Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OPP 85-1 (Metabolism and Pharmacokinetics)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Specific activity of 26.3mCi/mmol
Radiolabelling:
yes
Remarks:
14C labelled at the 5-ring position

Test animals

Species:
rat
Strain:
other: Charles River CD
Sex:
male/female

Administration / exposure

Route of administration:
other: Oral (single and repeat dose) and I.V
Duration and frequency of treatment / exposure:
Rats in the repeat oral low-dose were administered non-radiolabelled DMH daily at a dose level of 100mg/kg /day for days 1-7 and 80mg/kg/day for days 8-14 by gavage prior to a single dose of 14C-DMH. All other regimens were provided as a single dose.
Doses / concentrations
Remarks:
Doses / Concentrations:
Single oral high dose: 1000mg/kg
Single oral low dose 100 mg/kg
Repeat oral low - dose: 100mg/kg (days 1-7), 80mg/kg (days 8-15) and (radiolabelled material for the last dose only)
I.V: 100mg/kg
No. of animals per sex per dose:
5/sex/group
Control animals:
no
Details on dosing and sampling:
Urine, faeces, and washings of urine/faeces separators were collected at the following intervals: 0-4 , 4-8, 8-12, 12-24, 24-36, 36-48, 48-72, 72-96, 96-120, 120-144 and 144-168 hours.
Blood , tissues and organs were harvested 7 days (168 h) after administration of 14C-DMH

Results and discussion

Main ADME resultsopen allclose all
Type:
other: Recovery
Results:
Single oral low-dose administration Males: 94.96 ± 5.23% Females: 94.09 ± 2.55%
Type:
other: Recovery
Results:
Single oral high-dose administration Males: 91.65 ± 4.71% Females: 94.14 ± 2.46%
Type:
other: Recovery
Results:
Repeat oral low-dose administration Males: 96.57 ± 4.51% Females: 97.73 ± 4.88%
Type:
other: Recovery
Results:
Single I.V low-dose administration Males: 96.69 ± 3.72% Females: 94.51 ± 3.15%

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
Tissue residues expressed as ppm 14C-DMH equivalents and percent of administered dose were very low and with the exception of the single oral high-dose group, were similar for all dosage regimens. The slightly higher tissue residue levels in a few tissues in the single oral high-dose group were considered to be a reflection of the higher dose administered to the animals in this group.
Only in hair and possibly fat, were residue levels above those found in plasma found with any regularity. The slightly higher residue levels in fat were not of the magnitude to suggest significant bioaccumulation. The residue levels in hair may indicate some preference for 14C-DMH to accumulate in this matrix or may be an artefact of trying to determine 14C residue levels in extremely small samples.
Details on excretion:
Regardless of dosing regimes, more than 90% of the dosed radioactivity in both male and female rats was excreted, unchanged, in the urine (90.50-96.25%) while less than 1.37% was excreted in the faeces. Most of the radioactivity recovered in the urine was excreted within the first 12 hours. Urinary half lives (obtained graphically from the data in the reports by Σ- plots) were superimposable, with values of 3.0-3.25h (males) and 2.4-2.8 h (females).

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
Only one substance was excreted in urine; it was identified as unchanged 14C-DMH

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
The data from the study demonstrated that 14C-DMH is rapidly and quantitatively excreted, unchanged, in the urine following oral or intravenous administration. There was no significant evidence for tissue accumulation.