Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1969
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: not GLP
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:

Data source

Reference
Reference Type:
publication
Title:
Digestive tract absorption of alkyl α-cyanoacrylate-β-14C
Author:
Douglas K. Ousterhout
Year:
1969
Bibliographic source:
Oral Surg., Oral Med. & Oral Path.,Vol 27, (3), 410-416, 1969
Report Date:
1969

Materials and methods

Objective of study:
absorption
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
derivations in application, number of animals
Principles of method if other than guideline:
The Guideline followed was according OECD 417 with modification, because of that fast polymerizing test item. The test item was administered orally (was applied to the intact oral muscusa of the ceeks in Part 1 and orally by gavage in Part 2). In Part 1 the urin was sampled for 48 h and the labelled metobolite collected. In Part 2 urine and stool samples were collected from each rat for 4 days.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: methyl α-cyanoacrylate-β-14C (MCA), as monomer in Part 1 and as polymer powder in Part 2
- Specific activity of radiolabelling: Part 1: 18400000 dpm/ml / Part 2: 21800000 dpm/g
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
Part 1:
- Weight at study initiation: approximately 375 g
- Individual limited-motion metabolic cages: yes
- Hydration was maintained, during the period of the study, with subcutanoeus and intraperitoneal injections of sterile normal saline solution

Part 2:
- Weight at study initiation: approximately 425 g
- Individual limited-motion metabolic cages: yes
- Diet: ad libitum
- Water: ad libitum

Administration / exposure

Route of administration:
other: oral: Part 1:applied to the intact oral mucosa of the cheeks / Part 2: oral gavage
Vehicle:
other: Part 1: unchanged / Part 2: vegetable oil
Details on exposure:
Part 1:
On the second day, 0.05 ml of methyl α-cyanoacrylate-β-14C was applied to the intact oral mucosa of the cheeks of each of the two anesthetized rats.
Part 2:
Two rats were given 100 mg of methyl α-cyanoacrylate-β-14C polymer powder, placed in the stomach via a size 8 French feeding tibe, with vegetable oil as a vehicle.
Duration and frequency of treatment / exposure:
One treatment
Doses / concentrations
Remarks:
Doses / Concentrations:
Part 1 : 0.05 ml of methyl α-cyanoacrylate-β-14C
Part 2 : 100 mg of methyl α-cyanoacrylate-β-14C polymer powder
No. of animals per sex per dose:
2 animals per part
Control animals:
not specified
Positive control:
no
Details on study design:
Part 1: Two Sprague-Dawley rats were placed singly in limited-motion metabolic cages following transabdominal catheterization of the bladder and suture ligation of the abdominal esophagus under intraperitoneal pentobarbitual sodium anesthesia (50 mg/kg). Hydration was maintained, during the period of the study, with subcutanoeus and intraperitoneal injections of sterile normal saline solution. On the second day, 0.05 ml of methyl α-cyanoacrylate-β-14C was applied to the intact oral mucosa of the cheeks of each of the two anesthetized rats. Urine was collected daily from the two rats. On the third day the rats were killed.
Part 2: With intraperitonal anesthesia (pentobarbitual sodium, 50 mg/kg), each of two Sprague-Dawley rats were subjected to bladder catherization through a transabdominal approach. The rats were then placed singley in limited-motion metabolic cages and allowed to eat and drink ad libitum. Following the collection of a one-day control urine specimen and stool fromeach rat, the animals were anesthetized. The two rats were given 100 mg of methyl α-cyanoacrylate-β-14C polymer powder, placed in the stomach via a size 8 French feeding tibe, with vegetable oil as a vehicle. Urine and stool ssamples were collected from each rat for 4 days, after which the rats were killed. All urine and stool samples were placed in a refigerator and kept at 6°C.
Details on dosing and sampling:
Part 1: Urine was collected daily from the two rats.
Part 2: Urine and stool ssamples were collected from each rat for 4 days.

Results and discussion

Main ADME results
Type:
excretion
Results:
The radioactivity of urine and stool, representing carbon-14 oral absorption from MCA was determined.

Toxicokinetic / pharmacokinetic studies

Details on excretion:
Part 1: The radioactivity of urine, representing carbon-14 oral absorption fromMCA monomer polymerized on intact oral mucosa, was determined.
Part 2: The carbon-14 radioactivity of urine and stool was determined. The urine radioactivity represents polymer degradation, while the stool carbon-14 activity probably represents primarily undegraded polymer.

Metabolite characterisation studies

Metabolites identified:
no

Any other information on results incl. tables

Part 1:

Per cent of the orignial radioactivity applied to oral mucosa and counted in the urine.

Rat number

First day

Second day

Total

1

1.1

1.1

2.2

2

1.0

0.4

1.4

Average

1.1

0.8

1.8

Part 2:

Per cent of original radioactivity delivered to stomach

 

Rat number

First day

Second day

Third day

Fourth day

Total

Urine

5

5.7

2.8

0.6

0.1

9.2

6

9.4

11.5

1.7

N.R.

22.6

Average

7.6

7.2

1.2

0.1

15.9

Stool

5

2.5

8.0

0.4

N.R.

10.9

6

0.6

20.2

3.6

0.2

24.6

Average

1.6

14.1

2.0

0.1

17.8

N.R. : No significant radioactivity

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
No resorption due to polymerisation after contact with water at the oral mucosa or in the stomach. Polymerized compound is not digested but excreted oraly or via feces. The gastrointestinal route is done with a extension of time in comparison to normal food.
Executive summary:

In this study the absorption and assimilation of methyl α-cyanoacrylate-β-14C was evaluated in the digestive tract of the rat.

For the rats receiving methyl cyanoacrylate into the oral cavity, approximately 1% of the radiolabel administered was recovered in urine on each of the two days, the total recovery being 2%.

For the rats receiving poly-methyl cyanoacrylate directly into the stomach, approximately 7.6% of the radiolabel administered was recovered in urine samples on day 1, 7.2% on day 2, 1.2% on day 3 and 0.1% on day 4. The total mean recovery from urine samples on completion of 4 days was approximately 16% although there was some variation between the two rats. From stool samples individual recoveries again varied between the two animals; the mean values were 1.6% on day 1, 14.1% on day 2, 2.0% on day 3 and 0.1% on day 4 with a mean total of 17.8% on completion of the 4 day sampling period.