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Toxicological information

Basic toxicokinetics

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Administrative data

basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: older study; not conducted in accordance with GLP guidelines

Data source

Reference Type:
study report
Report Date:

Materials and methods

Objective of study:
Test guideline
no guideline followed
Principles of method if other than guideline:
The bile ducts of 3 rats and a dog were cannulated and bile was collected following a single oral dose of 14C-labeled SAIB.
GLP compliance:

Test material

Details on test material:
Sucrose-14C(U) Acetate Isobutyrate (SAIB-14C) was prepared from uniformly labeled sucrose-14C as previously described by Reynolds et al (HAEL report no BCH-72-1, 1972). The specific activity was 0.359 uCi/mg. This was incorporated into an aqueous concentrate by homogenizing with citrus oil, mucilage, and water.

Test animals

Details on test animals and environmental conditions:
A male, beagle dog weighing 11.4 kg was anesthetized with sodium pentobarbital (30 mg/kg iv). The thoracic and abdominal areas were clipped and shaved free of hair, scrubbed with pHisoderm and swabbed with 70% alcohol and rinsed with tincture of iodine. The animal was then placed on the operating table and draped with sterile towels. Under nearly aseptic conditions, a mid-line incision was made from below the xiphisterntm caudad for approximately 15 cm. The incision was retracted using self-sustaining retractors and the curvature of the duodenum was reflected to the left side to expose the gall bladder. The cystic duct was identified and two ligatures (000 silk) were placed about 2 mm apart. The duct was severed between these ligatures and the gall bladder was aspirated by means of a hypodermic syringe. While maintaining traction on the duodenum the common bile duct was located and bluntly dissected from the surrounding tissue. from a point near the hilus of the liver to within a few mm of the entrance of the duct to the duodenum. Using fine pointed scissors, the duct was cut transversely through half its diameter at two points approximately 1-1.5 cm apart. Two cannulae (Technicon, standard transmission tubing, 0.056 I.D.) were inserted; one into the anterior portion of the duct and the other into the posterior portion continuing through the sphincter of Oddi into the duodenum. At least two ligatures (000 silk) were placed around each portion of the duct where the cannulae laid and the cannulae were further anchored to the surrounding tissue. To prevent possible reconstitution of the duct, it was severed between the cannulae. The cannulae were then directed to the outside of the animal between the sutures used to close the incision. The entero-hepatic circulation was restored by connecting the anterior and posterior cannulae by means of a plastic connector made for use with this tubing. The operative area was wrapped in a sterile towel and the animal was garbed in a specially tailored jacket of a light duck material. This jacket was designed to prevent the dog from getting at and dislodging the cannulae.

Administration / exposure

Route of administration:
oral: gavage
Details on exposure:
The radioactive dose was given by a single intragastric intubation of the diluted emulsion in water. The dog was fed unlabeled SAIB in the diet for 7 days before dosing with the emulsion in the second trial and far 4 days before the third trial. The dog also received 15 g of unlabeled SAIB in corn oil immediately before receiving the emulsion in the third trial.
Duration and frequency of treatment / exposure:
Bile was continuously collected for 11-16 hours in each trial after which the bile circulation was restored and short collections made daily thereafter. Feces were collected when voided and frozen. Several days after the first dose the bile duct cannula came loose and it was reconnected, which required reopening the animal. After a period of recuperation the dog lived uneventfully for 4 months.
Doses / concentrations
Doses / Concentrations:
4.0 mg/kg
No. of animals per sex per dose:
Control animals:
Details on study design:
A single male beagle dog was surgically outfitted with a biliary cannula prior to administration of single oral doses of SAIB 14C. Following recovery from cannula inplantation, the dog was administered SAIB 14C, and bile was collected for the following 11-hour period. For the next 7 days, the dog was fed unlabeled SAIB. After 7 days, a second dose of SAIB 14C was administered, and bile was collected for the following 15-hour period. For the next 4 days, the dog again was fed unlabeled SAIB. After 4 days, a third dose of SAIB 14C was administered, and bile was collected for the following 16-hour period. Radioactivity in bile samples were evaluated using paper chromatography. Chromatograms of all dog bile samples, collected from 1-11 hours after dosing, showed only a large broad peak of radioactivity with a maximum at Rf 0.8-0.9. No sample showed any radioactivity at Rf less than 0.65.

Results and discussion

Main ADME results

Toxicokinetic / pharmacokinetic studies

Details on excretion:
The dog eliminated radioactivity slightly slower than the rats; although maximum rates were seen l-3 hours after dosing, then declined at a rate that was slower compared to the rats. The dog eliminated somewhat more than 6% of the dose in the bile ·dthin 11-15 hours in the first two runs but only ca. 2% in the last. Fecal elimination was very rapid; the dog eliminated over 60% of the dose within 9 hours in the second trial and over 50% within 7.5 hours in the third.

Applicant's summary and conclusion

Interpretation of results (migrated information): no bioaccumulation potential based on study results
In the beagle dog, 67-75% of an administered dose of SAIB was eliminated in feces within 7.5 - 9 hours. In contrast, 2 - 6% the administered dose was excreted in bile after 11-16 hours.
Executive summary:

To determine if dogs eliminate absorbed SAIB or its metabolites in the bile and to provide more information on the kinds of molecules absorbed, a bile duct cannula was placed in a dog and bile was collected after intragastric intubation of sucrose-14C(U) acetate isobutyrate. The bile was assayed for radioactivity by counting and paper chromatography. The data indicate that 67-75% of an administered dose of SAIB was eliminated in feces within 7.5 - 9 hours. In contrast, 2 - 6% the administered dose was excreted in bile after 11-16 hours.