Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Aug 2002 to Dec 2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: study performed using commercial SAYTEX 8010 Flame Retardant commercial product and 14C-labelled decabromodiphenyl ethane by a laboratory skilled in PK studies and according to GLPs

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004

Materials and methods

Objective of study:
other: ababsorption, distribution, metabolism, elimination
Test guideline
Qualifier:
equivalent or similar to
Guideline:
EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
14C-decabromodiphenyl ethane (DBDPEthane) synthesized by Perkin Elmer LIfe Sciences, Inc (Boston, MA); specific activity: 21.63 uCi/mg; radiochemical purity 97.4% by HPLC.

Unlabeled DBDPEthane supplied by the Sponsor (Albemarle Corporation) as the commercial flame retardant product.
Radiolabelling:
yes
Remarks:
14C-ring labelled

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
Rats,8 wks of age, were obtained from Charles River Laboratories, Portage, MI. Group 1 rats were not cannulated. Group 2 rats were received with surgically implanted jugular vein cannulas, and Group 3 with both jugular and bile duct cannulas. The animals were acclimated for 48 hrs only due to the implants. Each animal was identified by ear tages. Housed in environmentally controlled rooms, 12/12 light cycle, 63-78 degrees F and 30 to 64% humidity. Rats in the PK phase were housed in polycarbonate cages; rats in the excretion and bile phases were housed in polycarbonate metabolism cages. Harlan Teklad Certified Global 18% Protein Rodent Diet was offered ad libitum. Tap was provided ad libitum. Rats were fasted overnight prior to test article administration.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Duration and frequency of treatment / exposure:
Once
Doses / concentrations
Remarks:
Doses / Concentrations:
1000 mg/kg bw; 50 uCi/kg
No. of animals per sex per dose:
6 M/group
Control animals:
no
Positive control:
No
Details on study design:
See below
Details on dosing and sampling:
GROUP 1, METABOLISM CAGES:
Urine and Cage Rinse Collections: 0-6, 6-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144 and 144-168 hr post-dosing
Feces Collections: 0-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168 hr post-dosing

GROUP 2, JUGULAR CATH:
Blood collections (0.25 ml) pre-dose, 15 and 30 minutes, and 1, 2, 6, 12, 24, 48, 72, 96, 120, 144, 168 hr post-dosing

GROUP 3, JUGULAR AND BILE CATH:
Blood Collections: pre-dose, 30 min, 6, 12, 24, 48 hr post-dosing
Bile Collection: 0-6, 6-12, 12-24, 24-48 hr post-dosing
Statistics:
Samples were considered to be below the limit of detection when the corrected dpm value (gross dpm - background dpm) was less than twice the mean background value for each group of samples counted. These samples were indicated as NT (not detected) and treated as zero in any calculations.

Results and discussion

Preliminary studies:
See other information on materials and methods.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The absorption, distribution, metabolism and elimination of DBDPEthane (1000 mg/kg; 50 uCi/kg) were studied in Sprague-Dawley rats following a single oral dose of 14C-DBDPEthane. No 14C-activity was detectable in the plasma, bile or urine of treated rats at any time point (up to 168 hours post-dosing).
Details on distribution in tissues:
No 14C-activity was detectable in the plasma, bile or urine of treated rats at any time point (up to 168 hours post-dosing).
Details on excretion:
No 14C-activity was detectable in the plasma, bile or urine of treated rats at any time point (up to 168 hours post-dosing).  A mass balance could not be determined because the presence of the test article in the feces prevented combustion and subsequent quantitation of 14C-CO2. Levels of 14C-activity in plasma, bile, urine and cage rinses were below the limit of detection in all samples.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
All samples analyzed by LSC were found to be below the limit of detection. Therefore, it was not possible to perform HPLC radiometabolite analyses or calculate pharmacokinetic parameters.

Any other information on results incl. tables

Levels of 14C-activity in plasma, bile, urine and cage rinses were below the limit of detection in all samples at all time points. A mass balance could not be determined, because the presence of the test article in the feces prevented combustion and subsequent quantitation of 14C-CO2. Based on the absence of 14C-activity in plasma, bile, urine and cage rinses and noncombustability of the feces, the majority of the administered dose was not recovered and indicates that the test article was not orally absorbed and therefore excreted in the feces.

In conclusion, a single oral dose of 14C-decabromodiphenyl ethane (1000 mg/kg) to bile duct- and jugular vein-cannulated male Sprague Dawley rats was very poorly, if at all, absorbed from the gastrointestinal tract, and subsequently eliminated in the feces (based on the inability to combust feces at extreme temperatures). No or negligible absorption is consistent with the test article’s poor solubility and high molecular weight.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
DBDPEthane was very poorly, if at all, absorbed from the gastrointestinal tract, and was subsequently eliminated in the feces. No or negligible absorption is consistent with the poor solubiltiy and high molecular weight of the test article and with the in vitro results reported in "Basic toxicokineicts #2".
Executive summary:

The absorption, distribution, metabolism and elimination of DBDPEthane (1000 mg/kg; 50 uCi/kg) were studied in Sprague-Dawley rats following a single oral dose of14C-DBDPEthane. No14C-activity was detectable in the plasma, bile or urine of treated rats at any time point (up to 168 hours post-dosing). A mass balance could not be determined because the presence of the test article in the feces prevented combustion and subsequent quantitation of14C-CO2; however, levels of14C-activity in plasma, bile, urine and cage rinses were below the limit of detection in all samples. Based on the absence of14C-activity in these samples, the majority of the administered dose was not recovered and indicates that the test article was not orally absorbed and therefore excreted in the feces. Decabromodiphenyl etthanewas very poorly, if at all, absorbed from the gastrointestinal tract, and was subsequently eliminated in the feces. No or negligible absorption is consistent with the poor solubility and high molecular weight of the test article.  Based on these results, the substance does not have bioaccumulation potential.