data indicate that they are glucuronide or sulfate conjugates. Metabolism of the sec-hexadecyl side-chain group rather than oxidation of the aromatic ring has been proposed as major biotransformation pathway for this material