Enbucrilate

Specific investigations: other studies

Administrative data

Endpoint:

specific investigations: other studies

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well documented medical guideline study with GLP

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2003

Report date:

2003

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: ISO 10993-6 (1994), Biological Evaluation of Medical Devices Part 6: Tests for Local Effects After Implantation

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: ASTM Section 13 Vol. 13.01 Medical Devices, Designation: F 981-99, 1999

GLP compliance:

yes

Type of method:

in vivo

Endpoint addressed:

other: Long term IM implantation toxicity

Test material

Test material information

Constituent 1

Reference substance name:

Enbucrilate

EC Number:

229-552-2

EC Name:

Enbucrilate

Cas Number:

6606-65-1

Molecular formula:

C8H11NO2

IUPAC Name:

butyl 2-cyanoprop-2-enoate

Test material form:

other: rods or liquid

Details on test material:

(1) POLYMERISED INDERMIL (n-butylcyanoacrylate, CAS 6606-65-1) RODS
- Lot/Batch #: U02B42, Lab Book Refs: 2696/76-1; Date of Fabrication 29/4/02
- Physical State: Solid
- Color: Amber
- Stability: Highly Stable
- Solubility: Practically Insoluble in aqueous

(2) LIQUID INDERMIL (n-butylcyanoacrylate, CAS 6606-65-1)
- Lot/Batch #: U02B42, Lab Book Refs: 2696/76-1; Date of Fabrication 29/4/02
- Physical State: Liquid
- Color: Amber
- Density: Approx. 1
- Stability: Will polymerize when in contact with most materials
- Solubility: N/A

(3) CONTROL ARTICLE
- Negative Control Plastic, QC Inventory #: CSC-00-07-002-CC
- Physical State: Solid
- Color: White

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

ANIMALS
- 3 New Zealand White rabbits (Oryctolagus cuniculus)
- Sex: 1 male and 2 females
- W eight/Age range: 2.58-2.80 kg / at least 11 weeks old
- Health status: healthy, previously used in other experimental procedures
- Animal selection: selected from a larger pool of animals and examined to ensure lack of adverse clinical signs
- Animal purchase: Millbrook Breeding Labs, Amherst, MA
- Acclimatization: Minimum 5 days, under same conditions as for the actual test
- Animal identification: ear marker

CARE AND MAINTANANCE
- Housing: individually housed
- Cages: suspended stainless steel cages
- Bedding: hardwood chips, P.W.I. Industries, St-Hyacinthe, Quebec, Canada (non-contact)
- Animal room temperature: 68±5°F
- Animal room relative humidity: 30-70%
- Air exchanges per hour: 10 to 15
- Lights: 12-hour light/dark cycle, full spectrum fluorescent lights
- The laboratory and animal rooms were maintained as limited-access facilities.
- Animal rations: TEK 8630 Rabbit Diet, Harlan Teklad, Madison, WI, ad libitum
- Water: tap water, ad libitum
There were no known contaminants present in the feed, water, or bedding expected to interfere with the test data.

Administration / exposure

Route of administration:

other: intramuscular implantation or injection

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

26 w

Frequency of treatment:

continuous

Post exposure period:

not applicable

Doses / concentrations

Remarks:

Doses / Concentrations:
up to 4 test article strips / test article injections / negative control strips
Basis:
other: per animal

No. of animals per sex per dose:

1 male and 2 females

Control animals:

other: yes, concurrent control article

Results and discussion

Details on results:

The results indicated that the solid test article (Polymerised Indermil) was non-toxic (Toxicity Rating of 0.12) and that the liquid test article (Liquid Indermil) was non-toxic (Toxicity Rating of 0.96) when implanted for 26 weeks when compared to control article implant sites.

Any other information on results incl. tables

RESULTS

Animal Weights: All three of the test animals increased in weight.

Clinical Observations: None of the test animals exhibited any signs of toxicity over the course of the study.

Animal	Day 0	Day 182	Weight Change	Signs of Toxicity*
20821 (m)	2.80	4.37	+ 1.57	None
20822 (f)	2.60	4.20	+ 1.60	None
20824 (f)	2.58	4.62	+ 2.04	None

*Summary of Clinical Observations day 0 through day 182, excluding muscle implantation scores 

Implantation Site Observations (Macroscopic):

Macroscopic evaluation of the test article implant sites indicated no significant signs of inflammation, encapsulation, hemorrhage, necrosis, or discoloration at the 26 week time period.

 

Implantation Site Observations (Microscopic):

Microscopic evaluation of the test article implant sites indicated no significant signs of inflammation, fibrosis, hemorrhage, necrosis or degeneration as compared to the control article sites. The toxicity rating for the 26 week time period (average of three animals) of the solid test article was 0.12, indicating non-toxicity. The toxicity rating for the 26 week time period (average of three animals) of the liquid test article was 0.96, indicating non-toxicity.

Applicant's summary and conclusion

Conclusions:

The test articles, Polymerised Indermil (n-butylcyanoacrylate) Rods and Liquid Indermil, were implanted or injected in the paravertebral muscle tissue of New Zealand White rabbits for a period of 26 weeks. The results indicated that both, the solid test article and the liquid test article were non-toxic.

Executive summary:

SUMMARY

The test articles, Polymerised Indermil (n-butylcyanoacrylate) Rods and Liquid Indermil, were implanted or injected in the paravertebral muscle tissue of New Zealand White rabbits for a period of 26 weeks.

The results indicated that the test article, Polymerised Indermil (n-butylcyanoacrylate) Rods, was non-toxic when implanted for 26 weeks (Toxicity Rating of 0.12) when compared to control article implant sites.

The results indicated that the test article, Liquid Indermil, was non-toxic when implanted for 26 weeks (Toxicity Rating 0.96) when compared to control article implant sites.